腺样囊性癌临床病理分析及Glut-1、PI3K/AKT信号通路的表达和意义
|
摘要
背景和目的：
发生在耳鼻咽喉气管部位的腺样囊性癌(adenoid cystic carcinoma, ACC)极为少见,生长位置较为隐蔽,早期症状不典型,早期确诊较为困难。与大涎腺的腺样囊性癌一样,耳鼻咽喉气管部位的腺样囊性癌生长较为缓慢但侵袭性强,常沿神经、血管生长,易复发和转移,手术与放化疗联合治疗的方法尚达不到理想的治疗效果,预后极差。不同的病变部位、病理类型、TNM分期、治疗方法、切缘等因素差异可直接影响ACC患者的预后,但影响其预后的真正原因尚不明了。因此探讨腺样囊性癌浸润与转移的发病机制及预后的相关因素,寻求新的诊断和治疗方法有良好的应用前景。
随着免疫学、分子生物学技术的不断发展,从分子水平探讨ACC发生、发展的机制,对于认识ACC的发病机制、判断预后、发现潜在的治疗靶点具有重要意义。ACC与其它恶性肿瘤一样,恶性细胞所处的生理环境能量相对匮乏,呈现局部缺氧状态,并引起肿瘤细胞因子的过度表达。恶性肿瘤细胞的葡萄糖代谢率较高,这种现象已被正电子发射计算机断层(Positron emission tomography, PET)检查所证实,PET/CT也证实ACC中存在此现象。恶性肿瘤细胞对葡萄糖的代谢率增高与葡萄糖转运蛋白(Glucose transporter protein, Glut)及基因的异常表达有关,其中葡萄糖转运蛋白-1(Glut-1)在恶性肿瘤细胞的葡萄糖吸收和转运中起主导作用,Glut-1的异常表达与多种信号转导通路有关,而PI3K/Akt在Glut-1表达的调节中起重要作用。PI3K/Akt是一种对生长和增殖有重要作用的异二聚体酶,是近年来发现的生长因子信号转导途径。研究发现在人类许多肿瘤中都有PI3K-Akt的过度表达。从恶性肿瘤葡萄糖能量供应的层面已有研究发现,PI3K/Akt途径的激活与Glut-1表达的增加有关。
我们的前期研究已经发现,Glut-1的异常表达与头颈部癌的生物学行为有关,与头颈部癌的预后差有关,可以作为靶向治疗的新方法之一,并且我们已通过反义寡脱氧核苷酸技术阻断喉癌Hep-2细胞Glut-1的表达,能抑制喉癌细胞的葡萄糖吸收的影响及Hep-2细胞增殖,可能是喉癌治疗的一种理想靶标。
目前,Glut-1在肿瘤发生机制中的研究,多集中于头颈部较常见肿瘤类型如鳞状细胞癌,而在腺样囊性癌中Glut-1的表达情况与临床生物学特性的关系研究较为少见,尤其是腺样囊性癌中PI3K/Akt信号通路调控Glut-1表达的研究更为少见,国内尚未见有文献报道。本课题在前期研究基础上,从癌细胞能量供应的层面,采用免疫组织化学方法检测耳鼻咽喉气管腺样囊性癌组织中Glut-1及PI3K和磷酸化Akt (p-Akt)蛋白的表达,回顾性分析患者的临床病例特点,探讨Glut-1及PI3K和p-Akt蛋白表达与耳鼻咽喉腺样囊性癌生物学行为的关系。
材料与方法：
收集1993.1～2010.2期间浙江大学医学院附属第一医院耳鼻咽喉科收治的14例耳鼻咽喉气管腺样囊性癌病例进行回顾性分析,观察临床病理参数对患者生存状态和预后的影响。并应用免疫组织化学EliVisionTM法检测14例耳鼻喉气管腺样囊性癌病例以及对照组15例炎性病变(5例鼻息肉组织及10例声带息肉)、14例良性肿瘤(5例鼻腔良性神经鞘瘤、1例耵聍腺瘤、1例喉部良性软骨瘤、7例鼻腔内翻性乳头状瘤)的Glut-1. PI3K和p-Akt的蛋白表达情况,14例腺样囊性癌病理学分类分别为筛孔型、管状型及实体性,临床病理学分期在T1、T2、T3期；显微镜下计数阳性细胞,结果进行统计学分析。采用SPSS15.0软件,各临床病理因素的关系因素及Glut-1、PI3K和p-Akt之间的关系用χ2检验、Fisher精确概率法,以α=0.05为差异有统计学意义检验水准,相关性分析采用Kappa检验(即一致性检验),如果kappa)0.75,提示两个指标的一致性非常好,即相关性高,kappa值在0.4～0.75之间,两个指标间的一致性中等,kappa<0.4,两个指标间一致性较差。
结果：
1、14例腺样囊性癌(ACC)患者,男性6例,女性8例,年龄32～80岁,平均54岁。位于外耳道者4例,鼻腔3例,鼻窦3例,喉部3例,气管1例。T1 6例、T2 5例or T3 3例,所有患者均未发现淋巴结及远处转移。全部患者均行手术治疗,10例患者术后进行了放射治疗。本组资料显示,10例患者术后进行了放射治疗,随访至今仍分别存活6年9个月(病例1),4年3个月(病例3),15年(病例4),24年(病例5),9年5个月(病例6),5年7个月(病例7),1年5个月(病例9),5年8个月(病例11),6年6个月(病例12),7年(病例14),8例((病例1、3、4、6、9、11、12、14)放射剂量不清,2例放射剂量50Gy。在放射的10例中,接受手术+放疗后2年(病例6)、5年(病例5)出现局部复发,行多次手术,现1例带瘤生存(病例6),1例无瘤生存(病例5),其余8例均无复发,说明放射治疗控制局部复发有一定效果；3例无术后放射治疗,其中1例随访24个月后失访,1例随访半年后失访,‘1例随访至今存活1年8个月；1例第一次在外院手术后9个月,在我院再次手术,术后失访,有无术后放疗情况不清楚。本组鼻腔-鼻窦及外耳道ACC局部复发率高,喉及气管ACC未见复发,无颈淋巴结转移及远处转移。
2、14例耳鼻喉气管腺样囊性癌组织中Glut-1阳性表达率为35.7%(5/14)PI3K阳性表达率为28.6%(4/14),p-Akt阳性表率为71.4%(10/14)；对照组：15例炎性病变Glut-1、PI3K和p-Akt均为阴性表达；14例良性肿瘤中,Glut-1均呈阴性表达,1例PI3K、2例p-Akt呈阳性表达,阳性表达率分别为7.14%(1/14)；14.3%(2/14)。耳鼻喉气管腺样囊性癌组织组Glut-1, PI3K、p-Akt阳性表达率明显高于对照组,差异有显著性(P<0.05,P<0.01)。
ACC中Glut-1和PI3K表达、Glut-1p-Akt表达、p-Akt和PI3K表达,经kappa检验,kappa值分别为0.186、0.364、0.276,说明Glut-1、PI3K、p-Akt表达之间相关一致性较差。
结论：
临床病理特点：
1、本组资料显示：本组鼻腔-鼻窦及外耳道ACC局部复发率高,喉及气管ACC未见复发,无颈淋巴结转移及远处转移。
2、本组资料显示：第一次的确诊及第一次彻底手术治疗、术后放疗对控制局部复发有一定效果。
3、本组资料显示：腺样囊性癌极易误诊,腺样囊性癌应作为耳鼻咽喉气管部位疾病的鉴别诊断
Glut-1、PI3K/AKT信号通路的表达和意义：
1、本组资料显示Glut-1表达增高与腺样囊性癌的发生可能有关。
2、PI3K/Akt信号传导通路的异常活化与腺样囊性癌的发生有关。
Background:
Adenoid cystic carcinomas(ACC) in ear, nasal cavity, paranasal sinus, larynx and trachea are uncommon. These malignant tumours often are asymptomatic or mimic inflammatory diseases, leading to a delay in diagnosis. ACC was noted for its slow growth and indolent course, like ACCs in general, patients with ACC of these sites often experienced recurrence and distant metastasis many years after diagnosis and definitive treatment. Patterns of disease included perineural and vascular invasion. The most important modalities for primary treatment of local and locoregional disease are surgery and/or irradiation. However, the outcome of these treatment is unfavorable. Several studies have identified clinicopathological factors in ACC with an unfavorable effect on survival, including old age, tumor location, advanced stage, solid histological subtype, high grade, TNM staging, major nerve involvement, the presence of perineural invasion, a positive surgical margin, and lymph node metastasis. However, real prognostic factors are still unknown. Thus, more studies are needed for pathogenesis, prognostic factors, new diagnostic and therapeutic methods, especially in the molecular level.
Like other malignant tumors, cells of ACC exhibit increased glucose uptake and utilization in comparison to their nonmalignant counterparts. The phenomenon has been demonstrated by positron emission tomography (PET),using 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG).Many mechanisms of FDG uptake have been proposed for accelerated glucose use in growing tumors and in transformed and malignant cells: passive diffusion, Na+-dependent glucose transport, and via facilitative glucose transporters (GLUT). The latter is considered to be the most important mechanism for enhancing glucose influx into cells. Gluts are membrane proteins that facilitate the transport of glucose across cellular membranes. Thirteen (14) members of the facilitative sugar transporter family are now recognized (Glut-1-Glut-12 and HMIT; genename SLC2A).The human genes encoding these proteins are named Glut 1-5 and Glut 7-13; Glut-6 and Glut-14 are now known to be pseudogenes. Of the 14 isoforms, Glut-1 appears to be the most ubiquitously distributed. Increased Glutl levels and glucose uptake correlate with increased cellular growth and proliferation. This isoform is overexpressed in many human cancer cells, and its appearance is correlated with aggressive biological behavior. Therefore, control of Glutl trafficking and activity are also key elements regulating glucose uptake. Similar to the insulin-responsive glucose transporter, Glut-4, Glut-1 cell surface localization is controlled by extrinsic signals. Among signaling pathways initiated in cell activation, the PI3K/Akt pathway has been shown to promote both Glut-1 cell surface trafficking and activity.
PI3K is a heterodimeric enzyme important for growth and proliferation and Akt is a downstream serine-threonine kinase that transmits survival signals from growth factors. The PI3-K/AKT pathway is frequently overactivated in a wide range of tumors and triggers a cascade of responses, from cell growth and proliferation to cell survival and motility, which drive tumor progression. It has been shown that the PI3K/Akt pathway is involved in translocating the GLUT-1 glucose transporter from the cytosol to the plasma membrane in some endocrine organs such as the thyroid gland, pancrea.
Our previous study revealed that FDG uptake was higher in malignant lymphoma than in other head and neck malignant tumors by SPECT/CT, and a significant correlation was found between FDG levels and glucose transporter-1 (Glut-1) mRNA or Glut-1 protein levels. We also showed that the increased expression of Glut-1 in head and neck carcinomas was correlated with lymph node metastasis, poor survival and clinical stage.Then,we revealed that Glut-1 overexpression in vitro is associated with cell proliferation and increased glucose uptake by laryngeal carcinoma Hep-2 cells. Conversely, the suppression of Glut-1 expression by antisense oligodeoxynucleotides (AS-ODNs) may decrease glucose uptake and inhibit the proliferation of Hep-2 cells. Therefore, we propose the suppression of Glut-1 expression as a new therapeutic target for laryngeal carcinoma.
To date, only a few studies have investigated the expression of Glut-1 in ACC,especilly in the effect of regulation of expression of Glut-1 by PI3K/Akt signal pathway.In present study, we retrospectively investigated the clincopathigical features of external auditory canal, sinonasal, laryngeal and tracheal ACC and we also assessed expression of Glut-1, PI3K and p-Akt protein in these ACCs by immunohistochemistry. Additionally, we examined possible correlations between Glut-1, PI3K and p-Akt protein and clinicopathological parameters in this cohort of patients.
Materials and methods:
14 patients with ACC from Otolaryngology Department, the First Affiliated Hospital, College of Medicine, Zhejiang University were collected between January 1993 and February 2010. The institutional review board approved this study and written informed consent was obtained from the patients before inclusion. The clinicopathological findings (including age, sex, site, TNM stage, pathological type, recurrence, metastasis, follow-up) were analysed. The expression of Glut-1, PI3K and p-Akt proteins were examined in ACC tissue samples by an EliVisionTM plus IHC Kit (Maixin Biological, Fuzhou, China) immunohistochemical analysis.5 paraffin-embedded archival tissue blocks from patients with nasal polyps,10 paraffin-embedded archival tissue blocks from patients with vocal cord polyps,5 tissue blocks from patients with nasal benign schwannomas,1 tissue block from patient with laryngeal benign chondroma and 7 tissue blocks from patients with nasal inverted papilloma were also obtained. Formalin fixed, paraffin-embedded archival tissues were obtained from institutional and consultation files.
Statistical analyses:
Analyses were performed using SPSS 15.0 software package. Associations between Glut-1, PI3K and p-Akt protein expression and the other pretreatment parameters were analyzed using the chi-squared test. A P-value of<0.05 was deemed to indicate statistical significance.The correlation analysis using Kappa test. A value of 1 indicates perfect agreement. We calculated weighted k-values to describe concordance in reporting as slight ( 0.4), moderate(0.4-0.75), or almost perfect (>0.75).
Results:
Patient Characteristics:
Of the 14 ACC tumor tissues,4 cases (28.6%) were located in the external auditory canal,3 (21.40%) in the nasal cavity,3 (21.4%) in the paranasal sinus,3 (21.4%) in larynx and 1(7.2%) in the trachea. The median age of the 14 patients was 54 (range, 32-80).6 patients were males and 8 patients were females. All patients had no lymph node and distant metastasis. Six of the patients (42.9%) had cancer classified as T1 stage, 5 (35.7%) with T2 stage and 3(21.4%) with T3 stage. Surgery was performed in all patients. Ten patients were received radiotherapy postoperative. The patients'average follow-up period was 74 months (range,6-288 months). Three patients were lost to follow-up.
Of 10 patients received radiotherapy, two patients suffered disease recurrence(one patient had local recurrence 2 years after initial surgery and another had local recurrence 5 years after initial surgery) and they received several surgeries. The two patients were alive over 24 years,9 years, respectively, one was living without evidence disease and one was living with recurrence. Other eight patients were living without evidence disease at a mean follow-up time of 8.6 years after diagnosis (range,1.4-24 years). Three patients were not received radiotherapy after surgery. Of these patients, one was lost to follow-up 24 months after surgery, one was lost to follow-up six months after surgery, and one was living without evidence disease over twenty months.One was performed operation at another hospital 9 months ago and lost to follow-up after surgery in our hospital.
Glut-1, PI3K and Aktprotein expression in ACC
The positive rate of Glut-1,PI3K and Akt protein in ACC was 35.7%(5/14), 28.6%,71.4%, respectively. The expression of Glut-1 or PI3K or Akt protein in ACC was higher than that in inflammatory lesions or benign tumor (p<0.05).
The correlation between Glut-1, PI3K and Akt protein expression
Kappa test showed that correlation between Glut-1 and PI3K expression, between Glut-1 and p-Akt expression, between p-Akt and PI3K expression was slight correlation(K=0.186,0.364,0.276, respectively).
Association of Glut-1, PI3K and Akt with Clinicopathological Parameters
There was no statistically significant association between Glut-1,PI3K and Akt protein in ACC and all clinicopathological variables examined (P>0.05).
Conclusions:
Clinicopathological findings
1、The presnt study showed that there were high recurrent rate in the sinonasal and external auditory canal ACC. had no lymph node and distant metastasis.
2、This study also revealed that it was very important for the initial treatment and radiotherapy may be effective on control local recurrenc.
3、Additionally, this study suggested that adenoid cystic carcinoma shoule be as differentiatial diagnosis in diseases of the external auditory canal, nasal cavity, paranasal sinus,larynx and trachea.
The implication of Glut-1 expression and PI3K/AKT signal pathway in ACC
1. Our results showed that over-expression of Glut-1 may be associated with the occurrence of ACC.
2、Our data also suggested that abnormal activation of PI3K/Akt signaling pathways may play a role in the process of occurrence of ACC.
