AnnexinⅡ和TGF-β_1信号分子在韧带样型纤维瘤病中的表达研究
摘要
背景
韧带样型纤维瘤病(Desmoid-type fibromatosis，DTF)，也称侵袭性纤维瘤病，是发生于深部软组织的克隆性纤维母细胞增生性肿瘤，具有浸润性生长、局部复发但不转移的特点。其治疗主要通过手术扩大切除及术后辅以适当的放疗和／或化疗，但术后局部复发率仍很高，需要多次手术。分子靶向治疗作为肿瘤治疗的新手段已显示其重要的临床价值。AnnexinⅡ是新近发现的纤溶酶原(plasminogen，PLG)和组织纤溶酶原激活物(tissue plasmin activator，tPA)的共同受体，涉及乳腺癌等实体肿瘤的转移。最近发现AnnexinⅡ可以和靶向药物血管抑素结合，可能是血管抑素抑制肿瘤进展的重要靶点。TGF-β_1是一种多功能细胞因子，在调节细胞增殖、分化和凋亡等方面发挥着重要作用。我们先前的研究表明TGF-β_1参与结节性筋膜炎的发病，发现其除涉及肌纤维母细胞的分化，可能还参与血管形成。检索Pubmed和万方数据库(1980-2008年)均未见DTF中AnnexinⅡ的研究；虽然已有个别文献报道TGF-β_1在DTF中的表达，但它在DTF发病中的作用尚不清楚。
目的：
1．了解AnnexinⅡ是否参与DTF的发病，进一步了解其是否与DTF的侵袭性相关，为今后临床开展血管抑素靶向治疗DTF提供实验依据。
2．证实TGF-β_1在DTF中表达，进一步了解其是否与DTF中肿瘤细胞分化、间质构建及血管新生相关。
方法：
选取手术切除后石蜡包埋DTF 34例为研究对象，应用免疫组织化学染色方法，分别检测(1)AnnexinⅡ在DTF和周围正常组织中的表达及分布，进一步分析其在DTF浸润区和非浸润区的表达及分布；(2)TGF-β_1和TGF-βRI在DTF和周围正常组织中的表达及分布；(3)用α-SMA标记肌纤维母细胞，用CD31标记肿瘤血管，观察分析TGF-β_1／TGF-βRI与肌纤维母细胞分化、fibronectin表达和MVD的关系；并检测VEGF在DTF中的表达，分析它与MVD的关系。
结果：
1．AnnexinⅡ在DTF中的表达主要分布于肿瘤细胞和内皮细胞，阳性率为85．3％(29／34)，阳性表达在浸润区尤为突出。AnnexinⅡ在肿瘤组织中的平均阳性细胞率(61．34％±11．08％)显著高于周围组织(19．75％±4．59％)(P<0．05)；DTF肿瘤组织中，浸润区平均阳性细胞率(65．22％±14．15％)显著高于非浸润区(46．75±9．01)(P<0．05)。
2．DTF肿瘤组织中，TGF-β_1阳性率为79．4％，其中+为29．4％(10／34)，++26．5％(9／34)，+++23．5％(8／34)；TGF-βRI阳性率82．3％，其中+为29．4％(10／34)，++23．5％(8／34)，+++29．4％(10／34)；TGF-β_1和TGF-βTI在肿瘤组织和周围组织中的表达水平均有显著性差异(P<0．05)；TGF-β_1和TGF-βRI表达水平之间呈正相关(P<0．05)。
3．DTF肿瘤组织中可见α-SMA的表达，阳性率为67．6％，其中+为14．7％(5／34)，++44．1％(15／34)，+++8．8％(3／34)；肿瘤细胞中TGF-βRI与α-SMA表达水平之间呈正相关(P<0．05)。
4．DTF肿瘤细胞和间质中可见fibronectin的表达，阳性率为100％。DTF肿瘤细胞中TGF-βRI与fibronectin表达水平之间呈正相关(P<0．05)。
5．VEGF主要表达于DTF肿瘤细胞，血管内皮呈不连续弱阳性着色，阳性率为88．2％。肿瘤组织MVD为9．14±2．08。TGF-β_1和VEGF平均阳性细胞率与MVD之间均呈正相关(P<0．05)。
结论：
1．AnnexinⅡ在DTF中过度表达，可能参与DTF的发病，推测其通过介导纤溶酶原激活途径涉及肿瘤的浸润性生长。本研究显示DTF中AnnexinⅡ弥漫强阳性表达，为进一步尝试应用血管抑素靶向治疗DTF提供了实验依据。
2．TGF-β_1和TGF-βRI在DTF中均过度表达，可能参与DTF的发病，DTF肿瘤细胞中可能存在TGF-β_1自分泌环。
3．DTF肿瘤细胞由纤维母细胞和肌纤维母细胞构成。TGF-β_1／TGF-βRI可能参与诱导部分肿瘤细胞的肌纤维母细胞分化、间质构建及肿瘤血管新生。
4．过度表达的VEGF可能也参与诱导肿瘤血管新生。结合我们和以往学者的研究结果，推测其肿瘤细胞VEGF表达的上调可能与TGF-β_1／TGF-βRI途径调节有关。
Background
Desmoid-type fibromatoses, also known as aggressive fibromatosis, are locally aggressive clonal fibroblastic proliferations that arise in deep soft tissues and are characterized by infiltrative growth and a tendency toward local recurrence, but an inability to metastasise. Treatment of patients with DTF usually involves surgery with the goal of complete local excision of the tumor. AnnexinⅡis a well established receptor for plasminogen and tissue plasmin activator, and may be a attractive target for anti-breast cancer therapy since it has been shown to bind to angiostatin. No study about the expression of AnnexinⅡin DTF was found in Pubmed and Wangfang database (1980-2008). TGF-β_1 is a multifunctional protein which plays an important role in cell proliferation, differentiation and apoptosis. It has been found in our previous study that TGF-β_1 may involve inducing transdifferentiaton of fibroblast to myofibroblast and angiogenesis in nodular fasciitis. Although TGF-β_1 expression in DTF has been demonstrated in recent two papers, its role in DTF is still not well known.