发生在耳鼻咽喉气管部位的腺样囊性癌(adenoid cystic carcinoma, ACC)极为少见,生长位置较为隐蔽,早期症状不典型,早期确诊较为困难。与大涎腺的腺样囊性癌一样,耳鼻咽喉气管部位的腺样囊性癌生长较为缓慢但侵袭性强,常沿神经、血管生长,易复发和转移,手术与放化疗联合治疗的方法尚达不到理想的治疗效果,预后极差。不同的病变部位、病理类型、TNM分期、治疗方法、切缘等因素差异可直接影响ACC患者的预后,但影响其预后的真正原因尚不明了。因此探讨腺样囊性癌浸润与转移的发病机制及预后的相关因素,寻求新的诊断和治疗方法有良好的应用前景。
随着免疫学、分子生物学技术的不断发展,从分子水平探讨ACC发生、发展的机制,对于认识ACC的发病机制、判断预后、发现潜在的治疗靶点具有重要意义。ACC与其它恶性肿瘤一样,恶性细胞所处的生理环境能量相对匮乏,呈现局部缺氧状态,并引起肿瘤细胞因子的过度表达。恶性肿瘤细胞的葡萄糖代谢率较高,这种现象已被正电子发射计算机断层(Positron emission tomography, PET)检查所证实,PET/CT也证实ACC中存在此现象。恶性肿瘤细胞对葡萄糖的代谢率增高与葡萄糖转运蛋白(Glucose transporter protein, Glut)及基因的异常表达有关,其中葡萄糖转运蛋白-1(Glut-1)在恶性肿瘤细胞的葡萄糖吸收和转运中起主导作用,Glut-1的异常表达与多种信号转导通路有关,而PI3K/Akt在Glut-1表达的调节中起重要作用。PI3K/Akt是一种对生长和增殖有重要作用的异二聚体酶,是近年来发现的生长因子信号转导途径。研究发现在人类许多肿瘤中都有PI3K-Akt的过度表达。从恶性肿瘤葡萄糖能量供应的层面已有研究发现,PI3K/Akt途径的激活与Glut-1表达的增加有关。
我们的前期研究已经发现,Glut-1的异常表达与头颈部癌的生物学行为有关,与头颈部癌的预后差有关,可以作为靶向治疗的新方法之一,并且我们已通过反义寡脱氧核苷酸技术阻断喉癌Hep-2细胞Glut-1的表达,能抑制喉癌细胞的葡萄糖吸收的影响及Hep-2细胞增殖,可能是喉癌治疗的一种理想靶标。
目前,Glut-1在肿瘤发生机制中的研究,多集中于头颈部较常见肿瘤类型如鳞状细胞癌,而在腺样囊性癌中Glut-1的表达情况与临床生物学特性的关系研究较为少见,尤其是腺样囊性癌中PI3K/Akt信号通路调控Glut-1表达的研究更为少见,国内尚未见有文献报道。本课题在前期研究基础上,从癌细胞能量供应的层面,采用免疫组织化学方法检测耳鼻咽喉气管腺样囊性癌组织中Glut-1及PI3K和磷酸化Akt (p-Akt)蛋白的表达,回顾性分析患者的临床病例特点,探讨Glut-1及PI3K和p-Akt蛋白表达与耳鼻咽喉腺样囊性癌生物学行为的关系。
材料与方法：
收集1993.1～2010.2期间浙江大学医学院附属第一医院耳鼻咽喉科收治的14例耳鼻咽喉气管腺样囊性癌病例进行回顾性分析,观察临床病理参数对患者生存状态和预后的影响。并应用免疫组织化学EliVisionTM法检测14例耳鼻喉气管腺样囊性癌病例以及对照组15例炎性病变(5例鼻息肉组织及10例声带息肉)、14例良性肿瘤(5例鼻腔良性神经鞘瘤、1例耵聍腺瘤、1例喉部良性软骨瘤、7例鼻腔内翻性乳头状瘤)的Glut-1. PI3K和p-Akt的蛋白表达情况,14例腺样囊性癌病理学分类分别为筛孔型、管状型及实体性,临床病理学分期在T1、T2、T3期；显微镜下计数阳性细胞,结果进行统计学分析。采用SPSS15.0软件,各临床病理因素的关系因素及Glut-1、PI3K和p-Akt之间的关系用χ2检验、Fisher精确概率法,以α=0.05为差异有统计学意义检验水准,相关性分析采用Kappa检验(即一致性检验),如果kappa)0.75,提示两个指标的一致性非常好,即相关性高,kappa值在0.4～0.75之间,两个指标间的一致性中等,kappa<0.4,两个指标间一致性较差。
结果：
1、14例腺样囊性癌(ACC)患者,男性6例,女性8例,年龄32～80岁,平均54岁。位于外耳道者4例,鼻腔3例,鼻窦3例,喉部3例,气管1例。T1 6例、T2 5例or T3 3例,所有患者均未发现淋巴结及远处转移。全部患者均行手术治疗,10例患者术后进行了放射治疗。本组资料显示,10例患者术后进行了放射治疗,随访至今仍分别存活6年9个月(病例1),4年3个月(病例3),15年(病例4),24年(病例5),9年5个月(病例6),5年7个月(病例7),1年5个月(病例9),5年8个月(病例11),6年6个月(病例12),7年(病例14),8例((病例1、3、4、6、9、11、12、14)放射剂量不清,2例放射剂量50Gy。在放射的10例中,接受手术+放疗后2年(病例6)、5年(病例5)出现局部复发,行多次手术,现1例带瘤生存(病例6),1例无瘤生存(病例5),其余8例均无复发,说明放射治疗控制局部复发有一定效果；3例无术后放射治疗,其中1例随访24个月后失访,1例随访半年后失访,‘1例随访至今存活1年8个月；1例第一次在外院手术后9个月,在我院再次手术,术后失访,有无术后放疗情况不清楚。本组鼻腔-鼻窦及外耳道ACC局部复发率高,喉及气管ACC未见复发,无颈淋巴结转移及远处转移。
2、14例耳鼻喉气管腺样囊性癌组织中Glut-1阳性表达率为35.7%(5/14)PI3K阳性表达率为28.6%(4/14),p-Akt阳性表率为71.4%(10/14)；对照组：15例炎性病变Glut-1、PI3K和p-Akt均为阴性表达；14例良性肿瘤中,Glut-1均呈阴性表达,1例PI3K、2例p-Akt呈阳性表达,阳性表达率分别为7.14%(1/14)；14.3%(2/14)。耳鼻喉气管腺样囊性癌组织组Glut-1, PI3K、p-Akt阳性表达率明显高于对照组,差异有显著性(P<0.05,P<0.01)。
ACC中Glut-1和PI3K表达、Glut-1p-Akt表达、p-Akt和PI3K表达,经kappa检验,kappa值分别为0.186、0.364、0.276,说明Glut-1、PI3K、p-Akt表达之间相关一致性较差。
结论：
临床病理特点：
1、本组资料显示：本组鼻腔-鼻窦及外耳道ACC局部复发率高,喉及气管ACC未见复发,无颈淋巴结转移及远处转移。
2、本组资料显示：第一次的确诊及第一次彻底手术治疗、术后放疗对控制局部复发有一定效果。
3、本组资料显示：腺样囊性癌极易误诊,腺样囊性癌应作为耳鼻咽喉气管部位疾病的鉴别诊断
Glut-1、PI3K/AKT信号通路的表达和意义：
1、本组资料显示Glut-1表达增高与腺样囊性癌的发生可能有关。
2、PI3K/Akt信号传导通路的异常活化与腺样囊性癌的发生有关。
Background:
Adenoid cystic carcinomas(ACC) in ear, nasal cavity, paranasal sinus, larynx and trachea are uncommon. These malignant tumours often are asymptomatic or mimic inflammatory diseases, leading to a delay in diagnosis. ACC was noted for its slow growth and indolent course, like ACCs in general, patients with ACC of these sites often experienced recurrence and distant metastasis many years after diagnosis and definitive treatment. Patterns of disease included perineural and vascular invasion. The most important modalities for primary treatment of local and locoregional disease are surgery and/or irradiation. However, the outcome of these treatment is unfavorable. Several studies have identified clinicopathological factors in ACC with an unfavorable effect on survival, including old age, tumor location, advanced stage, solid histological subtype, high grade, TNM staging, major nerve involvement, the presence of perineural invasion, a positive surgical margin, and lymph node metastasis. However, real prognostic factors are still unknown. Thus, more studies are needed for pathogenesis, prognostic factors, new diagnostic and therapeutic methods, especially in the molecular level.
Like other malignant tumors, cells of ACC exhibit increased glucose uptake and utilization in comparison to their nonmalignant counterparts. The phenomenon has been demonstrated by positron emission tomography (PET),using 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG).Many mechanisms of FDG uptake have been proposed for accelerated glucose use in growing tumors and in transformed and malignant cells: passive diffusion, Na+-dependent glucose transport, and via facilitative glucose transporters (GLUT). The latter is considered to be the most important mechanism for enhancing glucose influx into cells. Gluts are membrane proteins that facilitate the transport of glucose across cellular membranes. Thirteen (14) members of the facilitative sugar transporter family are now recognized (Glut-1-Glut-12 and HMIT; genename SLC2A).The human genes encoding these proteins are named Glut 1-5 and Glut 7-13; Glut-6 and Glut-14 are now known to be pseudogenes. Of the 14 isoforms, Glut-1 appears to be the most ubiquitously distributed. Increased Glutl levels and glucose uptake correlate with increased cellular growth and proliferation. This isoform is overexpressed in many human cancer cells, and its appearance is correlated with aggressive biological behavior. Therefore, control of Glutl trafficking and activity are also key elements regulating glucose uptake. Similar to the insulin-responsive glucose transporter, Glut-4, Glut-1 cell surface localization is controlled by extrinsic signals. Among signaling pathways initiated in cell activation, the PI3K/Akt pathway has been shown to promote both Glut-1 cell surface trafficking and activity.
PI3K is a heterodimeric enzyme important for growth and proliferation and Akt is a downstream serine-threonine kinase that transmits survival signals from growth factors. The PI3-K/AKT pathway is frequently overactivated in a wide range of tumors and triggers a cascade of responses, from cell growth and proliferation to cell survival and motility, which drive tumor progression. It has been shown that the PI3K/Akt pathway is involved in translocating the GLUT-1 glucose transporter from the cytosol to the plasma membrane in some endocrine organs such as the thyroid gland, pancrea.
Our previous study revealed that FDG uptake was higher in malignant lymphoma than in other head and neck malignant tumors by SPECT/CT, and a significant correlation was found between FDG levels and glucose transporter-1 (Glut-1) mRNA or Glut-1 protein levels. We also showed that the increased expression of Glut-1 in head and neck carcinomas was correlated with lymph node metastasis, poor survival and clinical stage.Then,we revealed that Glut-1 overexpression in vitro is associated with cell proliferation and increased glucose uptake by laryngeal carcinoma Hep-2 cells. Conversely, the suppression of Glut-1 expression by antisense oligodeoxynucleotides (AS-ODNs) may decrease glucose uptake and inhibit the proliferation of Hep-2 cells. Therefore, we propose the suppression of Glut-1 expression as a new therapeutic target for laryngeal carcinoma.
To date, only a few studies have investigated the expression of Glut-1 in ACC,especilly in the effect of regulation of expression of Glut-1 by PI3K/Akt signal pathway.In present study, we retrospectively investigated the clincopathigical features of external auditory canal, sinonasal, laryngeal and tracheal ACC and we also assessed expression of Glut-1, PI3K and p-Akt protein in these ACCs by immunohistochemistry. Additionally, we examined possible correlations between Glut-1, PI3K and p-Akt protein and clinicopathological parameters in this cohort of patients.
Materials and methods:
14 patients with ACC from Otolaryngology Department, the First Affiliated Hospital, College of Medicine, Zhejiang University were collected between January 1993 and February 2010. The institutional review board approved this study and written informed consent was obtained from the patients before inclusion. The clinicopathological findings (including age, sex, site, TNM stage, pathological type, recurrence, metastasis, follow-up) were analysed. The expression of Glut-1, PI3K and p-Akt proteins were examined in ACC tissue samples by an EliVisionTM plus IHC Kit (Maixin Biological, Fuzhou, China) immunohistochemical analysis.5 paraffin-embedded archival tissue blocks from patients with nasal polyps,10 paraffin-embedded archival tissue blocks from patients with vocal cord polyps,5 tissue blocks from patients with nasal benign schwannomas,1 tissue block from patient with laryngeal benign chondroma and 7 tissue blocks from patients with nasal inverted papilloma were also obtained. Formalin fixed, paraffin-embedded archival tissues were obtained from institutional and consultation files.
Statistical analyses:
Analyses were performed using SPSS 15.0 software package. Associations between Glut-1, PI3K and p-Akt protein expression and the other pretreatment parameters were analyzed using the chi-squared test. A P-value of<0.05 was deemed to indicate statistical significance.The correlation analysis using Kappa test. A value of 1 indicates perfect agreement. We calculated weighted k-values to describe concordance in reporting as slight ( 0.4), moderate(0.4-0.75), or almost perfect (>0.75).
Results:
Patient Characteristics:
Of the 14 ACC tumor tissues,4 cases (28.6%) were located in the external auditory canal,3 (21.40%) in the nasal cavity,3 (21.4%) in the paranasal sinus,3 (21.4%) in larynx and 1(7.2%) in the trachea. The median age of the 14 patients was 54 (range, 32-80).6 patients were males and 8 patients were females. All patients had no lymph node and distant metastasis. Six of the patients (42.9%) had cancer classified as T1 stage, 5 (35.7%) with T2 stage and 3(21.4%) with T3 stage. Surgery was performed in all patients. Ten patients were received radiotherapy postoperative. The patients'average follow-up period was 74 months (range,6-288 months). Three patients were lost to follow-up.
Of 10 patients received radiotherapy, two patients suffered disease recurrence(one patient had local recurrence 2 years after initial surgery and another had local recurrence 5 years after initial surgery) and they received several surgeries. The two patients were alive over 24 years,9 years, respectively, one was living without evidence disease and one was living with recurrence. Other eight patients were living without evidence disease at a mean follow-up time of 8.6 years after diagnosis (range,1.4-24 years). Three patients were not received radiotherapy after surgery. Of these patients, one was lost to follow-up 24 months after surgery, one was lost to follow-up six months after surgery, and one was living without evidence disease over twenty months.One was performed operation at another hospital 9 months ago and lost to follow-up after surgery in our hospital.
Glut-1, PI3K and Aktprotein expression in ACC
The positive rate of Glut-1,PI3K and Akt protein in ACC was 35.7%(5/14), 28.6%,71.4%, respectively. The expression of Glut-1 or PI3K or Akt protein in ACC was higher than that in inflammatory lesions or benign tumor (p<0.05).
The correlation between Glut-1, PI3K and Akt protein expression
Kappa test showed that correlation between Glut-1 and PI3K expression, between Glut-1 and p-Akt expression, between p-Akt and PI3K expression was slight correlation(K=0.186,0.364,0.276, respectively).
Association of Glut-1, PI3K and Akt with Clinicopathological Parameters
There was no statistically significant association between Glut-1,PI3K and Akt protein in ACC and all clinicopathological variables examined (P>0.05).
Conclusions:
Clinicopathological findings
1、The presnt study showed that there were high recurrent rate in the sinonasal and external auditory canal ACC. had no lymph node and distant metastasis.
2、This study also revealed that it was very important for the initial treatment and radiotherapy may be effective on control local recurrenc.
3、Additionally, this study suggested that adenoid cystic carcinoma shoule be as differentiatial diagnosis in diseases of the external auditory canal, nasal cavity, paranasal sinus,larynx and trachea.
The implication of Glut-1 expression and PI3K/AKT signal pathway in ACC
1. Our results showed that over-expression of Glut-1 may be associated with the occurrence of ACC.
2、Our data also suggested that abnormal activation of PI3K/Akt signaling pathways may play a role in the process of occurrence of ACC.
引文
[1]Strick MJ, Kelly C, Soames JV, McLean NR. Malignant tumours of the minor salivary glands-a 20 year review. Br J Plast Surg 2004; 57(7):624-31.
[2]Yih WY, Kratochvil FJ, Stewart JC. Intraoral minor salivary gland neoplasms: review of 213 cases. J Oral Maxillofac Surg 2005; 63(6):805-10.
[3]Shin YJ, Percodani J, UroCoste E, et al. Laryngeal adenoid cystic carcinoma. Rev Laryngol Otol Rhinol 1998; 119:1052.
[4]Zvrko E, Golubovic M.Laryngeal adenoid cystic carcinoma. Acta Otorhinolaryngol Ital 2009;29(5):279-82.
[5]Lupinetti AD, Roberts DB, Williams MD, Kupferman ME, Rosenthal DI, Demonte F, El-Naggar A, Weber RS, Hanna EY. Sinonasal adenoid cystic carcinoma: the M. D. Anderson Cancer Center experience. Cancer 2007;110(12):2726-31.
[6]Cruz Perez DE, Pires FR, Lopes MA, de Almeida OP,Kowalski LP. Adenoid cystic carcinoma and mucoepidermoid carcinoma of the maxillary sinus:report of a 44-year experience of 25 cases from a single institution. J Oral Maxillofac Surg 2006;64:1592-1597.
[7]Conley J, Schuller DE. Malignancies of the ear. Laryngoscope 1976; 86 (8):1147-1163.
[8]Ko YH, Lee MA, Hong YS, Lee KS, Jung CK, Kim YS, Sun DI, Kim BS, Kim MS, Kang JH. Prognostic factors affecting the clinical outcome of adenoid cystic carcinoma of the head and neck. Jpn J Clin Oncol 2007;37(11):805-811.
[9]de Lima Mde D, Marques YM, Alves Sde M Jr, Freitas VM, Soares FA, de Araujo VC, Pinto Ddos S Jr, Mantesso A. MDM2, P53, P21WAF1 and pAKT protein levels in genesis and behaviour of adenoid cystic carcinoma. Cancer Epidemiol 2009;33(2):142-146.
[10]Suzuki N, Onda T, Yamamoto N, Katakura A, Mizoe JE, Shibahara T. Mutation of the p16/CDKN2 gene and loss of heterozygosity in malignant mucosal melanoma and adenoid cystic carcinoma of the head and neck.Int J Oncol 2007;31(5):1061-1067.
[11]Shahsavari F, Eslami M, Baghaie F, Tirgari F, Motahhary P. Immunohistochemical evaluation of p27 (kipl) in pleomorphic adenomas and adenoid cystic carcinomas of the minor salivary glands.Asian Pac J Cancer Prev 2005;6(4):527-530.
[12]Maruyama S, Cheng J, Yamazaki M, Zhou XJ, Zhang ZY, He RG, Saku T. Metastasis-associated genes in oral squamous cell carcinoma and salivary adenoid cystic carcinoma:a differential DNA chip analysis between metastatic and nonmetastatic cell systems.Cancer Genet Cytogenet 2010 196(1):14-22.
[13]Ko YH, Roh SY, Won HS, Jeon EK, Hong SH, Lee MA, Kang JH, Hong YS, Kim MS, Jung CK. Prognostic significance of nuclear survivin expression in resected adenoid cystic carcinoma of the head and neck. Head Neck Oncol 2010,30(2):30.
[14]Vansteenkiste J, Fischer BM, Dooms C, Mortensen J. Positron-emission tomography in prognostic and therapeutic assessment of lung cancer: systematic review. Lancet Oncol 2004; 5(9):531-540.
[15]Campistron M, Rouquette I, Courbon F, Chabbert V, Rochaix P, Prevot G, Laroumagne S, Tetu L, Didier A, Mazieres J.Adenoid cystic carcinoma of the lung:interest of 18FDG PET/CT in the management of an atypical presentation. Lung Cancer 2008;59(1):133-136.
[16]Tohma T, Okazumi S, Makino H, Cho A, Mochiduki R, Shuto K, Kudo H,Matsubara K,Gunji H, Ochiai T. Relationship between glucose transporter, hexokinase and FDG-PET in esophageal cancer. Hepatogastroenterology 2005; 52(62):486-490.
[17]周水洪,吴求亮,汪审清,范骏.18F氟脱氧葡萄糖代谢功能图像在头颈部肿瘤诊断中的价值及机理研究.中华医学杂志2007；87(9)：109-113.
[18]Ling-Fa Li, Shui-Hong Zhou, Kui Zhao, Shen-Qing Wang, Qiu-Liang Wu, Jun Fan, Ke-Jia Cheng, Ling Ling.Clinical Significance of FDG Single-Photon Emission Computed Tomography: Computed Tomography in the Diagnosis of Head and Neck Cancers and Study of Its Mechanism. Cancer Biotherapy & Radiopharmaceuticals 2008; 23(6):701-714.
[19]Kunkel M, Moergel M, Stockinger M, Jeong JH, Fritz G, Lehr HA, Whiteside TL.Overexpression of GLUT-1 is associated with resistance to radiotherapy and adverse prognosis in squamous cell carcinoma of the oral cavity. Oral Oncol 2007;43(8):796-803.
[20]Turner M, Billadeau DD. VAV proteins as signal integrators for multi-subunit immune-recognition receptors. Nat Rev Immunol.2002; 2:476-486.
[21]Jacobs SR, Herman CE, Maciver NJ, Wofford JA, Wieman HL, Hammen JJ, Rathmell JC. Glucose Uptake Is Limiting in T Cell Activation and Requires CD28-Mediated Akt-Dependent and Independent Pathways. J Immunol.2008; 180(7):4476-4486.
[22]Melstrom LG, Salabat MR, Ding XZ, Milam BM, Strouch M, Pelling JC, et al. Apigenin Inhibits the GLUT-1 Glucose Transporter and the Phosphoinositide 3-Kinase/Akt Pathway in Human Pancreatic Cancer Cells. Pancreas. 2008;37(4):426-431.
[23]Wieman HL, Wofford JA, Rathmell JC. Cytokine stimulation promotes glucose uptake via PI3K/Akt regulation of Glutl activity and trafficking. Mol. Biol. Cell 2007; 18(4):1437-1446.
[24]Bussink J, van der Kogel AJ, Kaanders JH. Activation of the PI3-K/AKT pathway and implications for radioresistance mechanisms in head and neck cancer. Lancet Oncol.2008;9(3):288-296.
[25]Schuurbiers OC, Kaanders JH, van der Heijden HF, Dekhuijzen RP, Oyen WJ, Bussink J.The PI3-K/AKT-pathway and radiation resistance mechanisms in non-small cell lung cancer. J Thorac Oncol.2009;4(6):761-767.
[26]Soderlund K, Perez-Tenorio G, Stal O. Activation of the phosphatidylinositol 3-kinase/Akt pathway prevents radiation-induced apoptosis in breast cancer cells. Int J Oncol.2005;26(1):25-32.
[27]Elstrom RL,Bauer DE, Buzzai M, Karnauskas R,Harris MH, Plas DR, et al.Akt Stimulates Aerobic Glycolysis in Cancer Cells. Cancer Res.2004;64(6): 3892-3899.
[28]Ayala FR, Rocha RM, Carvalho KC, Carvalho AL, da Cunha IW, Lourenco SV, Soares FA. GLUT1 and GLUT3 as potential prognostic markers for Oral Squamous Cell Carcinoma.Molecules.2010;15(4):2374-87.
[29]Li SJ, Guo W, Ren GX, Huang G, Chen T, Song SL. Expression of Glut-1 in primary and recurrent head and neck squamous cell carcinomas, and compared with 2-[18F]fluoro-2-deoxy-D-glucose accumulation in positron emission tomography. Br J Oral Maxillofac Surg.2008;46(3):180-186.
[30]Zhou SH, Fan J, Chen XM, Cheng KJ, Wang SQ.. Inhibition of cell proliferation and glucose uptake in human laryngeal carcinoma cells by antisense oligonucleotides against glucose transporter-1. Head and Neck. 2009;31(12):1624-1633.
[31]Bonfitto VL, Demasi AP, Costa AF, Bonfitto JF, Araujo VC, Altemani A. High-grade transformation of adenoid cystic carcinomas:a study of the expression of GLUT1 glucose transporter and of mitochondrial antigen. Clin Pathol.2010;63(7):615-619.
[32]Volker HU, Scheich M, Berndt A, Haubitz I, Metzger A, Muller-Hermelink HK, Kammerer U, Schmidt M. Expression of p-AKT characterizes adenoid cystic carcinomas of head and neck with a higher risk for tumor relapses. Diagn Pathol.2009; 19(4):18.
[33]黄选兆,汪吉宝,孔维佳主编.2002年国际抗癌协会(UICC)头颈部癌TNM分期标准.实用耳鼻咽喉头颈外科学.2008：489-490.
[34]Still PM, Mc Cormick. Carcinoma of the external auditory meats and middle ear. Prognostic factors and a suggested staging system's Laryngeal Otol.1985; 99:847-850.
[35]Robin C, Laboulbene J. Trois productions morbides. C.R. Soc. Biol.1853; 5(2):185-196.
[36]Lorain C, Robin C. Des tumors heteradeniques. C.R. Soc. Biol.1854; 6(2): 209-221.
[37]Billroth T. Beobachtungen uber Geschwulste der Speicheldrusen. Arch Pathol Anat. Physiol. Klin. Med.1859;17(4):357-375.
[38]Spies, JW. Adenoid cystic carcinoma. Archic Surg.1930; 21(4):364-404.
[39]Reid JD. Adenoid cystic carcinoma (cylindroma) of the bronchial tree.Cancer. 1952;5(4):685-694
[40]Dockerty MB, Mayo CW. "Cylindroma"(adenocarcinoma, cylindroma type). Surgery.1943; 13(5):416-422.
[41]Foote FW, Frazell EL. Tumors of the major salivary glands. Altas of tumor pathology. AFIP FascicleⅡ, SectionⅣ, SeriesI, Washington DC.1954.
[42]Vander Poorten VL, Balm AJ, Hilgers FJ, Tan IB, Keus RB, Hart AA. Stage as major long term outcome predictor in minor salivary gland carcinoma. Cancer.2000;89:1195-1204.
[43]董震,毛钊.涎腺腺样囊性癌诊断及治疗的研究进展.医学研究生学报.2009；22(11)：1225-1228.
[44]Jones AS, Beasley NJ, Houghton DJ, et al. Tumors of the minor salivary glands. Clin Otolaryngol.1997;22:27-33.
[45]Kawashima O, Hirai T, Kamiyoshihara M, Ishikawa S, Morishita Y. Primary adenoid cystic carcinoma in the lung:report of two cases and therapeutic considerations. Lung Cancer.1998;19:211-217.
[46]Maziak DE,Todd TR, Keshavjee SH, Winton TL,Van Nostrand P.Pearson FG. Adenoid cystic carcinoma of the airway:thirty-two-year experience. J Thorac Cardiovasc Surg.1996; 112:1522-1531.
[47]Moran CA.Primary salivary gland-type tumors of the lung.Semin Diagn Pathol.1995;12:106-122.
[48]Carvalho C P, Barcellos A N, Teixeira DC, Sales J O, Silva NR. Adenoid cystic carcinoma of the external auditory canal. Braz J Otorhinolaryngol.2008; 74(5):794-796.
[49]Haug R. Beitrage zur klinki und mikroskopischen anatomie der neubildungen des ausseren und mittleren ohres. Archiv fur Ohrenheilkunde.1984;36:170-206.
[50]Dong F, Gidley PW, Ho T, Luna MA, Ginsberg LE, Sturgis EM. Adenoid cystic carcinoma of the external auditory canal. Laryngoscope.2008;118(9): 1591-1596.
[51]赵飞帆,王嘉陵,武文明,黄德亮,戴朴,杨仕明,韩维举,韩东一.外耳道腺样囊性癌临床分析.中华耳鼻咽喉头颈外科杂志.2009；44(6)：444-448.
[52]杜强,王正敏.外耳道腺样囊性癌6例.临床耳鼻咽喉科杂志.2006；20(4)：158-159.
[53]Moukarbel RV, Goldstein DP, O'Sullivan B, Gullane PJ, Brown DH, Wang L, Irish JC. Adenoid cystic carcinoma of the larynx:a 40-year experience. Head Neck.2008; 30(7):919-924.
[54]Eschwege F, Cachin Y, Micheau C. Treatment of adenocarcinomas of the larynx. Can J Otolaryngol.1975;4:290-292.
[55]Donovan DT, Conley J.A denoid cystic carcinoma of the subglottic region. Ann Otol Rhinol Laryngol.1983; 92(5):491-495.
[56]陶正德,冯本澄.声门下及气管腺样囊性癌二例.癌症.1984；3(1)：55.
[57]叶燕芬,程容荃,唐文青.鼻咽喉腺样囊性癌6例.上海第二医科大学学报.1995；15(1)：87-89.
[58]林鹏方,杨蓓蓓,王以仁.喉腺样囊性癌1例.中国实验诊断学.2001；5(6)：339.
[59]姜振华,贺德智,李力,马健,潘新良.喉腺样囊性癌1例及文献复习.山东大学基础医学院学报.2003；17(6)：380-381.
[60]Wang HL, Xu L, Li FJ. Subglottic adenoid cystic carcinoma mistaken for asthma.J Zhejiang Univ Sci B.2009;10(9):707-10.
[61]Murray BW, Lyons LC, Mancino AT, Huerta S. A report of laryngeal adenocystic carcinoma metastatic to the spleen and the role of splenectomy in the management of metastatic disease:a case report. J Med Case Reports.2010; 6(4):207.
[62]张芹,杨蕾,杨安全,郭朱明.鼻腔鼻窦腺样囊性癌88例临床分析.中华耳鼻咽喉头颈外科杂志.2009；44(4)：311-314.
[63]常英展,罗伟,缪东生,姜凤娥,张岚,王旭平,何飞.鼻腔鼻窦腺样囊性癌10例临床分析.临床耳鼻咽喉科杂志.2006；20(14)：660-661.
[64]吴瑞珊,林泼水,李水淼,等.原发性气管恶性肿瘤诊断体会.耳鼻咽喉一头颈外科.2002；7(5)：283-286.
[65]谷京城,孙连玉,李潮.气管腺样囊性癌远期疗效观察.中华耳鼻咽喉科杂志.1994；29(4)：212.
[66]戚建伟,王长宽,高志伟.误诊为甲状腺肿瘤的气管腺样囊性癌.中华耳鼻咽喉科杂志.2001；36(6)：472.
[67]顾雅佳,王玖华,王弘士,陈彤箴.头颈部腺样囊性癌的CT影像分析.中华放射学杂志.2000；34(9)：601-604.
[68]杜莉,刘艳如.左耳腺样囊性癌CT误诊1例.中国临床医学影像杂志.2005；16(5)：299-300.
[69]Aikawa H, Tomonari K, Okino Y, Hori F, Ueyama T, Suenaga S, Bundo J, Tsuji K. Adeniod cystic carcinoma of the external auditory canal:correlation between histological features and MR I appearances. Brit J Radiol.1997; 70 (833):530-532.
[70]杨亚英,宋光义,陈连有等.喉腺样囊性癌C T误诊一例.临床放射学杂志.2002；21(12)：950
[71]Sigal R, Monnet O, de Baere T, Micheau C, Shapeero LG, Julieron M, Bosq J, Vanel D, Piekarski JD, Luboinski B, et al. Adenoid cystic carcinoma of the head and neck:evaluation with MR imaging and clinical-pathologic correlation in 27 patients. Radiology.1992; 184:95-101.
[72]Lee LA, Fang TJ, Li HY,et al. Adenoid cystic carcinoma of the supraglottis mimicking a laryngeal cyst. Otolaryngol Head Neck Surg.2003;129:157-158.
[73]Szanto PA, Luna MA,Tortoledo ME. Histologic grading of adenoid cystic carcinoma of the salivary glands. Cancer.1984;54:1062-1069.
[74]Perzin KH, Gullane P, Clairmont AC. Adenoid cystic carcinoma arising in Salivary glands:a correlation of histologic features and clinical course. Cancer 1978; 42:265-282.
[75]Dodd RL,Slevin NJ:Salivary gland adenoid cystic carcinoma:a review of chemotherapy and molecular therapies.Oral Oncol.2006,42:759-769.