Objectives:
1. To investegate the expression of AnnexinⅡin DTF and its possible role in DTF.
2. To confirm the expression of TGF-β_1 in the DTF, and then to explore its possible role in DTF.
Methods:
The 34 cases of DTF tumor and matched surrouding tissues were studied byimmunohistochemistry stainings. The expressions of AnnexinⅡ, TGF-β_1/TGF-βRIand VEGF were examined, and the relationship between their expressions andmyofiberblast differentiaton, stroma production and angiogenesis in DTF wasestimated.
Results:
1. AnnexinⅡwas expressed in 67.6% (29/34) cases of DTF. The expression was markedly in infiltrating region. The average percentage of AnnexinⅡpositive cells (61.34%±11.08%) in DTF was significantly higher than that (19.75%±4.59 %) of surrounding tissues(P<0.05). Within the positive cases of DTF, the average percentage of AnnexinⅡpositive cells in infiltrating areas (65.22%±14.15%) was significantly higher than that in non-infiltrated ones(46.75±9.01)(P<0.05).
2. TGF-β_1 was detected in 79.4%(27/ 34) DTF, with a different expressing level [+ in 29.4% (10/34), ++ in 26.5%(9/34),and +++ in 23.5% (8/34) respectively]. TGF-βRI was detected in 82.3% DTF[+ in 29.4%(10/34), ++ in 23.5% (8/34), and +++ in 29.4% (10/34) respectively]. There was a significant difference between the expression levels of both of TGF-β_1 and TGF-βRI in DTF and those of surrounding tissues (P<0.05) .
3. 67.6% (23/34) cases of DTF shownα-SMA positive in the tumor spindle cells [+ in 14.7% (5/34), ++ in 44.1%(15/34), and +++ in 38.8%(3/34)]. There was a positive correlation between the expression level ofα-SMA and that of TGF-βRI in DTF (P<0.05).
4. Fibronectin was demonstrated in all cases of DTF. There was a positive correlation between the expression level of fibronectin and that of TGF-βRI in DTF (P<0.05).
5. The MVD in DTF was 9.14±2.08.VEGF positive spindle cells and endothelium were found in 88.2%(30/34)DTF. There was a positive correlation between MVD and the average percentage of both VEGF and TGF-β1 positive cells
Conclusion:
1. There is a overexpression of AnnexinⅡin DTF. AnnexinⅡmay participated in the development of DTF, possibly in promoting the infiltrative growth of tumour cells by mediating plasminogen activation pathway. AnnexinⅡreactivity may be the basis of a new attractive target for anti-DTF therapy.
2. Overexpressions of both TGF-β_1 and TGF-βRI in DTF indicate that TGF-β_1 may participated in the development of DTF. The results in our study suggest it might envolved in neoplastic myofiberblast differentiaton, stroma production and angiogenesis in DTF.
3. VEGF overexpression is present in DTF. Diffuse and strong VEGF reactivity in DTF surggests it may be another target for anti-angiogenic and anti-DTF therapies.
韧带样型纤维瘤病(Desmoid-type fibromatosis，DTF)，也称侵袭性纤维瘤病，是发生于深部软组织的克隆性纤维母细胞增生性肿瘤，具有浸润性生长、局部复发但不转移的特点。其治疗主要通过手术扩大切除及术后辅以适当的放疗和／或化疗，但术后局部复发率仍很高，需要多次手术。分子靶向治疗作为肿瘤治疗的新手段已显示其重要的临床价值。AnnexinⅡ是新近发现的纤溶酶原(plasminogen，PLG)和组织纤溶酶原激活物(tissue plasmin activator，tPA)的共同受体，涉及乳腺癌等实体肿瘤的转移。最近发现AnnexinⅡ可以和靶向药物血管抑素结合，可能是血管抑素抑制肿瘤进展的重要靶点。TGF-β_1是一种多功能细胞因子，在调节细胞增殖、分化和凋亡等方面发挥着重要作用。我们先前的研究表明TGF-β_1参与结节性筋膜炎的发病，发现其除涉及肌纤维母细胞的分化，可能还参与血管形成。检索Pubmed和万方数据库(1980-2008年)均未见DTF中AnnexinⅡ的研究；虽然已有个别文献报道TGF-β_1在DTF中的表达，但它在DTF发病中的作用尚不清楚。
目的：
1．了解AnnexinⅡ是否参与DTF的发病，进一步了解其是否与DTF的侵袭性相关，为今后临床开展血管抑素靶向治疗DTF提供实验依据。
2．证实TGF-β_1在DTF中表达，进一步了解其是否与DTF中肿瘤细胞分化、间质构建及血管新生相关。
方法：
选取手术切除后石蜡包埋DTF 34例为研究对象，应用免疫组织化学染色方法，分别检测(1)AnnexinⅡ在DTF和周围正常组织中的表达及分布，进一步分析其在DTF浸润区和非浸润区的表达及分布；(2)TGF-β_1和TGF-βRI在DTF和周围正常组织中的表达及分布；(3)用α-SMA标记肌纤维母细胞，用CD31标记肿瘤血管，观察分析TGF-β_1／TGF-βRI与肌纤维母细胞分化、fibronectin表达和MVD的关系；并检测VEGF在DTF中的表达，分析它与MVD的关系。
结果：
1．AnnexinⅡ在DTF中的表达主要分布于肿瘤细胞和内皮细胞，阳性率为85．3％(29／34)，阳性表达在浸润区尤为突出。AnnexinⅡ在肿瘤组织中的平均阳性细胞率(61．34％±11．08％)显著高于周围组织(19．75％±4．59％)(P<0．05)；DTF肿瘤组织中，浸润区平均阳性细胞率(65．22％±14．15％)显著高于非浸润区(46．75±9．01)(P<0．05)。
2．DTF肿瘤组织中，TGF-β_1阳性率为79．4％，其中+为29．4％(10／34)，++26．5％(9／34)，+++23．5％(8／34)；TGF-βRI阳性率82．3％，其中+为29．4％(10／34)，++23．5％(8／34)，+++29．4％(10／34)；TGF-β_1和TGF-βTI在肿瘤组织和周围组织中的表达水平均有显著性差异(P<0．05)；TGF-β_1和TGF-βRI表达水平之间呈正相关(P<0．05)。
3．DTF肿瘤组织中可见α-SMA的表达，阳性率为67．6％，其中+为14．7％(5／34)，++44．1％(15／34)，+++8．8％(3／34)；肿瘤细胞中TGF-βRI与α-SMA表达水平之间呈正相关(P<0．05)。
4．DTF肿瘤细胞和间质中可见fibronectin的表达，阳性率为100％。DTF肿瘤细胞中TGF-βRI与fibronectin表达水平之间呈正相关(P<0．05)。
5．VEGF主要表达于DTF肿瘤细胞，血管内皮呈不连续弱阳性着色，阳性率为88．2％。肿瘤组织MVD为9．14±2．08。TGF-β_1和VEGF平均阳性细胞率与MVD之间均呈正相关(P<0．05)。
结论：
1．AnnexinⅡ在DTF中过度表达，可能参与DTF的发病，推测其通过介导纤溶酶原激活途径涉及肿瘤的浸润性生长。本研究显示DTF中AnnexinⅡ弥漫强阳性表达，为进一步尝试应用血管抑素靶向治疗DTF提供了实验依据。
2．TGF-β_1和TGF-βRI在DTF中均过度表达，可能参与DTF的发病，DTF肿瘤细胞中可能存在TGF-β_1自分泌环。
3．DTF肿瘤细胞由纤维母细胞和肌纤维母细胞构成。TGF-β_1／TGF-βRI可能参与诱导部分肿瘤细胞的肌纤维母细胞分化、间质构建及肿瘤血管新生。
4．过度表达的VEGF可能也参与诱导肿瘤血管新生。结合我们和以往学者的研究结果，推测其肿瘤细胞VEGF表达的上调可能与TGF-β_1／TGF-βRI途径调节有关。
Background
Desmoid-type fibromatoses, also known as aggressive fibromatosis, are locally aggressive clonal fibroblastic proliferations that arise in deep soft tissues and are characterized by infiltrative growth and a tendency toward local recurrence, but an inability to metastasise. Treatment of patients with DTF usually involves surgery with the goal of complete local excision of the tumor. AnnexinⅡis a well established receptor for plasminogen and tissue plasmin activator, and may be a attractive target for anti-breast cancer therapy since