[76]Sharma K, Rathi AK, Khurana N, Mukherji A, Kumar V, Singh K, Bahadur AK.A retrospective study of 18 cases of adenoid cystic cancer at a tertiary care centre in Delhi. Indian J Cancer.2010;47(4):424-429.
[77]Terhaard CH, Lubsen H, Rasch CR, Levendag PC, Kaanders HH, Tjho-Heslinga RE, et al. The role of radiotherapy in the treatment of malignant salivary gland tumors. Int J Radiat Oncol Biol Phys.2005;61:103-111.
[78]Li Q, Xu T, Gao JM, Ye WJ, Gu MF, Hu WH, Wang F, Cai XY.Surgery alone provides long-term survival rates comparable to those of surgery plus postoperative radiotherapy for patients with adenoid cystic carcinoma of the palate. Oral Oncol.2011;47(3):170-173.
[79]周梁,陈小玲,黄维庭等.小涎腺肿瘤的外科治疗.临床耳鼻咽喉头颈外科杂志.2007；21(21)：963-965.
[80]Koopot R, Reyes C, Pifarr(?) R. Multiple pulmonary metastases from adenoid cystic carcinoma of the ceruminous glands of external auditory canal:A case report and review of the literature. J Thorac Cardiovasc Surg.1973;65:909-913.
[81]Creagan ET, Woods JE, Schutt AJ, O'Fallon JR. Cyclophosphamide, Adriamycin, and cis-diamminedichloroplatinum (Ⅱ) in the treatment of advanced nonsquamous cell head and neck cancer. Cancer.1983;52:2007-2010.
[82]Vermorken JB, Verweij J, de Mulder PH, Cognetti F, Clavel M, Rodenhuis S, et al. Epirubicin in patients with advanced or recurrent adenoid cystic carcinoma of the head and neck: A phase II study of the EORTC Head and Neck Cancer Cooperative Group. Ann Oncol.1993;4:785-788.
[83]Gilbert J, Li Y, Pinto HA, et al. Phase II trial of taxol in salivary gland malignancies (E1394):a trial of the Eastern Cooperative Oncology Group. Head Neck.2006;28:197-220.
[84]Van Herpen CM, Locati LD, Buter J, et al. Phase II study on gemcitabine in recurrent and/or metastatic adenoid cystic carcinoma of the head and neck (EORTC 24982). Eur J Cancer.2008;44:2542-2545.
[85]Le Tourneau C, Razak AR, Levy C, Calugaru V, Galatoire O, Dendale R, Desjardins L, Gan HK. Role of chemotherapy and molecularly targeted agents in the treatment of adenoid cystic carcinoma of the lacrimal gland.Br J Ophthalmol.2010; Dec:22.
[86]Papaspyrou G, Hoch S, Rinaldo A, Rodrigo JP, Takes RP, van Herpen C, Werner JA, Ferlito A. Chemotherapy and targeted therapy in adenoid cystic carcinoma of the head and neck:A review.Head Neck.2010;Jul:22.
[87]Wiseman SM, Popat SR, Rigual NR, Hicks WL Jr, Orner JB, Wein RO, McGary CT, Loree TR. Adenoid cystic carcinoma of the paranasal sinuses or nasal cavity:a 40-year review of 35 cases. Ear Nose Throat J.2002;81(8): 510-4,516-7.
[88]李正江唐平章,徐国镇,等.126例涎腺腺样囊性癌的疗效及预后因素.中华放射学杂志.1999；8：204-207.
[89]Oplatek A, Ozer E, Agrawal A, Bapna S, Schuller DE. Patterns of recurrence and survival of head and neck adenoid cystic carcinoma after definitive resection. Laryngoscope.2010; 120:65-70.
[90]Gomez DR, Hoppe BS, Wolden SL, et al. Outcomes and prognostic variables in adenoid cystic carcinoma of the head and neck:a recent experience. Int J Radiat Oncol Biol Phys.2008;70:1365-1372.
[91]Takata T,Kudo Y,Zhao M,et al.Reduced expression of p27(Kip1)protein in relation to salivary adenoid cystic carcinoma metastasis.Cancer.1999,86(6): 928-935.
[92]黄志权,李劲松,陈伟良,等.细胞外基质金属蛋白酶诱导因子表达与唾液腺肿瘤侵袭性的关系.中国口腔颌面外科杂志.2007；5(4)：291-295.
[93]唐峰,王虹,赵为之,等.53例涎腺腺样囊性癌MMP—2和MMP—9表达与神经浸润和淋巴结转移的关系.复旦学报(医学科学版).2001；28(2)：121-123
[94]Yu F,Jiang XZ,Chen WT,et al.Microvessel density and expression ofvascular endothelial growth factor in adenoid cystic carcinoma of salivary gland. Shanghai Kou Qiang Yi Xue.2003;12(6):443-446.
[95]Zhang J,Peng B,Chen X. Expressions of nuclear factor kappaB,inducible nitric oxide synthase,and vascular endothelial growth factor in adenoid cystic carcinoma of salivary glands:correlations with the angiogenesis and clinical outcome. Clin Cancer Res.2005;11(20):7334-7343.
[96]Zhou SH, Wang SQ, Wu QL, et al. Expressionof glucose transporter-1 and-3 in the head and neck carcinoma the correlation of the expression with the biological behaviors. J Otorhinolaryngl Head Neck Surg.2008;70(3):189-194.
[97]Roberts MS,Woods AJ, DaleTC,Van Der Sluijs P, Norman JC. Protein kinase B/Akt acts via glycogen synthase kinase 3 to regulate recycling of alpha v beta 3 and alpha 5 beta 1 integrins.Mol.Cell Biol.2004;24:1505-1515.
[98]Weiner MF,Miranda RN,Bardales RH,Mukunyadzi P,Baker SJ,Korourian S,De Las Casas LE:Diagnostic value of GLUT-limmunoreactivity to distinguish benign from malignant cystic squamous lesions of the head and neck in fine-needle aspiration biopsy material.Diagn Cytopathol.2004,31:294-299.
[99]Hu K,Li SL,Gan YH,Wang CY,Yu GY:Epiregulin promotes migration and invasion of salivary adenoid cystic carcinoma cell line SACC-83 through activation of ERK and Akt.Oral Oncol.2009;45:156-163.
[100]Aleskandarany MA, Rakha EA, Ahmed MA, Powe DG, Ellis 10, Green AR. Clinicopathologic and molecular significance of phospho-Akt expression in early invasive breast cancer. Breast Cancer Res Treat.2010;6:1-10.
[101]Jiang BH,Liu LZ.PI3K/PTEN signaling in tumorigenesis and angiogenesis. Biochim Biophys Acta:Proteins Proteomics.2008; 1784:150-158.
[102]Staal SP.Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2:amplification of AKT1 in a primary human gastric adenocarcinoma.Proc Natl Acad Sci USA.1987;84:5034-5037.
[103]Carpten JD,Faber AL,Horn C,Donoho GP,Briggs SL,Robbins CM,Hostetter G,Boguslawski S,Moses TY,Savage S.Uhlik M,Lin A,Du J,Qian YW,Zeckner DJ,Tucker-Kellogg G,Touch-man J,Patel K,Mousses S,Bittner M,Schevitz R,Lai MH,Blanchard KL,Thomas JE.A transforming mutation in the pleckstrin homology domain of AKT1 in cancer.Nature.2007;448:439-444.
[104]Zimmermann S and MOELLING K: Phosphorylation and regulation of Raf by Akt (ptotein kinase B).Science.1999; 286:1741-1744.
[105]Moelling K,Schad K, Bosse M, Zimmermann S and Schweneker M: Regulation of Raf-Akt Cross-talk. J BIOL Chem.2002;277:31099-31106.
[1]Jacobs SR, Herman CE, Maciver NJ, Wofford JA, Wieman HL, Hammen JJ, Rathmell JC. Glucose Uptake Is Limiting in T Cell Activation and Requires CD28-Mediated Akt-Dependent and Independent Pathways. J Immunol.2008; 180(7):4476-4486.
[2]Vansteenkiste J, Fischer BM, Dooms C, Mortensen J. Positron-emission tomography in prognostic and therapeutic assessment of lung cancer: systematic review. Lancet Oncol.2004; 5(9):531-540.
[3]Tohma T, Okazumi S, Makino H, Cho A, Mochiduki R, Shuto K, Kudo H,Matsubara K,Gunji H, Ochiai T. Relationship between glucose transporter, hexokinase and FDG-PET in esophageal cancer. Hepatogastroenterology.2005; 52(62):486-490.
[4]周水洪,吴求亮,汪审清,范骏.18F氟脱氧葡萄糖代谢功能图像在头颈部肿瘤 诊断中的价值及机理研究.中华医学杂志.2007；87(9)：109-113.
[5]Ling-Fa Li, Shui-Hong Zhou, Kui Zhao, Shen-Qing Wang, Qiu-Liang Wu, Jun Fan, Ke-Jia Cheng, Ling Ling.Clinical Significance of FDG Single-Photon Emission Computed Tomography: Computed Tomography in the Diagnosis of Head and Neck Cancers and Study of Its Mechanism. Cancer Biotherapy & Radiopharmaceuticals.2008; 23(6):701-714.
[6]Kunkel M, Moergel M, Stockinger M, Jeong JH, Fritz G, Lehr HA, Whiteside TL.Overexpression of GLUT-1 is associated with resistance to radiotherapy and adverse prognosis in squamous cell carcinoma of the oral cavity. Oral Oncol.2007;43(8):796-803.
[7]Bussink J, van der Kogel AJ, Kaanders JH. Activation of the PI3-K/AKT pathway and implications for radioresistance mechanisms in head and neck cancer. Lancet Oncol.2008;9(3):288-296.
[8]Doki Y, Takachi K, Ishikawa O, Sasaki Y, Miyashiro I, Ohigashi H, Yano M, Ishihara R, Tsukamoto Y, Nishiyama K, Ishiguro S, Imaoka S.Reduced tumor vessel density and high expression of glucose transporter 1 suggest tumor hypoxia of squamous cell carcinoma of the esophagus surviving after radiotherapy. Surgery.2005;137(5):536-44.
[9]Pedersen MW, Holm S, Lund EL, Hojgaard L, Kristjansen PE.Coregulation of glucose uptake and vascular endothelial growth factor (VEGF) in two small-cell lung cancer (SCLC) sublines in vivo and in vitro. Neoplasia.2001(1); 3:80-87.
[10]Zhou SH, Fan J, Chen XM, Cheng KJ, Wang SQ. Inhibition of cell proliferation and glucose uptake in human laryngeal carcinoma cells by antisense oligonucleotides against glucose transporter-1. Head and Neck.2009; 31(12):1624-1633.
[11]Michel F, Attal-Bonnefoy G, Mangino G, Mise-Omata S, Acuto O. CD28 as a molecular amplifier extending TCR ligation and signaling capabilities. Immunity.2001; 15:935-945.
[12]Turner M, Billadeau DD. VAV proteins as signal integrators for multi-subunit immune-recognition receptors. Nat Rev Immunol.2002;2(7):476-486.
[13]Melstrom LG, Salabat MR, Ding XZ, Milam BM, Strouch M, Pelling JC, et al.Apigenin Inhibits the GLUT-1 Glucose Transporter and the Phosphoinositide 3-Kinase/Akt Pathway in HumanPancreatic Cancer Cells. Pancreas.2008;37(4):426-431.
[14]Wieman HL, Wofford JA, Rathmell JC. Cytokine stimulation promotes glucose uptake via PI3K/Akt regulation of Glutl activity and trafficking. Mol Biol Cell.2007;18(4):1437-1446.
[15]Elstrom RL,Bauer DE, Buzzai M, Karnauskas R,Harris MH, Plas DR, Zhuang H, Cinalli RM, Alavi A, Rudin CM, Thompson CB. Akt Stimulates Aerobic Glycolysis in Cancer Cells. Cancer Res.2004;64(6):3892-3899.
[16]Kunkel M, Reichert TE, Benz P, Bartenstein P, Wagner W, Whiteside TL. Overexpression of Glut-1 and increased glucose metabolism in the tumor are associated with poor prognosis in oral squamous cell carcinoma. Cancer.2003; 97:1015-1024.
[17]Oliver RJ,Woodwards RTM, Sloan P, Thakker NS, Stratford IJ, Airley RE. Prognostic value of facilitative glucose transporter Glut-1 in oral squamous cell carcinoma treated by surgical resection: results of EORTC translational research fund studies. Eur J Cancer 2004;40(4):503-507.
[18]Brophy S, Sheehan KM, McNamara DA, Deasy J, Bouchier-Hayes DJ, Kay EW. GLUT-1 expression and response to chemoradiotherapy in rectal cancer. Int J Cancer.2009;125(12):2778-82.
[19]Markowska J, Grabowski JP, Tomaszewska K, Kojs Z, Pudelek J, Skrzypczak M, Sobotkowski J, Emerich J, Olejek A, Filas V. Significance of hypoxia in uterine cervical cancer. Multicentre study. Eur J Gynaecol Oncol.2007;28(5): 386-388.
[20]Sax JK, Eldeiry WS. p53 downstream targets and chemosensitivity. Cell Death Differ.2003;10(4):413-417.
[21]Schuurbiers OC, Kaanders JH, Van der Heijden HF, Dekhuijzen RP, Oyen WJ, Bussink J.The PI3-K/AKT-pathway and radiation resistance mechanisms in non-small cell lung cancer. J Thorac Oncol.2009;4(6):761-767.
[22]Gupta AK, McKenna WG, Weber CN, Feldman MD, Goldsmith JD, Mick R, Machtay M, Rosenthal DI, Bakanauskas VJ, Cerniglia GJ, Bernhard EJ, Weber RS, Muschel RJ. Local recurrence in head and neck cancer: relationship to radiation resistance and signal transduction. Clin Cancer Res.2002; 8(3):885-892.
[23]Soderlund K, Perez-Tenorio G, Stal O. Activation of the phosphatidylinositol 3-kinase/Akt pathway prevents radiation-induced apoptosis in breast cancer cells. Int J Oncol.2005;26(1):25-32.
[24]Skvortsova I, Skvortsov S, Stasyk T, Raju U, Popper BA, Schiestl B, von Guggenberg E, Neher A, Bonn GK, Huber LA, Lukas P.Intracellular signaling pathways regulating radioresistance of human prostate carcinoma cells. Proteomics.2008;8(21):4521-4533.
[25]Gupta AK, Bakanauskas VJ, Cerniglia GJ, Cheng Y, Bernhard EJ, Muschel RJ, McKenna WG. The Ras radiation resistance pathway. Cancer Res.2001; 61 (10):4278-4282.
[26]McKenna WG, Muschel RJ, Gupta AK, Hahn SM, Bernhard EJ. The RAS signal transduction pathway and its role in radiation sensitivity. Oncogene. 2003; 22(37):5866-5875.
[27]Toulany M, Kasten-Pisula U, Brammer I, Wang S, Chen J, Dittmann K, Baumann M, Dikomey E, Rodemann HP. Blockage of epidermal growth factor receptor-phosphatidylinositol 3-kinase-AKT signaling increases radiosensitivity of K-RAS mutated human tumor cells in vitro by affecting DNA repair. Clin Cancer Res.2006;12(13):4119-4126.
[28]O'Driscoll M, Jeggo PA. The role of double-strand break repair insights from human genetics. Nat Rev Genet.2006;7(1):45-54.
[29]Sakata K, Someya M, Matsumoto Y, Hareyama M. Ability to repair DNA double-strand breaks related to cancer susceptibility and radiosensitivity. Radiat Med.2007;25(9):433-438.
[30]Zhuang W, Qin Z, Liang Z.The role of autophagy in sensitizing malignant glioma cells to radiation therapy. Acta Biochim Biophys Sin (Shanghai). 2009;41(5):341-351.
[31]Newton HR. Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors. Part 2:PI3K/Akt/PTEN, mTOR,SHH/ PTCH and angiogenesis. Expert rev anticancer Ther.2004;4 (1):105-128.
[32]Weinert T. A DNA damage checkpoint meets the cell cycle engine. Science.1997; 277(5331):1450-1451.
[33]Virsik-Kopp P, Hofman-Huther H, Rave-Frank M, Schmidberger H. The effect of wortmannin on radiation-induced chromosome aberration formation in the radioresistant tumor cell line WiDr. Radiat Res.2005; 164(2):148-156.
[34]Fuhrman CB, Kilgore J, LaCoursiere YD, Lee CM, Milash BA, Soisson AP, Zempolich KA. Radiosensitization of cervical cancer cells via double-strand DNA break repair inhibition. Gynecol Oncol.2008;110(1):93-98.
[35]Gao X, Xing D.Molecular mechanisms of cell proliferation induced by low power laser irradiation. J Biomed Sci.2009; 16:4.
[36]傅深,蒋国,刘泰福PI3K/Akt生存信号转导通路在肿瘤放射生物学中的意义.肿瘤.2006；26：298-301.
[37]Numico G, Russi EG, Colantonio I, Lantermo RA, Silvestris N, Vitiello R, Comino A, Abrate M, Zavattero C, Melano A, Merlano M.EGFR status and prognosis of patients with locally advanced head and neck cancer treated with chemoradiotherapy. Anticancer Res.2010;30(2):671-676.
[38]McKenna WG, Muschel RJ, Gupta A, Hahn S, Bernhard EJ.Signaling inhibition with radiation in colorectal cancer: clinical trials. Semin Oncol. 2003;30(3 Suppl 6):56-67.
[39]Kim CS, Kim JK, Nam SY, Yang KH, Jeong M, Kim HS, Kim CS, Jin YW, Kim J. Low-dose radiation-induced senescent stromal fibroblasts render nearby breast cancer cells radioresistant. Mol Cells.2007;24(3):424-430.
[40]Vincenzi B, Zoccoli A, Pantano F, Venditti O, Galluzzo S. Cetuximab:from bench to bedside.Curr Cancer Drug Targets.2010;10(1):80-95.
[41]Bouche O, Beretta GD, Alfonso PG, Geissler M.The role of anti-epidermal growth factor receptor monoclonal antibody monotherapy in the treatment of metastatic colorectal cancer. Cancer Treat Rev.2010;36 (Suppl 1):S1-10.
[42]Lu Z, Cox-Hipkin MA, Windsor WT, Boyapati A.3-phosphoinositide-dependent protein kinase-1 regulates proliferation and survival of cancer cells with an activated mitogen-activated protein kinase pathway. Mol Cancer Res. 2010;8(3):421-432.
[43]Kong D, Yamori T.Phosphatidylinositol 3-kinase inhibitors:promising drug candidates for cancer therapy. Cancer Sci.2008;99(9):1734-1740.
[44]Prevo R, Deutsch E, Sampson O, Diplexcito J, Cengel K, Harper J, O'Neill P, McKenna WG, Patel S, Bernhard EJ. Class I PI3 kinase inhibition by the pyridinylfuranopyrimidine inhibitor PI-103 enhances tumor radiosensitivity. Cancer Res.2008;68(14):5915-5923.
[45]Shinohara ET, Maity A. Increasing sensitivity to radiotherapy and chemotherapy by using novel biological agents that alter the tumor microenvironment. Curr Mol Med.2009;9(9):1034-1045.
[46]Fan S, Ma YX, Gao M, Yuan RQ, Meng Q, Goldberg ID, Rosen EM.The multisubstrate adapter Gabl regulates hepatocyte growth factor (scatter factor)-c-Met signaling for cell survival and DNA repair. Mol Cell Biol. 2001;21(15):4968-4984.
[47]El-Deiry WS. Akt takes centre stage in cell-cycle deregulation. Nat Cell Biol.2001;3(3):E71-73.
[48]Fujita Y, Kato I, Iwai S, Ono K, Suzuki M, Sakurai Y, Ohnishi K, Ohnishi T, Yura Y. Role of p53 mutation in the effect of boron neutron capture therapy on oral squamous cell carcinoma. Radiat Oncol.2009; 4:63.
[49]Levav-Cohen Y, Haupt S, Haupt Y. Mdm2 in growth signaling and cancer. Growth Factors.2005;23(3):183-192.
[50]Shin S, Asano T, Yao Y, Zhang R, Claret FX, Korc M, Sabapathy K, Menter DG, Abbruzzese JL, Reddy SA. Activator protein-1 has an essential role in pancreatic cancer cells and is regulated by a novel Akt-mediated mechanism.Mol Cancer Res.2009;7(5):745-754.
[51]Mukherji A, Janbandhu VC, Kumar V. HBx protein modulates PI3K/Akt pathway to overcome genotoxic stress-induced destabilization of cyclin D1 and arrest of cell cycle.Indian J Biochem Biophys.2009;46(1):37-44.
[52]Kandel ES,Hay N.The regulation and activaties of the multifunctional serine/threonine kinase Akt/PKB. Exp Cell Res.1999;253(1):210-229.
[53]Muise-Helmericks RC, Grimes HL, Bellacosa A, Malstrom SE, Tsichlis PN, Rose N. Cyclin D expression is controlled post-transcriptionally via a phosphatidylinositol 3-kinase/Akt-dependent pathway. J Biol Chem.1998; 273(45):29864-29872.
[54]Zhou BP, Liao Y,Xia W, Spohn B,Lee MH and Hung MC. Cytoplasmic localization of p21Cipl/WAFl by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nat Cell Biol.2001;3(3):245-252.
[55]Webster L, Hodgkiss RJ, Wilson GD. Cell cycle distribution of hypoxia and progression of hypoxic tumour cells in vivo. Br J Cancer.1998;77(2):227-234.
[56]Hoogsteen IJ, Marres HA, Wijffels KI, Rijken PF, Peters JP, van den Hoogen FJ, Oosterwijk E, van der Kogel AJ, Kaanders JH.Colocalization of carbonic anhydrase 9 expression and cell proliferation in human head and neck squamous cell carcinoma.Clin Cancer Res.2005;11(1):97-106.
[57]Harris AL.Hypoxia—a key regulatory factor of in tumour growth.Nat Re Cancer.2002;2(1):38-47.
[58]Koumenis C.ER stress, hypoxia tolerance and tumor progression.Curr Mol Med.2006;6(1):55-69.
[59]Brizel DM,Sibley GS,Prosnitz LR,Scher RL,Dewhirst MW.Tumour hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys.1997;38(3):285-289.
[60]Nordsmark M.Bentzen SM,Rudat V, Brizel D, Lartigau E, Stadler P, Becker A, Adam M, Molls M, Dunst J, Terris DJ, Overgaard J.Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy.An international multi-center study.Radiother Oncol.2005;77(1):18-24.
[61]Kaanders JH,Wijffels KI,Marres HA, Ljungkvist AS, Pop LA, van den Hoogen FJ, de Wilde PC, Bussink J, Raleigh JA, van der Kogel AJ. Pimonidazole binding and tumor vascularity predict for treatment outcome in head and neck cancer.Cancer Res.2002;62(23):7066-7074.
[62]Semenza GL.HIF-1:mediator of physiological and pathophysiological responses to hypoxia.J Appl Physiol.2000;88(4):1474-1480.
[63]Lal A,Peters H,St Croix B, Haroon ZA, Dewhirst MW, Strausberg RL, Kaanders JH, van der Kogel AJ, Riggins GJ..Transcriptional response to hypoxia in human tumors.J Natl Cancer Inst.2001;93(17):1337-1343.
[64]Zlobec I,Steele R,Compton CC.VEGF as a predictive marker of rectal tumor response to preoperative radiotherapy.Cancer.2005;104(11):2517-2521.
[65]Kufe DW,Pollock RE,Weichselbaum RR.Bast RC,Gansler TS,Holland JF,Free E.Cancer medicine.Hamilton(Canada).BC Decker,2003.
[66]Opavsky R,Pastorekova S, Zelnik V,Gibadulinova A,Stanbridge EJ,Zavada J, Gibadulinova A, Stanbridge EJ, Zavada J, Kettmann R, Pastorek J.Human MN/CA9 gene,a novel member of the carbonic anhydrase family:structure and exon to protein domainrelationships.Genomics.1996;33(3):480-487.
[67]Vordermark D,Brown JM. Endogenous markers of tumor hypoxia predictors of clinical radiation resistance.Strahlenther Onkol.2003;179(12):801-811.
[68]Koukourakis MI,Giatromanolaki A,Sivridis E,Simopoulos K,Pastorek J,Wykoff CC, Gatter KC, Harris AL..Hypoxia-regulated carbonic anhydrase-9(CA9)relates to poor vascularization and resistance of squamous cell head and neck cancer to chemoradiotherapy. Clin Cancer Res.2001;7(11):3399-3403.
[69]Hui EP.Chan AT,Pezzella F,Turley H,To KF,Poon TC, Turley H, To KF, Poon TC, Zee B, Mo F, Teo PM, Huang DP, Gatter KC, Johnson PJ, Harris AL.Coexpression of hypoxia-inducible factors 1 alpha and 2alpha,carbonic anhydrase Ⅸ,and vascular endothelial growth factor in nasopharyngealcarcinoma and relationship to survival.Clin Cancer Res.2002;8(8):2595-2604.
[70]Zhong H,Chiles K,Feldser D, Laughner E, Hanrahan C, Georgescu MM, Simons JW, Semenza GL.Modulation of hypoxia-inducible factor 1 alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/ PTEN/AKT/FRAP pathway in human prostate cancer cells:implications for tumor angiogenesis and therapeutics.Cancer Res.2000; 60(6):1541-1545.
[71]Dragowska WH,Verreault M,Yapp DT, Warburton C, Edwards L, Ramsay EC, Huxham LA, Minchinton AI, Gelmon K, Bally MB.Decreased levels of hypoxic cells in gefitinib treated ER(+)HER-2 overexpressing MCF-7 breast cancer tumors are associated with hyperactivation of the mTOR pathway:therapeutic implications for combination therapy with rapamycin. Breast Cancer Res Treat.2007;106(3):319-331.
[72]Krause M,Ostermann G,Petersen C, Yaromina A, Hessel F, Harstrick A, van der Kogel AJ, Thames HD, Baumann M.Decreased repopulation as well as increased reoxygenation contribute to the improvement in local control after targeting of the EGFR by C225 during fractionated irradiation.Radiother Oncol. 2005;76(2):162-167.
[73]Edwards E. Phosphatidylinositol 3-kinase/Akt signaling in the response of vascular endothelium to Ionizing radiation. Cancer Res.2002; 62 (16):4671-4677.
[74]Fang J,Xia C,Cao Z, Zheng JZ, Reed E, Jiang BH. Apigenin inhibits VEGF and HIF-1 expression via PI3K/AKT/p70S6K1 and HDM2/p53 pathways. FASEB J.2005;19(3):342-353.
[75]Skinner HD, Zheng JZ,Fang J, Agani F, Jiang BH. Vascular endothelial growth factor transcriptional activation is mediated by hypoxia-inducible factor lalpha, HDM2, and p70S6K1 in response to phosphatidylinositol 3-kinase/AKT signaling. J Biol Chem.2004;279(44):45643-45651.
[76]Bussink J,Kaanders JH,van der Kogel AJ.Tumor hypoxia at the microregional level:clinical relevance and predictive value of exogenous and endogenous hypoxic cell markers.Radiother Oncol.2003;67(l):3-15.
[77]Gort EH, Groot AJ, Derks van de Ven TL, van der Groep P, Verlaan I, van Laar T, van Diest PJ, van der Wall E, Shvarts A.Hypoxia-inducible factor-la expression requires PI3-kinase activity and correlates with Aktl phosphorylation in invasive breast carcinomas. Oncogene.2006;25(45): 6123-6127.
[78]Blancher C,Moore JW, Robertson N, Harris AL. Effects of ras and von Hippel-Lindau (VHL) gene mutations on hypoxia-inducible factor (HIF)-lalpha, HIF-2alpha, and vascular endothelial growth factor expression and their regulation by the phosphatidylinositol 3'-kinase/Akt signaling pathway. Cancer Res.2001;61(19):7349-7355.
[79]Kan O,Baldwin SA,Whetton AD. Apoptosis is regulated by the rate of glucose transport in an interleukin 3 dependent cell line. J ExpMed.1994;180(3):917-923.
[80]Edinger AL,Thompson CB.Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake. Mol Biol Cell.2002;13(7):2276-2288.
[81]Rathmell JC, Fox CJ, Plas DR, Hammerman PS, Cinalli RM,Thompson CB.Akt-directed glucose metabolism can prevent Bax conformation change and promote growth factor-independent survival. Mo lCell Biol.2003;23(8): 7315-7328.
[82]Plas DR, Talapatra S, Edinger AL, Rathmell JC, Thompson CB. Akt and Bcl-xL promote growth factor-independent survival through distinct effects on mitochondrial physiology.J Biol Chem.2001;276(15):12041-12048.
[83]Zhao Y, Altman BJ, Coloff JL, Herman CE,J acobs SR, Wieman HL, Wofford JA, Dimascio LN, Ilkayeva O, Kelekar A, Reya T, Rathmell JC. Glycogen synthase kinase 3alpha and 3beta mediate a glucose-sensitive antiapoptotic signaling pathway to stabilize Mel-1..Mol Cell Biol.2007;27(12):4328-4339.
[84]Jope RS, Johnson GV. The glamour and gloom of glycogen synthase kinase-3.Trends BiochemSci.2004;29(2):95-102.
[85]Roberts MS, Woods AJ, Dale TC, Van Der Sluijs P, Norman JC.Protein kinase B/Akt acts via glycogen synthase kinase 3 to regulate recycling of alpha v beta 3 and alpha 5 beta 1 integrins. Mol Cell Biol.2004;24(4):1505-1515.
[86]Doughty CA, Bleiman BF, Wagner DJ, Dufort FJ, Mataraza JM, Roberts MF, Chiles TC. Antigen receptor-mediated changes in glucose metabolism in B lymphocytes:role of phosphatidylinositol 3-kinase signaling in the glycolytic control of growth.Blood.2006;107(11):4458-4465.
[87]Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC, Plas DR, Elstrom RL, June CH, Thompson CB. The CD28 signaling pathway regulates glucose metabolism. Immunity.2002;16(6):769-777.
[88]Bentley J, Itchayanan D, Barnes K, McIntosh E, Tang X, Downes CP, Holman GD, Whetton AD, Owen-Lynch PJ, Baldwin SA.Interleukin-3-mediated cell survival signals include phosphatidylinositol 3-kinase-dependent translocation of the glucose transporter GLUT1 to the cell surface. J Biol Chem.2003; 278(41):39337-39348.
[89]Barata JT, Cardoso AA, Nadler LM, Boussiotis VA.Interleukin-7 promotes survival and cell cycle progression of T-cell acute lymphoblastic leukemia cells by down-regulating the cyclin-dependent kinase inhibitor p27(kip1). Blood.2001;98(5):1524-1531.
[90]Samih N,Hovsepian S,Aouani A, Lombardo D, Fayet G. Glut-1 translocation in FRTL-5 thyroid cells:role of phosphatidylinositol 3-kinase and N-glycosylation. Endrocrinology.2000;141(1):4146-4155.
[91]Clarke JF, Young PW, Yonezawa K, et al.Inhibition of the translocationof GLUT1 and GLUT4 in 3T3-L1 cells by the phosphatidylinosit13-kinase inhibitor, wortmannin.Biochem J.1994;300:631-635.
[92]Ding XZ, Fehsenfeld DM,Murphy LO, Permert J, Adrian TE. Physiological concentrations of insulin augment pancreatic cancer cell proliferation and glucose utilization by activating MAP kinase, PI3 kinase and enhancing GLUT-1 expression. Pancreas.2000;21(3):310-320.
[93]Okada T, Kawano Y, Sakakibara T, Hazeki O, Ui M.. Essential role of phosphatidylinositol 3-kinase in insulin-induced glucose transport and anti-lipolysis in rat adipocytes.Studies with a selective inhibitor wortmannin. J Biol Chem.1994;269(5):3568-3573.
[94]Barthel A, Okino ST, Liao J, Nakatani K, Li J, Whitlock JP Jr, Roth RA.Regulation of GLUT1 Gene Transcription by the Serine/Threonine Kinase Akt1. J Biol Chem.1999;274(29):20281-20286.