it has been shown to bind to angiostatin. No study about the expression of AnnexinⅡin DTF was found in Pubmed and Wangfang database (1980-2008). TGF-β_1 is a multifunctional protein which plays an important role in cell proliferation, differentiation and apoptosis. It has been found in our previous study that TGF-β_1 may involve inducing transdifferentiaton of fibroblast to myofibroblast and angiogenesis in nodular fasciitis. Although TGF-β_1 expression in DTF has been demonstrated in recent two papers, its role in DTF is still not well known.
Objectives:
1. To investegate the expression of AnnexinⅡin DTF and its possible role in DTF.
2. To confirm the expression of TGF-β_1 in the DTF, and then to explore its possible role in DTF.
Methods:
The 34 cases of DTF tumor and matched surrouding tissues were studied byimmunohistochemistry stainings. The expressions of AnnexinⅡ, TGF-β_1/TGF-βRIand VEGF were examined, and the relationship between their expressions andmyofiberblast differentiaton, stroma production and angiogenesis in DTF wasestimated.
Results:
1. AnnexinⅡwas expressed in 67.6% (29/34) cases of DTF. The expression was markedly in infiltrating region. The average percentage of AnnexinⅡpositive cells (61.34%±11.08%) in DTF was significantly higher than that (19.75%±4.59 %) of surrounding tissues(P<0.05). Within the positive cases of DTF, the average percentage of AnnexinⅡpositive cells in infiltrating areas (65.22%±14.15%) was significantly higher than that in non-infiltrated ones(46.75±9.01)(P<0.05).
2. TGF-β_1 was detected in 79.4%(27/ 34) DTF, with a different expressing level [+ in 29.4% (10/34), ++ in 26.5%(9/34),and +++ in 23.5% (8/34) respectively]. TGF-βRI was detected in 82.3% DTF[+ in 29.4%(10/34), ++ in 23.5% (8/34), and +++ in 29.4% (10/34) respectively]. There was a significant difference between the expression levels of both of TGF-β_1 and TGF-βRI in DTF and those of surrounding tissues (P<0.05) .
3. 67.6% (23/34) cases of DTF shownα-SMA positive in the tumor spindle cells [+ in 14.7% (5/34), ++ in 44.1%(15/34), and +++ in 38.8%(3/34)]. There was a positive correlation between the expression level ofα-SMA and that of TGF-βRI in DTF (P<0.05).
4. Fibronectin was demonstrated in all cases of DTF. There was a positive correlation between the expression level of fibronectin and that of TGF-βRI in DTF (P<0.05).
5. The MVD in DTF was 9.14±2.08.VEGF positive spindle cells and endothelium were found in 88.2%(30/34)DTF. There was a positive correlation between MVD and the average percentage of both VEGF and TGF-β1 positive cells
Conclusion:
1. There is a overexpression of AnnexinⅡin DTF. AnnexinⅡmay participated in the development of DTF, possibly in promoting the infiltrative growth of tumour cells by mediating plasminogen activation pathway. AnnexinⅡreactivity may be the basis of a new attractive target for anti-DTF therapy.