[2]Yih WY, Kratochvil FJ, Stewart JC. Intraoral minor salivary gland neoplasms: review of 213 cases. J Oral Maxillofac Surg 2005; 63(6):805-10.
[3]Shin YJ, Percodani J, UroCoste E, et al. Laryngeal adenoid cystic carcinoma. Rev Laryngol Otol Rhinol 1998; 119:1052.
[4]Zvrko E, Golubovic M.Laryngeal adenoid cystic carcinoma. Acta Otorhinolaryngol Ital 2009;29(5):279-82.
[5]Lupinetti AD, Roberts DB, Williams MD, Kupferman ME, Rosenthal DI, Demonte F, El-Naggar A, Weber RS, Hanna EY. Sinonasal adenoid cystic carcinoma: the M. D. Anderson Cancer Center experience. Cancer 2007;110(12):2726-31.
[6]Cruz Perez DE, Pires FR, Lopes MA, de Almeida OP,Kowalski LP. Adenoid cystic carcinoma and mucoepidermoid carcinoma of the maxillary sinus:report of a 44-year experience of 25 cases from a single institution. J Oral Maxillofac Surg 2006;64:1592-1597.
[7]Conley J, Schuller DE. Malignancies of the ear. Laryngoscope 1976; 86 (8):1147-1163.
[8]Ko YH, Lee MA, Hong YS, Lee KS, Jung CK, Kim YS, Sun DI, Kim BS, Kim MS, Kang JH. Prognostic factors affecting the clinical outcome of adenoid cystic carcinoma of the head and neck. Jpn J Clin Oncol 2007;37(11):805-811.
[9]de Lima Mde D, Marques YM, Alves Sde M Jr, Freitas VM, Soares FA, de Araujo VC, Pinto Ddos S Jr, Mantesso A. MDM2, P53, P21WAF1 and pAKT protein levels in genesis and behaviour of adenoid cystic carcinoma. Cancer Epidemiol 2009;33(2):142-146.
[10]Suzuki N, Onda T, Yamamoto N, Katakura A, Mizoe JE, Shibahara T. Mutation of the p16/CDKN2 gene and loss of heterozygosity in malignant mucosal melanoma and adenoid cystic carcinoma of the head and neck.Int J Oncol 2007;31(5):1061-1067.
[11]Shahsavari F, Eslami M, Baghaie F, Tirgari F, Motahhary P. Immunohistochemical evaluation of p27 (kipl) in pleomorphic adenomas and adenoid cystic carcinomas of the minor salivary glands.Asian Pac J Cancer Prev 2005;6(4):527-530.
[12]Maruyama S, Cheng J, Yamazaki M, Zhou XJ, Zhang ZY, He RG, Saku T. Metastasis-associated genes in oral squamous cell carcinoma and salivary adenoid cystic carcinoma:a differential DNA chip analysis between metastatic and nonmetastatic cell systems.Cancer Genet Cytogenet 2010 196(1):14-22.
[13]Ko YH, Roh SY, Won HS, Jeon EK, Hong SH, Lee MA, Kang JH, Hong YS, Kim MS, Jung CK. Prognostic significance of nuclear survivin expression in resected adenoid cystic carcinoma of the head and neck. Head Neck Oncol 2010,30(2):30.
[14]Vansteenkiste J, Fischer BM, Dooms C, Mortensen J. Positron-emission tomography in prognostic and therapeutic assessment of lung cancer: systematic review. Lancet Oncol 2004; 5(9):531-540.
[15]Campistron M, Rouquette I, Courbon F, Chabbert V, Rochaix P, Prevot G, Laroumagne S, Tetu L, Didier A, Mazieres J.Adenoid cystic carcinoma of the lung:interest of 18FDG PET/CT in the management of an atypical presentation. Lung Cancer 2008;59(1):133-136.
[16]Tohma T, Okazumi S, Makino H, Cho A, Mochiduki R, Shuto K, Kudo H,Matsubara K,Gunji H, Ochiai T. Relationship between glucose transporter, hexokinase and FDG-PET in esophageal cancer. Hepatogastroenterology 2005; 52(62):486-490.
[17]周水洪,吴求亮,汪审清,范骏.18F氟脱氧葡萄糖代谢功能图像在头颈部肿瘤诊断中的价值及机理研究.中华医学杂志2007；87(9)：109-113.
[18]Ling-Fa Li, Shui-Hong Zhou, Kui Zhao, Shen-Qing Wang, Qiu-Liang Wu, Jun Fan, Ke-Jia Cheng, Ling Ling.Clinical Significance of FDG Single-Photon Emission Computed Tomography: Computed Tomography in the Diagnosis of Head and Neck Cancers and Study of Its Mechanism. Cancer Biotherapy & Radiopharmaceuticals 2008; 23(6):701-714.
[19]Kunkel M, Moergel M, Stockinger M, Jeong JH, Fritz G, Lehr HA, Whiteside TL.Overexpression of GLUT-1 is associated with resistance to radiotherapy and adverse prognosis in squamous cell carcinoma of the oral cavity. Oral Oncol 2007;43(8):796-803.
[20]Turner M, Billadeau DD. VAV proteins as signal integrators for multi-subunit immune-recognition receptors. Nat Rev Immunol.2002; 2:476-486.
[21]Jacobs SR, Herman CE, Maciver NJ, Wofford JA, Wieman HL, Hammen JJ, Rathmell JC. Glucose Uptake Is Limiting in T Cell Activation and Requires CD28-Mediated Akt-Dependent and Independent Pathways. J Immunol.2008; 180(7):4476-4486.
[22]Melstrom LG, Salabat MR, Ding XZ, Milam BM, Strouch M, Pelling JC, et al. Apigenin Inhibits the GLUT-1 Glucose Transporter and the Phosphoinositide 3-Kinase/Akt Pathway in Human Pancreatic Cancer Cells. Pancreas. 2008;37(4):426-431.
[23]Wieman HL, Wofford JA, Rathmell JC. Cytokine stimulation promotes glucose uptake via PI3K/Akt regulation of Glutl activity and trafficking. Mol. Biol. Cell 2007; 18(4):1437-1446.
[24]Bussink J, van der Kogel AJ, Kaanders JH. Activation of the PI3-K/AKT pathway and implications for radioresistance mechanisms in head and neck cancer. Lancet Oncol.2008;9(3):288-296.
[25]Schuurbiers OC, Kaanders JH, van der Heijden HF, Dekhuijzen RP, Oyen WJ, Bussink J.The PI3-K/AKT-pathway and radiation resistance mechanisms in non-small cell lung cancer. J Thorac Oncol.2009;4(6):761-767.
[26]Soderlund K, Perez-Tenorio G, Stal O. Activation of the phosphatidylinositol 3-kinase/Akt pathway prevents radiation-induced apoptosis in breast cancer cells. Int J Oncol.2005;26(1):25-32.
[27]Elstrom RL,Bauer DE, Buzzai M, Karnauskas R,Harris MH, Plas DR, et al.Akt Stimulates Aerobic Glycolysis in Cancer Cells. Cancer Res.2004;64(6): 3892-3899.
[28]Ayala FR, Rocha RM, Carvalho KC, Carvalho AL, da Cunha IW, Lourenco SV, Soares FA. GLUT1 and GLUT3 as potential prognostic markers for Oral Squamous Cell Carcinoma.Molecules.2010;15(4):2374-87.
[29]Li SJ, Guo W, Ren GX, Huang G, Chen T, Song SL. Expression of Glut-1 in primary and recurrent head and neck squamous cell carcinomas, and compared with 2-[18F]fluoro-2-deoxy-D-glucose accumulation in positron emission tomography. Br J Oral Maxillofac Surg.2008;46(3):180-186.
[30]Zhou SH, Fan J, Chen XM, Cheng KJ, Wang SQ.. Inhibition of cell proliferation and glucose uptake in human laryngeal carcinoma cells by antisense oligonucleotides against glucose transporter-1. Head and Neck. 2009;31(12):1624-1633.
[31]Bonfitto VL, Demasi AP, Costa AF, Bonfitto JF, Araujo VC, Altemani A. High-grade transformation of adenoid cystic carcinomas:a study of the expression of GLUT1 glucose transporter and of mitochondrial antigen. Clin Pathol.2010;63(7):615-619.
[32]Volker HU, Scheich M, Berndt A, Haubitz I, Metzger A, Muller-Hermelink HK, Kammerer U, Schmidt M. Expression of p-AKT characterizes adenoid cystic carcinomas of head and neck with a higher risk for tumor relapses. Diagn Pathol.2009; 19(4):18.
[33]黄选兆,汪吉宝,孔维佳主编.2002年国际抗癌协会(UICC)头颈部癌TNM分期标准.实用耳鼻咽喉头颈外科学.2008：489-490.
[34]Still PM, Mc Cormick. Carcinoma of the external auditory meats and middle ear. Prognostic factors and a suggested staging system's Laryngeal Otol.1985; 99:847-850.
[35]Robin C, Laboulbene J. Trois productions morbides. C.R. Soc. Biol.1853; 5(2):185-196.
[36]Lorain C, Robin C. Des tumors heteradeniques. C.R. Soc. Biol.1854; 6(2): 209-221.
[37]Billroth T. Beobachtungen uber Geschwulste der Speicheldrusen. Arch Pathol Anat. Physiol. Klin. Med.1859;17(4):357-375.
[38]Spies, JW. Adenoid cystic carcinoma. Archic Surg.1930; 21(4):364-404.
[39]Reid JD. Adenoid cystic carcinoma (cylindroma) of the bronchial tree.Cancer. 1952;5(4):685-694
[40]Dockerty MB, Mayo CW. "Cylindroma"(adenocarcinoma, cylindroma type). Surgery.1943; 13(5):416-422.
[41]Foote FW, Frazell EL. Tumors of the major salivary glands. Altas of tumor pathology. AFIP FascicleⅡ, SectionⅣ, SeriesI, Washington DC.1954.
[42]Vander Poorten VL, Balm AJ, Hilgers FJ, Tan IB, Keus RB, Hart AA. Stage as major long term outcome predictor in minor salivary gland carcinoma. Cancer.2000;89:1195-1204.
[43]董震,毛钊.涎腺腺样囊性癌诊断及治疗的研究进展.医学研究生学报.2009；22(11)：1225-1228.
[44]Jones AS, Beasley NJ, Houghton DJ, et al. Tumors of the minor salivary glands. Clin Otolaryngol.1997;22:27-33.
[45]Kawashima O, Hirai T, Kamiyoshihara M, Ishikawa S, Morishita Y. Primary adenoid cystic carcinoma in the lung:report of two cases and therapeutic considerations. Lung Cancer.1998;19:211-217.
[46]Maziak DE,Todd TR, Keshavjee SH, Winton TL,Van Nostrand P.Pearson FG. Adenoid cystic carcinoma of the airway:thirty-two-year experience. J Thorac Cardiovasc Surg.1996; 112:1522-1531.
[47]Moran CA.Primary salivary gland-type tumors of the lung.Semin Diagn Pathol.1995;12:106-122.
[48]Carvalho C P, Barcellos A N, Teixeira DC, Sales J O, Silva NR. Adenoid cystic carcinoma of the external auditory canal. Braz J Otorhinolaryngol.2008; 74(5):794-796.
[49]Haug R. Beitrage zur klinki und mikroskopischen anatomie der neubildungen des ausseren und mittleren ohres. Archiv fur Ohrenheilkunde.1984;36:170-206.
[50]Dong F, Gidley PW, Ho T, Luna MA, Ginsberg LE, Sturgis EM. Adenoid cystic carcinoma of the external auditory canal. Laryngoscope.2008;118(9): 1591-1596.
[51]赵飞帆,王嘉陵,武文明,黄德亮,戴朴,杨仕明,韩维举,韩东一.外耳道腺样囊性癌临床分析.中华耳鼻咽喉头颈外科杂志.2009；44(6)：444-448.
[52]杜强,王正敏.外耳道腺样囊性癌6例.临床耳鼻咽喉科杂志.2006；20(4)：158-159.
[53]Moukarbel RV, Goldstein DP, O'Sullivan B, Gullane PJ, Brown DH, Wang L, Irish JC. Adenoid cystic carcinoma of the larynx:a 40-year experience. Head Neck.2008; 30(7):919-924.
[54]Eschwege F, Cachin Y, Micheau C. Treatment of adenocarcinomas of the larynx. Can J Otolaryngol.1975;4:290-292.
[55]Donovan DT, Conley J.A denoid cystic carcinoma of the subglottic region. Ann Otol Rhinol Laryngol.1983; 92(5):491-495.
[56]陶正德,冯本澄.声门下及气管腺样囊性癌二例.癌症.1984；3(1)：55.
[57]叶燕芬,程容荃,唐文青.鼻咽喉腺样囊性癌6例.上海第二医科大学学报.1995；15(1)：87-89.
[58]林鹏方,杨蓓蓓,王以仁.喉腺样囊性癌1例.中国实验诊断学.2001；5(6)：339.
[59]姜振华,贺德智,李力,马健,潘新良.喉腺样囊性癌1例及文献复习.山东大学基础医学院学报.2003；17(6)：380-381.
[60]Wang HL, Xu L, Li FJ. Subglottic adenoid cystic carcinoma mistaken for asthma.J Zhejiang Univ Sci B.2009;10(9):707-10.
[61]Murray BW, Lyons LC, Mancino AT, Huerta S. A report of laryngeal adenocystic carcinoma metastatic to the spleen and the role of splenectomy in the management of metastatic disease:a case report. J Med Case Reports.2010; 6(4):207.
[62]张芹,杨蕾,杨安全,郭朱明.鼻腔鼻窦腺样囊性癌88例临床分析.中华耳鼻咽喉头颈外科杂志.2009；44(4)：311-314.
[63]常英展,罗伟,缪东生,姜凤娥,张岚,王旭平,何飞.鼻腔鼻窦腺样囊性癌10例临床分析.临床耳鼻咽喉科杂志.2006；20(14)：660-661.
[64]吴瑞珊,林泼水,李水淼,等.原发性气管恶性肿瘤诊断体会.耳鼻咽喉一头颈外科.2002；7(5)：283-286.
[65]谷京城,孙连玉,李潮.气管腺样囊性癌远期疗效观察.中华耳鼻咽喉科杂志.1994；29(4)：212.
[66]戚建伟,王长宽,高志伟.误诊为甲状腺肿瘤的气管腺样囊性癌.中华耳鼻咽喉科杂志.2001；36(6)：472.
[67]顾雅佳,王玖华,王弘士,陈彤箴.头颈部腺样囊性癌的CT影像分析.中华放射学杂志.2000；34(9)：601-604.
[68]杜莉,刘艳如.左耳腺样囊性癌CT误诊1例.中国临床医学影像杂志.2005；16(5)：299-300.
[69]Aikawa H, Tomonari K, Okino Y, Hori F, Ueyama T, Suenaga S, Bundo J, Tsuji K. Adeniod cystic carcinoma of the external auditory canal:correlation between histological features and MR I appearances. Brit J Radiol.1997; 70 (833):530-532.
[70]杨亚英,宋光义,陈连有等.喉腺样囊性癌C T误诊一例.临床放射学杂志.2002；21(12)：950
[71]Sigal R, Monnet O, de Baere T, Micheau C, Shapeero LG, Julieron M, Bosq J, Vanel D, Piekarski JD, Luboinski B, et al. Adenoid cystic carcinoma of the head and neck:evaluation with MR imaging and clinical-pathologic correlation in 27 patients. Radiology.1992; 184:95-101.
[72]Lee LA, Fang TJ, Li HY,et al. Adenoid cystic carcinoma of the supraglottis mimicking a laryngeal cyst. Otolaryngol Head Neck Surg.2003;129:157-158.
[73]Szanto PA, Luna MA,Tortoledo ME. Histologic grading of adenoid cystic carcinoma of the salivary glands. Cancer.1984;54:1062-1069.
[74]Perzin KH, Gullane P, Clairmont AC. Adenoid cystic carcinoma arising in Salivary glands:a correlation of histologic features and clinical course. Cancer 1978; 42:265-282.
[75]Dodd RL,Slevin NJ:Salivary gland adenoid cystic carcinoma:a review of chemotherapy and molecular therapies.Oral Oncol.2006,42:759-769.