2. Overexpressions of both TGF-β_1 and TGF-βRI in DTF indicate that TGF-β_1 may participated in the development of DTF. The results in our study suggest it might envolved in neoplastic myofiberblast differentiaton, stroma production and angiogenesis in DTF.
3. VEGF overexpression is present in DTF. Diffuse and strong VEGF reactivity in DTF surggests it may be another target for anti-angiogenic and anti-DTF therapies.
引文
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[26] SuzukiH , YagiK ,KondoM ,et al. c-Ski inhibits the TGF-beta signaling pathway through stabilization of inactive Smad complexes on Smad-binding elements [J].Oncogene,2004,23(29):5068～5076.
[27] ten Dijke P, Hill CS. New insights into TGF-β-Smad singnalling[J]. Trends Biochem Sci ,2004,29:265-273.
[28] DerinlerS, PrunierC, Ferrand N, et al. c-Jun inhibits transforming growth factor beta -m ediated transcription by repressing Smad3 transcriptional activity [J]. J BiolChem,2000,275(37):28858～28865.
[29] Eunjoo HL, Choun KJ. Role of transforming growth factor-β in transdifferen-tiation and fibrosis of lens epithelial cells[J]. Investigative Ophthalmology and Visual Science, 1999,40(9):2025- 2032.
[30] Yuko, Akihiro K, Yoshiyuki U, et al. triggering the induction of myofi- broblast and fibrogenesis by airway epithelial shedding[J]. Am J Respir Cell Mol Biol, 2001,24(1):1-11.
[31] Eunjoo HL, Choun KJ. Role of transforming growth factor-β in transdifferen-tiation and fibrosis of lens epithelial cells[J]. Investigative Ophthalmology and Visual Science, 1999,40(9):2025- 2032.
[32] Roy SG, Nozaki Y, Phan SH. Regulation of alpha-smooth muscle actin gene expression in myofibroblast differentiation from rat lung fibroblasts[J]. Int J Biochem Cell Biol.2001 ,33(7):723-734
[33] Locci P, Balducci C, Lilli C.Desmoid and fibroma tumors differently respond to TGFbeta(1) stimulus and ECM macromolecule accumulation[J]. Biomed Pharmacother. 2007,61(2-3):131-136.
[34] Buniatian GH. Stages of activation of hepatic stellate cells:effects of ellagic acid, an inhibiter of liver fibrosis, on their differentiation in culture [J].CellProli,2003, 36(6): 307-319.
[35] Cassiman D, Dene fc, Desmet VJ, et al. Human and rat hepatic stellote cell expressn eurotrophins and neurotrophin receptoors[J] Hepatology, 2001, 33(1): 148-158.
[36] Morini S, Carotti S, Carpino G, et a.l GFAP expression in the liver as an early markerofstellate cells activation [J]. Ital JAnat Embryo,l 2005,110(4): 193-207.
[37] Hisataki T, Itoh N, SuzukiK ,et al. Modulation of phenotype of human prostatic stromal cells by transforming growth factor-betas[J]. Prostate, 2004, 58(2): 174-182.
[38] Goumans MJ, Lebrin F, Valdimarsdottir G. Controlling the angiogenic switch: a balance between two distinct TGF-β receptor signaling pathways[J]. Trends Cardiovasc Med 2003;13:301-307.
[39] Johnson DW, Berg JN, Baldwin MA, et al.Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2[J]. Nat Genet. 1996, 3(2):189-195.
[40] Seki T, Yun J, Oh SP.Arterial endothelium-specific activin receptor-like kinase 1 expression suggests its role in arterialization and vascular remodeling[J]. Circ Res. 2003,93(7):682-9.
[41] Goumans MJ, Valdimarsdottir G, Itoh S, et al. Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors[J]. EMBO J. 2002,21(7):1743-53.
[42] Shi-Wen X, Rodriguez-Pascual F, Lamas S, et al.Constitutive ALK5-independent c-Jun N-terminal kinase activation contributes to endothelin-1 overexpression in pulmonary fibrosis: evidence of an autocrine endothelin loop operating through the endothelin A and B receptors [J]. Mol Cell Biol. 2006 ,26(14):5518-5527.
[43] van den Driesche S, Mummery CL, Westermann CJ. Hereditary hemorrhagic telangiectasia: an update on transforming growth factor beta signaling in vasculogenesis and angiogenesis[J]. Cardiovasc Res. 2003 ,58(1):20-31
[44] Rajnoch J, Viklicky O. Angiogenesis and organ transplantation[J]. Folia Microbiol (Praha), 2004,49(5):499-505.
[45] Jung ST, Moon ES, Seo HY, et al. Expression and significance of TGF-beta isoform and VEGF in osteosarcoma[J]. Orthopedics. 2005 ,28(8):755-60
[46] Kim KY, Lee JW, Ahn BW, et al.Loss of endogenous TGF-beta effect induces mouse hepatoma malignancy by correlation with cyclooxygenase -2 and VEGF[J]. Hepatol Res ,2003 ,26(4):302-310.
[47] Toi M, Matsumoto T, Bando H. Vascular endpthelial growth factor :itsprognostic, predictive ,and therapeutic implications [J].Lancet Oncol,2001,2(11):667-673.
[48] Brekken RA, Thorpe PE.Vascular endothelial growth factor and vascular targeting of solid tumors[J].Anticancer Res,2001,21(6B): 4221-4229.
[49] Malik AK, Baldwin ME,Peale F, et al.Redundant roles of VEGF-B and P1GF during selective VEGF-A blockade in mice[J].Blood,2006;107(2):550-557.
[50] Benckert C, Jonas S, Cramer T, et al. Transforming Growth Factor beta 1 Stimulates Vascular Endothelial Growth Factor Gene Transcription in Human Cholangio cellular Carcinoma Cellsl. Cancer Res. 2003,63(5): 1083-1092.
[51] Raymond J, Ogoudikpe C, Salazkin I, et al. Endovascular treatment of aneurysms: gene expression of neointimal cells recruited on the embolic agent and evolution with recurrence in an experimental model [J]. J Vasc Interv Radiol. 2005 ,16 (10) :1355-1363.
[52] Bisson C, Blacher S, PoletteM, et al.Restricted expression of membrane type-I-matrix metalloproteinase by myofibroblasts adjacent to human breast cancer cells[J]. Int J Cancer, 2003,105: 7-13.
[53] Offersen BV, Nielsen BS, HansenGH, etal. The myofibroblast is the predominant plasminogen activator inhibitor-1 expressing cell type in human breast carcinomas [ J]. Ann J Pathol ,2003,163 (5): 1887-1899.
[54] Givant- Horwitz V, Davidson B, Van de Putte G, et al. Epression of the 67 kDa laminin receptor and the alpha6 intergrinsubunit in serous ovarian carcinoma [J]. Clin Exp Metastasis, 2003,20(7):599- 609.
[1]Spano F, Raugei G, Palla E, et al. Characterization of the human lipocortin-2-encoding multigene family: its structure suggests the existence of a short amino acid unit undergoing duplication[J]. Gene,1990,95(2):243-251.
[2]Deier R, Schmid KW, Gerke V, et al. Differential expression of annexins I, II and IV in human tissues: an irnmunohistochemical study. Histochem Cell Biol, 1998 Aug; 110(2): 137-148.
[3]Tanaka T, Akatsuka S, Ozeki M, et al. Redox regulation of annexin 2 and its implications for oxidative stress-induced renal carcinogenesis and metastasis[J]. Oncogene, 2004 ,23(22):3980-3989.
[4]Xu TR, Rumsby MG. Phorbol ester-induced translocation of PKC epsilon to the nucleus in fibroblasts: identification of nuclear PKC epsilon-associating proteins[J]. FEBS Lett, 2004,570(1-3):20-4.
[5]Rengifo-Cam W, Umar S, Sarkar S, et al. Antiapoptotic effects of progastrin on pancreatic cancer cells are mediated by sustained activation of nuclear factor -{kappa}B[J]. Cancer Res,2007,67(15):7266-7274.
[6] Choi KS, Fogg DK, Yoon CS, et al.p11 regulates extracellular plasmin production and invasiveness of HT1080 fibrosarcoma cells[J]. FASEB , 2003 , 17 (2): 235 - 246.
[7] Esposito I, Penzel R, Chaib-Harrireche M, et al. Tenascin C and annexin II expression in the process of pancreatic carcinogenesis[J] J Pathol, 2006, 208 (5):673-685.