[76]Sharma K, Rathi AK, Khurana N, Mukherji A, Kumar V, Singh K, Bahadur AK.A retrospective study of 18 cases of adenoid cystic cancer at a tertiary care centre in Delhi. Indian J Cancer.2010;47(4):424-429.
[77]Terhaard CH, Lubsen H, Rasch CR, Levendag PC, Kaanders HH, Tjho-Heslinga RE, et al. The role of radiotherapy in the treatment of malignant salivary gland tumors. Int J Radiat Oncol Biol Phys.2005;61:103-111.
[78]Li Q, Xu T, Gao JM, Ye WJ, Gu MF, Hu WH, Wang F, Cai XY.Surgery alone provides long-term survival rates comparable to those of surgery plus postoperative radiotherapy for patients with adenoid cystic carcinoma of the palate. Oral Oncol.2011;47(3):170-173.
[79]周梁,陈小玲,黄维庭等.小涎腺肿瘤的外科治疗.临床耳鼻咽喉头颈外科杂志.2007；21(21)：963-965.
[80]Koopot R, Reyes C, Pifarr(?) R. Multiple pulmonary metastases from adenoid cystic carcinoma of the ceruminous glands of external auditory canal:A case report and review of the literature. J Thorac Cardiovasc Surg.1973;65:909-913.
[81]Creagan ET, Woods JE, Schutt AJ, O'Fallon JR. Cyclophosphamide, Adriamycin, and cis-diamminedichloroplatinum (Ⅱ) in the treatment of advanced nonsquamous cell head and neck cancer. Cancer.1983;52:2007-2010.
[82]Vermorken JB, Verweij J, de Mulder PH, Cognetti F, Clavel M, Rodenhuis S, et al. Epirubicin in patients with advanced or recurrent adenoid cystic carcinoma of the head and neck: A phase II study of the EORTC Head and Neck Cancer Cooperative Group. Ann Oncol.1993;4:785-788.
[83]Gilbert J, Li Y, Pinto HA, et al. Phase II trial of taxol in salivary gland malignancies (E1394):a trial of the Eastern Cooperative Oncology Group. Head Neck.2006;28:197-220.
[84]Van Herpen CM, Locati LD, Buter J, et al. Phase II study on gemcitabine in recurrent and/or metastatic adenoid cystic carcinoma of the head and neck (EORTC 24982). Eur J Cancer.2008;44:2542-2545.
[85]Le Tourneau C, Razak AR, Levy C, Calugaru V, Galatoire O, Dendale R, Desjardins L, Gan HK. Role of chemotherapy and molecularly targeted agents in the treatment of adenoid cystic carcinoma of the lacrimal gland.Br J Ophthalmol.2010; Dec:22.
[86]Papaspyrou G, Hoch S, Rinaldo A, Rodrigo JP, Takes RP, van Herpen C, Werner JA, Ferlito A. Chemotherapy and targeted therapy in adenoid cystic carcinoma of the head and neck:A review.Head Neck.2010;Jul:22.
[87]Wiseman SM, Popat SR, Rigual NR, Hicks WL Jr, Orner JB, Wein RO, McGary CT, Loree TR. Adenoid cystic carcinoma of the paranasal sinuses or nasal cavity:a 40-year review of 35 cases. Ear Nose Throat J.2002;81(8): 510-4,516-7.
[88]李正江唐平章,徐国镇,等.126例涎腺腺样囊性癌的疗效及预后因素.中华放射学杂志.1999；8：204-207.
[89]Oplatek A, Ozer E, Agrawal A, Bapna S, Schuller DE. Patterns of recurrence and survival of head and neck adenoid cystic carcinoma after definitive resection. Laryngoscope.2010; 120:65-70.
[90]Gomez DR, Hoppe BS, Wolden SL, et al. Outcomes and prognostic variables in adenoid cystic carcinoma of the head and neck:a recent experience. Int J Radiat Oncol Biol Phys.2008;70:1365-1372.
[91]Takata T,Kudo Y,Zhao M,et al.Reduced expression of p27(Kip1)protein in relation to salivary adenoid cystic carcinoma metastasis.Cancer.1999,86(6): 928-935.
[92]黄志权,李劲松,陈伟良,等.细胞外基质金属蛋白酶诱导因子表达与唾液腺肿瘤侵袭性的关系.中国口腔颌面外科杂志.2007；5(4)：291-295.
[93]唐峰,王虹,赵为之,等.53例涎腺腺样囊性癌MMP—2和MMP—9表达与神经浸润和淋巴结转移的关系.复旦学报(医学科学版).2001；28(2)：121-123
[94]Yu F,Jiang XZ,Chen WT,et al.Microvessel density and expression ofvascular endothelial growth factor in adenoid cystic carcinoma of salivary gland. Shanghai Kou Qiang Yi Xue.2003;12(6):443-446.
[95]Zhang J,Peng B,Chen X. Expressions of nuclear factor kappaB,inducible nitric oxide synthase,and vascular endothelial growth factor in adenoid cystic carcinoma of salivary glands:correlations with the angiogenesis and clinical outcome. Clin Cancer Res.2005;11(20):7334-7343.
[96]Zhou SH, Wang SQ, Wu QL, et al. Expressionof glucose transporter-1 and-3 in the head and neck carcinoma the correlation of the expression with the biological behaviors. J Otorhinolaryngl Head Neck Surg.2008;70(3):189-194.
[97]Roberts MS,Woods AJ, DaleTC,Van Der Sluijs P, Norman JC. Protein kinase B/Akt acts via glycogen synthase kinase 3 to regulate recycling of alpha v beta 3 and alpha 5 beta 1 integrins.Mol.Cell Biol.2004;24:1505-1515.
[98]Weiner MF,Miranda RN,Bardales RH,Mukunyadzi P,Baker SJ,Korourian S,De Las Casas LE:Diagnostic value of GLUT-limmunoreactivity to distinguish benign from malignant cystic squamous lesions of the head and neck in fine-needle aspiration biopsy material.Diagn Cytopathol.2004,31:294-299.
[99]Hu K,Li SL,Gan YH,Wang CY,Yu GY:Epiregulin promotes migration and invasion of salivary adenoid cystic carcinoma cell line SACC-83 through activation of ERK and Akt.Oral Oncol.2009;45:156-163.
[100]Aleskandarany MA, Rakha EA, Ahmed MA, Powe DG, Ellis 10, Green AR. Clinicopathologic and molecular significance of phospho-Akt expression in early invasive breast cancer. Breast Cancer Res Treat.2010;6:1-10.
[101]Jiang BH,Liu LZ.PI3K/PTEN signaling in tumorigenesis and angiogenesis. Biochim Biophys Acta:Proteins Proteomics.2008; 1784:150-158.
[102]Staal SP.Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2:amplification of AKT1 in a primary human gastric adenocarcinoma.Proc Natl Acad Sci USA.1987;84:5034-5037.
[103]Carpten JD,Faber AL,Horn C,Donoho GP,Briggs SL,Robbins CM,Hostetter G,Boguslawski S,Moses TY,Savage S.Uhlik M,Lin A,Du J,Qian YW,Zeckner DJ,Tucker-Kellogg G,Touch-man J,Patel K,Mousses S,Bittner M,Schevitz R,Lai MH,Blanchard KL,Thomas JE.A transforming mutation in the pleckstrin homology domain of AKT1 in cancer.Nature.2007;448:439-444.
[104]Zimmermann S and MOELLING K: Phosphorylation and regulation of Raf by Akt (ptotein kinase B).Science.1999; 286:1741-1744.
[105]Moelling K,Schad K, Bosse M, Zimmermann S and Schweneker M: Regulation of Raf-Akt Cross-talk. J BIOL Chem.2002;277:31099-31106.
[1]Jacobs SR, Herman CE, Maciver NJ, Wofford JA, Wieman HL, Hammen JJ, Rathmell JC. Glucose Uptake Is Limiting in T Cell Activation and Requires CD28-Mediated Akt-Dependent and Independent Pathways. J Immunol.2008; 180(7):4476-4486.
[2]Vansteenkiste J, Fischer BM, Dooms C, Mortensen J. Positron-emission tomography in prognostic and therapeutic assessment of lung cancer: systematic review. Lancet Oncol.2004; 5(9):531-540.
[3]Tohma T, Okazumi S, Makino H, Cho A, Mochiduki R, Shuto K, Kudo H,Matsubara K,Gunji H, Ochiai T. Relationship between glucose transporter, hexokinase and FDG-PET in esophageal cancer. Hepatogastroenterology.2005; 52(62):486-490.
[4]周水洪,吴求亮,汪审清,范骏.18F氟脱氧葡萄糖代谢功能图像在头颈部肿瘤 诊断中的价值及机理研究.中华医学杂志.2007；87(9)：109-113.
[5]Ling-Fa Li, Shui-Hong Zhou, Kui Zhao, Shen-Qing Wang, Qiu-Liang Wu, Jun Fan, Ke-Jia Cheng, Ling Ling.Clinical Significance of FDG Single-Photon Emission Computed Tomography: Computed Tomography in the Diagnosis of Head and Neck Cancers and Study of Its Mechanism. Cancer Biotherapy & Radiopharmaceuticals.2008; 23(6):701-714.
[6]Kunkel M, Moergel M, Stockinger M, Jeong JH, Fritz G, Lehr HA, Whiteside TL.Overexpression of GLUT-1 is associated with resistance to radiotherapy and adverse prognosis in squamous cell carcinoma of the oral cavity. Oral Oncol.2007;43(8):796-803.
[7]Bussink J, van der Kogel AJ, Kaanders JH. Activation of the PI3-K/AKT pathway and implications for radioresistance mechanisms in head and neck cancer. Lancet Oncol.2008;9(3):288-296.
[8]Doki Y, Takachi K, Ishikawa O, Sasaki Y, Miyashiro I, Ohigashi H, Yano M, Ishihara R, Tsukamoto Y, Nishiyama K, Ishiguro S, Imaoka S.Reduced tumor vessel density and high expression of glucose transporter 1 suggest tumor hypoxia of squamous cell carcinoma of the esophagus surviving after radiotherapy. Surgery.2005;137(5):536-44.
[9]Pedersen MW, Holm S, Lund EL, Hojgaard L, Kristjansen PE.Coregulation of glucose uptake and vascular endothelial growth factor (VEGF) in two small-cell lung cancer (SCLC) sublines in vivo and in vitro. Neoplasia.2001(1); 3:80-87.
[10]Zhou SH, Fan J, Chen XM, Cheng KJ, Wang SQ. Inhibition of cell proliferation and glucose uptake in human laryngeal carcinoma cells by antisense oligonucleotides against glucose transporter-1. Head and Neck.2009; 31(12):1624-1633.
[11]Michel F, Attal-Bonnefoy G, Mangino G, Mise-Omata S, Acuto O. CD28 as a molecular amplifier extending TCR ligation and signaling capabilities. Immunity.2001; 15:935-945.
[12]Turner M, Billadeau DD. VAV proteins as signal integrators for multi-subunit immune-recognition receptors. Nat Rev Immunol.2002;2(7):476-486.
[13]Melstrom LG, Salabat MR, Ding XZ, Milam BM, Strouch M, Pelling JC, et al.Apigenin Inhibits the GLUT-1 Glucose Transporter and the Phosphoinositide 3-Kinase/Akt Pathway in HumanPancreatic Cancer Cells. Pancreas.2008;37(4):426-431.
[14]Wieman HL, Wofford JA, Rathmell JC. Cytokine stimulation promotes glucose uptake via PI3K/Akt regulation of Glutl activity and trafficking. Mol Biol Cell.2007;18(4):1437-1446.
[15]Elstrom RL,Bauer DE, Buzzai M, Karnauskas R,Harris MH, Plas DR, Zhuang H, Cinalli RM, Alavi A, Rudin CM, Thompson CB. Akt Stimulates Aerobic Glycolysis in Cancer Cells. Cancer Res.2004;64(6):3892-3899.
[16]Kunkel M, Reichert TE, Benz P, Bartenstein P, Wagner W, Whiteside TL. Overexpression of Glut-1 and increased glucose metabolism in the tumor are associated with poor prognosis in oral squamous cell carcinoma. Cancer.2003; 97:1015-1024.
[17]Oliver RJ,Woodwards RTM, Sloan P, Thakker NS, Stratford IJ, Airley RE. Prognostic value of facilitative glucose transporter Glut-1 in oral squamous cell carcinoma treated by surgical resection: results of EORTC translational research fund studies. Eur J Cancer 2004;40(4):503-507.
[18]Brophy S, Sheehan KM, McNamara DA, Deasy J, Bouchier-Hayes DJ, Kay EW. GLUT-1 expression and response to chemoradiotherapy in rectal cancer. Int J Cancer.2009;125(12):2778-82.
[19]Markowska J, Grabowski JP, Tomaszewska K, Kojs Z, Pudelek J, Skrzypczak M, Sobotkowski J, Emerich J, Olejek A, Filas V. Significance of hypoxia in uterine cervical cancer. Multicentre study. Eur J Gynaecol Oncol.2007;28(5): 386-388.
[20]Sax JK, Eldeiry WS. p53 downstream targets and chemosensitivity. Cell Death Differ.2003;10(4):413-417.
[21]Schuurbiers OC, Kaanders JH, Van der Heijden HF, Dekhuijzen RP, Oyen WJ, Bussink J.The PI3-K/AKT-pathway and radiation resistance mechanisms in non-small cell lung cancer. J Thorac Oncol.2009;4(6):761-767.
[22]Gupta AK, McKenna WG, Weber CN, Feldman MD, Goldsmith JD, Mick R, Machtay M, Rosenthal DI, Bakanauskas VJ, Cerniglia GJ, Bernhard EJ, Weber RS, Muschel RJ. Local recurrence in head and neck cancer: relationship to radiation resistance and signal transduction. Clin Cancer Res.2002; 8(3):885-892.
[23]Soderlund K, Perez-Tenorio G, Stal O. Activation of the phosphatidylinositol 3-kinase/Akt pathway prevents radiation-induced apoptosis in breast cancer cells. Int J Oncol.2005;26(1):25-32.
[24]Skvortsova I, Skvortsov S, Stasyk T, Raju U, Popper BA, Schiestl B, von Guggenberg E, Neher A, Bonn GK, Huber LA, Lukas P.Intracellular signaling pathways regulating radioresistance of human prostate carcinoma cells. Proteomics.2008;8(21):4521-4533.
[25]Gupta AK, Bakanauskas VJ, Cerniglia GJ, Cheng Y, Bernhard EJ, Muschel RJ, McKenna WG. The Ras radiation resistance pathway. Cancer Res.2001; 61 (10):4278-4282.
[26]McKenna WG, Muschel RJ, Gupta AK, Hahn SM, Bernhard EJ. The RAS signal transduction pathway and its role in radiation sensitivity. Oncogene. 2003; 22(37):5866-5875.
[27]Toulany M, Kasten-Pisula U, Brammer I, Wang S, Chen J, Dittmann K, Baumann M, Dikomey E, Rodemann HP. Blockage of epidermal growth factor receptor-phosphatidylinositol 3-kinase-AKT signaling increases radiosensitivity of K-RAS mutated human tumor cells in vitro by affecting DNA repair. Clin Cancer Res.2006;12(13):4119-4126.
[28]O'Driscoll M, Jeggo PA. The role of double-strand break repair insights from human genetics. Nat Rev Genet.2006;7(1):45-54.
[29]Sakata K, Someya M, Matsumoto Y, Hareyama M. Ability to repair DNA double-strand breaks related to cancer susceptibility and radiosensitivity. Radiat Med.2007;25(9):433-438.
[30]Zhuang W, Qin Z, Liang Z.The role of autophagy in sensitizing malignant glioma cells to radiation therapy. Acta Biochim Biophys Sin (Shanghai). 2009;41(5):341-351.
[31]Newton HR. Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors. Part 2:PI3K/Akt/PTEN, mTOR,SHH/ PTCH and angiogenesis. Expert rev anticancer Ther.2004;4 (1):105-128.
[32]Weinert T. A DNA damage checkpoint meets the cell cycle engine. Science.1997; 277(5331):1450-1451.
[33]Virsik-Kopp P, Hofman-Huther H, Rave-Frank M, Schmidberger H. The effect of wortmannin on radiation-induced chromosome aberration formation in the radioresistant tumor cell line WiDr. Radiat Res.2005; 164(2):148-156.
[34]Fuhrman CB, Kilgore J, LaCoursiere YD, Lee CM, Milash BA, Soisson AP, Zempolich KA. Radiosensitization of cervical cancer cells via double-strand DNA break repair inhibition. Gynecol Oncol.2008;110(1):93-98.
[35]Gao X, Xing D.Molecular mechanisms of cell proliferation induced by low power laser irradiation. J Biomed Sci.2009; 16:4.
[36]傅深,蒋国,刘泰福PI3K/Akt生存信号转导通路在肿瘤放射生物学中的意义.肿瘤.2006；26：298-301.
[37]Numico G, Russi EG, Colantonio I, Lantermo RA, Silvestris N, Vitiello R, Comino A, Abrate M, Zavattero C, Melano A, Merlano M.EGFR status and prognosis of patients with locally advanced head and neck cancer treated with chemoradiotherapy. Anticancer Res.2010;30(2):671-676.
[38]McKenna WG, Muschel RJ, Gupta A, Hahn S, Bernhard EJ.Signaling inhibition with radiation in colorectal cancer: clinical trials. Semin Oncol. 2003;30(3 Suppl 6):56-67.
[39]Kim CS, Kim JK, Nam SY, Yang KH, Jeong M, Kim HS, Kim CS, Jin YW, Kim J. Low-dose radiation-induced senescent stromal fibroblasts render nearby breast cancer cells radioresistant. Mol Cells.2007;24(3):424-430.
[40]Vincenzi B, Zoccoli A, Pantano F, Venditti O, Galluzzo S. Cetuximab:from bench to bedside.Curr Cancer Drug Targets.2010;10(1):80-95.
[41]Bouche O, Beretta GD, Alfonso PG, Geissler M.The role of anti-epidermal growth factor receptor monoclonal antibody monotherapy in the treatment of metastatic colorectal cancer. Cancer Treat Rev.2010;36 (Suppl 1):S1-10.
[42]Lu Z, Cox-Hipkin MA, Windsor WT, Boyapati A.3-phosphoinositide-dependent protein kinase-1 regulates proliferation and survival of cancer cells with an activated mitogen-activated protein kinase pathway. Mol Cancer Res. 2010;8(3):421-432.
[43]Kong D, Yamori T.Phosphatidylinositol 3-kinase inhibitors:promising drug candidates for cancer therapy. Cancer Sci.2008;99(9):1734-1740.
[44]Prevo R, Deutsch E, Sampson O, Diplexcito J, Cengel K, Harper J, O'Neill P, McKenna WG, Patel S, Bernhard EJ. Class I PI3 kinase inhibition by the pyridinylfuranopyrimidine inhibitor PI-103 enhances tumor radiosensitivity. Cancer Res.2008;68(14):5915-5923.
[45]Shinohara ET, Maity A. Increasing sensitivity to radiotherapy and chemotherapy by using novel biological agents that alter the tumor microenvironment. Curr Mol Med.2009;9(9):1034-1045.
[46]Fan S, Ma YX, Gao M, Yuan RQ, Meng Q, Goldberg ID, Rosen EM.The multisubstrate adapter Gabl regulates hepatocyte growth factor (scatter factor)-c-Met signaling for cell survival and DNA repair. Mol Cell Biol. 2001;21(15):4968-4984.
[47]El-Deiry WS. Akt takes centre stage in cell-cycle deregulation. Nat Cell Biol.2001;3(3):E71-73.
[48]Fujita Y, Kato I, Iwai S, Ono K, Suzuki M, Sakurai Y, Ohnishi K, Ohnishi T, Yura Y. Role of p53 mutation in the effect of boron neutron capture therapy on oral squamous cell carcinoma. Radiat Oncol.2009; 4:63.
[49]Levav-Cohen Y, Haupt S, Haupt Y. Mdm2 in growth signaling and cancer. Growth Factors.2005;23(3):183-192.
[50]Shin S, Asano T, Yao Y, Zhang R, Claret FX, Korc M, Sabapathy K, Menter DG, Abbruzzese JL, Reddy SA. Activator protein-1 has an essential role in pancreatic cancer cells and is regulated by a novel Akt-mediated mechanism.Mol Cancer Res.2009;7(5):745-754.
[51]Mukherji A, Janbandhu VC, Kumar V. HBx protein modulates PI3K/Akt pathway to overcome genotoxic stress-induced destabilization of cyclin D1 and arrest of cell cycle.Indian J Biochem Biophys.2009;46(1):37-44.
[52]Kandel ES,Hay N.The regulation and activaties of the multifunctional serine/threonine kinase Akt/PKB. Exp Cell Res.1999;253(1):210-229.
[53]Muise-Helmericks RC, Grimes HL, Bellacosa A, Malstrom SE, Tsichlis PN, Rose N. Cyclin D expression is controlled post-transcriptionally via a phosphatidylinositol 3-kinase/Akt-dependent pathway. J Biol Chem.1998; 273(45):29864-29872.
[54]Zhou BP, Liao Y,Xia W, Spohn B,Lee MH and Hung MC. Cytoplasmic localization of p21Cipl/WAFl by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nat Cell Biol.2001;3(3):245-252.
[55]Webster L, Hodgkiss RJ, Wilson GD. Cell cycle distribution of hypoxia and progression of hypoxic tumour cells in vivo. Br J Cancer.1998;77(2):227-234.
[56]Hoogsteen IJ, Marres HA, Wijffels KI, Rijken PF, Peters JP, van den Hoogen FJ, Oosterwijk E, van der Kogel AJ, Kaanders JH.Colocalization of carbonic anhydrase 9 expression and cell proliferation in human head and neck squamous cell carcinoma.Clin Cancer Res.2005;11(1):97-106.
[57]Harris AL.Hypoxia—a key regulatory factor of in tumour growth.Nat Re Cancer.2002;2(1):38-47.
[58]Koumenis C.ER stress, hypoxia tolerance and tumor progression.Curr Mol Med.2006;6(1):55-69.
[59]Brizel DM,Sibley GS,Prosnitz LR,Scher RL,Dewhirst MW.Tumour hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys.1997;38(3):285-289.
[60]Nordsmark M.Bentzen SM,Rudat V, Brizel D, Lartigau E, Stadler P, Becker A, Adam M, Molls M, Dunst J, Terris DJ, Overgaard J.Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy.An international multi-center study.Radiother Oncol.2005;77(1):18-24.
[61]Kaanders JH,Wijffels KI,Marres HA, Ljungkvist AS, Pop LA, van den Hoogen FJ, de Wilde PC, Bussink J, Raleigh JA, van der Kogel AJ. Pimonidazole binding and tumor vascularity predict for treatment outcome in head and neck cancer.Cancer Res.2002;62(23):7066-7074.
[62]Semenza GL.HIF-1:mediator of physiological and pathophysiological responses to hypoxia.J Appl Physiol.2000;88(4):1474-1480.
[63]Lal A,Peters H,St Croix B, Haroon ZA, Dewhirst MW, Strausberg RL, Kaanders JH, van der Kogel AJ, Riggins GJ..Transcriptional response to hypoxia in human tumors.J Natl Cancer Inst.2001;93(17):1337-1343.
[64]Zlobec I,Steele R,Compton CC.VEGF as a predictive marker of rectal tumor response to preoperative radiotherapy.Cancer.2005;104(11):2517-2521.
[65]Kufe DW,Pollock RE,Weichselbaum RR.Bast RC,Gansler TS,Holland JF,Free E.Cancer medicine.Hamilton(Canada).BC Decker,2003.
[66]Opavsky R,Pastorekova S, Zelnik V,Gibadulinova A,Stanbridge EJ,Zavada J, Gibadulinova A, Stanbridge EJ, Zavada J, Kettmann R, Pastorek J.Human MN/CA9 gene,a novel member of the carbonic anhydrase family:structure and exon to protein domainrelationships.Genomics.1996;33(3):480-487.
[67]Vordermark D,Brown JM. Endogenous markers of tumor hypoxia predictors of clinical radiation resistance.Strahlenther Onkol.2003;179(12):801-811.
[68]Koukourakis MI,Giatromanolaki A,Sivridis E,Simopoulos K,Pastorek J,Wykoff CC, Gatter KC, Harris AL..Hypoxia-regulated carbonic anhydrase-9(CA9)relates to poor vascularization and resistance of squamous cell head and neck cancer to chemoradiotherapy. Clin Cancer Res.2001;7(11):3399-3403.
[69]Hui EP.Chan AT,Pezzella F,Turley H,To KF,Poon TC, Turley H, To KF, Poon TC, Zee B, Mo F, Teo PM, Huang DP, Gatter KC, Johnson PJ, Harris AL.Coexpression of hypoxia-inducible factors 1 alpha and 2alpha,carbonic anhydrase Ⅸ,and vascular endothelial growth factor in nasopharyngealcarcinoma and relationship to survival.Clin Cancer Res.2002;8(8):2595-2604.
[70]Zhong H,Chiles K,Feldser D, Laughner E, Hanrahan C, Georgescu MM, Simons JW, Semenza GL.Modulation of hypoxia-inducible factor 1 alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/ PTEN/AKT/FRAP pathway in human prostate cancer cells:implications for tumor angiogenesis and therapeutics.Cancer Res.2000; 60(6):1541-1545.
[71]Dragowska WH,Verreault M,Yapp DT, Warburton C, Edwards L, Ramsay EC, Huxham LA, Minchinton AI, Gelmon K, Bally MB.Decreased levels of hypoxic cells in gefitinib treated ER(+)HER-2 overexpressing MCF-7 breast cancer tumors are associated with hyperactivation of the mTOR pathway:therapeutic implications for combination therapy with rapamycin. Breast Cancer Res Treat.2007;106(3):319-331.
[72]Krause M,Ostermann G,Petersen C, Yaromina A, Hessel F, Harstrick A, van der Kogel AJ, Thames HD, Baumann M.Decreased repopulation as well as increased reoxygenation contribute to the improvement in local control after targeting of the EGFR by C225 during fractionated irradiation.Radiother Oncol. 2005;76(2):162-167.
[73]Edwards E. Phosphatidylinositol 3-kinase/Akt signaling in the response of vascular endothelium to Ionizing radiation. Cancer Res.2002; 62 (16):4671-4677.
[74]Fang J,Xia C,Cao Z, Zheng JZ, Reed E, Jiang BH. Apigenin inhibits VEGF and HIF-1 expression via PI3K/AKT/p70S6K1 and HDM2/p53 pathways. FASEB J.2005;19(3):342-353.
[75]Skinner HD, Zheng JZ,Fang J, Agani F, Jiang BH. Vascular endothelial growth factor transcriptional activation is mediated by hypoxia-inducible factor lalpha, HDM2, and p70S6K1 in response to phosphatidylinositol 3-kinase/AKT signaling. J Biol Chem.2004;279(44):45643-45651.
[76]Bussink J,Kaanders JH,van der Kogel AJ.Tumor hypoxia at the microregional level:clinical relevance and predictive value of exogenous and endogenous hypoxic cell markers.Radiother Oncol.2003;67(l):3-15.
[77]Gort EH, Groot AJ, Derks van de Ven TL, van der Groep P, Verlaan I, van Laar T, van Diest PJ, van der Wall E, Shvarts A.Hypoxia-inducible factor-la expression requires PI3-kinase activity and correlates with Aktl phosphorylation in invasive breast carcinomas. Oncogene.2006;25(45): 6123-6127.
[78]Blancher C,Moore JW, Robertson N, Harris AL. Effects of ras and von Hippel-Lindau (VHL) gene mutations on hypoxia-inducible factor (HIF)-lalpha, HIF-2alpha, and vascular endothelial growth factor expression and their regulation by the phosphatidylinositol 3'-kinase/Akt signaling pathway. Cancer Res.2001;61(19):7349-7355.
[79]Kan O,Baldwin SA,Whetton AD. Apoptosis is regulated by the rate of glucose transport in an interleukin 3 dependent cell line. J ExpMed.1994;180(3):917-923.
[80]Edinger AL,Thompson CB.Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake. Mol Biol Cell.2002;13(7):2276-2288.
[81]Rathmell JC, Fox CJ, Plas DR, Hammerman PS, Cinalli RM,Thompson CB.Akt-directed glucose metabolism can prevent Bax conformation change and promote growth factor-independent survival. Mo lCell Biol.2003;23(8): 7315-7328.
[82]Plas DR, Talapatra S, Edinger AL, Rathmell JC, Thompson CB. Akt and Bcl-xL promote growth factor-independent survival through distinct effects on mitochondrial physiology.J Biol Chem.2001;276(15):12041-12048.
[83]Zhao Y, Altman BJ, Coloff JL, Herman CE,J acobs SR, Wieman HL, Wofford JA, Dimascio LN, Ilkayeva O, Kelekar A, Reya T, Rathmell JC. Glycogen synthase kinase 3alpha and 3beta mediate a glucose-sensitive antiapoptotic signaling pathway to stabilize Mel-1..Mol Cell Biol.2007;27(12):4328-4339.
[84]Jope RS, Johnson GV. The glamour and gloom of glycogen synthase kinase-3.Trends BiochemSci.2004;29(2):95-102.
[85]Roberts MS, Woods AJ, Dale TC, Van Der Sluijs P, Norman JC.Protein kinase B/Akt acts via glycogen synthase kinase 3 to regulate recycling of alpha v beta 3 and alpha 5 beta 1 integrins. Mol Cell Biol.2004;24(4):1505-1515.
[86]Doughty CA, Bleiman BF, Wagner DJ, Dufort FJ, Mataraza JM, Roberts MF, Chiles TC. Antigen receptor-mediated changes in glucose metabolism in B lymphocytes:role of phosphatidylinositol 3-kinase signaling in the glycolytic control of growth.Blood.2006;107(11):4458-4465.
[87]Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC, Plas DR, Elstrom RL, June CH, Thompson CB. The CD28 signaling pathway regulates glucose metabolism. Immunity.2002;16(6):769-777.
[88]Bentley J, Itchayanan D, Barnes K, McIntosh E, Tang X, Downes CP, Holman GD, Whetton AD, Owen-Lynch PJ, Baldwin SA.Interleukin-3-mediated cell survival signals include phosphatidylinositol 3-kinase-dependent translocation of the glucose transporter GLUT1 to the cell surface. J Biol Chem.2003; 278(41):39337-39348.
[89]Barata JT, Cardoso AA, Nadler LM, Boussiotis VA.Interleukin-7 promotes survival and cell cycle progression of T-cell acute lymphoblastic leukemia cells by down-regulating the cyclin-dependent kinase inhibitor p27(kip1). Blood.2001;98(5):1524-1531.
[90]Samih N,Hovsepian S,Aouani A, Lombardo D, Fayet G. Glut-1 translocation in FRTL-5 thyroid cells:role of phosphatidylinositol 3-kinase and N-glycosylation. Endrocrinology.2000;141(1):4146-4155.
[91]Clarke JF, Young PW, Yonezawa K, et al.Inhibition of the translocationof GLUT1 and GLUT4 in 3T3-L1 cells by the phosphatidylinosit13-kinase inhibitor, wortmannin.Biochem J.1994;300:631-635.
[92]Ding XZ, Fehsenfeld DM,Murphy LO, Permert J, Adrian TE. Physiological concentrations of insulin augment pancreatic cancer cell proliferation and glucose utilization by activating MAP kinase, PI3 kinase and enhancing GLUT-1 expression. Pancreas.2000;21(3):310-320.
[93]Okada T, Kawano Y, Sakakibara T, Hazeki O, Ui M.. Essential role of phosphatidylinositol 3-kinase in insulin-induced glucose transport and anti-lipolysis in rat adipocytes.Studies with a selective inhibitor wortmannin. J Biol Chem.1994;269(5):3568-3573.
[94]Barthel A, Okino ST, Liao J, Nakatani K, Li J, Whitlock JP Jr, Roth RA.Regulation of GLUT1 Gene Transcription by the Serine/Threonine Kinase Akt1. J Biol Chem.1999;274(29):20281-20286.