[8]Hayes MJ, Shao D, Bailly M, et al. Regulation of actin dynamics by annexin 2[J]. EMBO J,2006,25(9): 1816-1826.
[9]Semov A, Moreno MJ, Onichtchenko A, et al. Metastasis-associated protein S100A4 induces angiogenesis through interaction with Annexin II and accelerated plasmin formation[J]. J Biol Chem,2005, 280(21):20833-20841.
[10]Domoto T, Miyama Y, Suzuki H,et al. Evaluation of S100A10, annexin II and B-FABP expression as markers for renal cell carcinoma[J]. Cancer Sci, 2007, 98(1):77-82.
[11]Ito Y, Arai K, Nozawa R, et al. S100A10 expression in thyroid neoplasms originating from the follicular epithelium: contribution to the aggressive characteristic of anaplastic carcinoma [J]. Anticancer Res, 2007, 27 (4C):2679-2683.
[12]Sharma MR, Koltowski L, Ownbey RT,et al. Angiogenesis-associated protein annexin II in breast cancer: selective expression in invasive breast cancer and contribution to tumor invasion and progression [J]. Expe Mol Pathol,2006, 81(2):146-156.
[13]Pei H, Zhu H, Zeng S,et al. Proteome analysis and tissue microarray for profiling protein markers associated with lymph node metastasis in colorectal cancer [J]. J Proteome Res, 2007, 6(7):2495-2501.
[14]Liu JW, Shen JJ , Angela TS , et al. Annexin II expression is reduced or lost in prostate cancer cells and its re-expression inhibits prostate cancer cell migration [J]. Oncogene ,2003 ,22 (10) :1475-1485.
[15]Yee DS, Narula N, Ramzy I, et al . Reduced annexin II protein expression in high-grade prostatic intraepithelial neoplasia and prostate cancer[J]. Arch Pathol Lab Med,2007 ,131(6):902-908.
[16]Qi YJ, Wang LD, Jiao XY, et al. Dysregulation of Annexin II expression in esophageal squamous cell cancer and adjacent tissues from a high-incidence area for esophageal cancer in Henan province [J]. Ai Zheng, 2007,26 (7): 730-736.
[17] Dowling P, Meleady P, Dowd A, et al. Proteomic analysis of isolated membrane fractions from superinvasive cancer cells[J]. Biochim Biophys Acta , 2007 , 1774(1):93-101.
[18] Kreunin P, Yoo C, Urquidi V, et al. Proteomic profiling identifies breast tumor metastasis-associated factors in an isogenic model[J]. Proteomics, 2007 , 7 (2):299-312.
[19] Katayama M, Nakano H, Ishiuchi A, et al. Protein pattern difference in the colon cancer cell lines examined by two-dimensional differential in-gel electrophoresis and mass spectrometry[J]. Surg Today, 2006,36(12):1085-1093.
[20] Qi YJ, Wang LD, Jiao XY, et al. Dysregulation of Annexin II expression in esophageal squamous cell cancer and adjacent tissues from a high-incidence area for esophageal cancer in Henan province[J]. Ai Zheng, 2007 ,26(7):730-736.
[2] Goldblum J, Fletcher JA. Desmoid-type fibromatosis. In: Fletcher CDM, Unni KK, Mertens F, eds. World Health Organization Classification of Tumors Pathology and Genetics of Tumors of Soft Tissue and Bone[J].1 st ed.Lyon: IARC Press, 2002,83-84.
[3] Dabek J, Kulach A, Monastyrska-Cup B, et al. Transforming growth factor beta and cardiovascular diseases:the other facet of the 'protective cytokine'[J]. Pharmacol Rep, 2006,58(6): 799-805.
[4] Garrets Q, Khaw PT, B labck TD,et al. Involvement of CTGF in TGF-betal stimulation of myofibroblast differentiation and collagen matrix contraction in the presence of mechanical stress[J]. Invest Ophthamol Vis Sci, 2004, 45: 1109- 1116.
[5] Schiffer M, von Gersdorff G,Bitzer M, et al. Smad proteins and transforming growth factor-beta signaling[J]. Kidney Int Suppl, 2000, 77:545-552.
[6] Kubo M, Ihn H, Yamane K, et al. The expression levels and the differential expression of transforming growth factor-beta receptors in dermatofibroma and dermatofibrosarcoma protuberans[J]. Br J Dermatol,2006,154(5):919-925.
[7] Salvatore Romeo, Brian Eyden, Frans A Prins, et al. TGF-β_1 drives partial myofi-broblastic differentiationin chondromyxoid fibroma of bone[J]. J Pathol, 2006,208: 26-34.
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[9] PistolesiS, Boldrinnir, GisfrediS,et al .Angiogeesis in intracranial Meningiomas :immunchistochemical and molecular Study[J].Neu2 Ropathol Appl Neurobiol, 2004, 30(2):118～125.
[10] Koomagi R, Volm M. Tissue-factor expression in human non-small-cell lung carcinoma measured by immunohistochemistry: correlation between tissue factor and angiogenesis. [J]. Int J Cancer, 1998,79(1):19-22.
[11] Choi KS, Fogg DK, Yoon CS, et al. p11 regulates extracellular plasmin production and invasiveness of HT1080 fibrosarcoma cells[J]. FASEB J, 2003 , 17(2):235-246.
[12] Kabiri EH,AI Aziz S,EI Maslout A,et al. desmoid tumours of the chest wall[J].Eur J Cardiothorac Surg,2001,19(5):580-583.
[13] Weidner N. Angiogenesis as a predictor of clinical outcome in cancer patients. [J]. Hum Pathol., 2000 Apr;31(4):403-405..
[14] Goldblum J, Fletcher JA. Desmoid-type fibromatosis. In: Fletcher CDM, Unni KK, Mertens F, eds. World Health Organization Classification of Tumors Pathology and Genetics of Tumors of Soft Tissue and Bone[J].l st ed.Lyon: IARC Press, 2002.83-84.
[15] Gabbiani G, Ryan GB, Majno G. Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction [J].Experiential 971,27: 549-550.
[16] Fletcher CD. Myofibroblastic tumours: an update [J]. Verh Dtsch GesPatho, 1998, 82: 75-82.
[17] Dreier R, Schmid KW, Gerke V, et al. Differential expression of annexins I, II and IV in human tissues: an immunohistochemical study[J]. Histochem Cell Biol,1998,110(2):137-148.
[18] Kwon M, Yoon CS, Jeong W, et al. Annexin A2-S100A10 heterotetramer, a novel substrate of thioredoxin[J]. J Biol Chem., 2005 Jun 24;280 (25): 23584-23592.
[19] Choi KS, Fogg DK, Yoon CS, et al.p11 regulates extracellular plasmin production and invasiveness of HT1080 fibrosarcoma cells[J]. FASEB J, 2003 ,17(2):235-246.
[20] Dowling P, Meleady P, Dowd A, et al. Proteomic analysis of isolated membrane fractions from superinvasive cancer cells[J]. Biochim Biophys Acta,2007 , 1774(1):93-101.
[21]Sharma MR, Koltowski L, Ownbey RT,et al. Angiogenesis-associated protein annexin II in breast cancer: selective expression in invasive breast cancer and contribution to tumor invasion and progression [J]. Expe Mol Pathol,2006, 81(2):146-156.
[22] Rengifo-Cam W, Umar S, Sarkar S, et al. Antiapoptotic effects of progastrin on pancreatic cancer cells are mediated by sustained activation of nuclear factor -{kappa}B[J]. Cancer Res,2007,67(15):7266-7274.
[23] Esposito I, Penzel R, Chaib-Harrireche M, et al. Tenascin C and annexin II expression in the process of pancreatic carcinogenesis[J] J Pathol, 2006, 208 (5):673-685.
[24] Hayes MJ, Shao D, Bailly M, et al. Regulation of actin dynamics by annexin 2[J]. EMBO J,2006,25(9):1816-1826.
[25] delRe E, BabittJL, PiraniA, et al. In the absence of type III receptor, the transforming growth factor (TGF)-beta type II-B receptor requires the type I receptor to bind TGF-beta2 [J]. J Biol Chem, 2004 ,279 (21): 22765-22772.
[26] SuzukiH , YagiK ,KondoM ,et al. c-Ski inhibits the TGF-beta signaling pathway through stabilization of inactive Smad complexes on Smad-binding elements [J].Oncogene,2004,23(29):5068～5076.
[27] ten Dijke P, Hill CS. New insights into TGF-β-Smad singnalling[J]. Trends Biochem Sci ,2004,29:265-273.
[28] DerinlerS, PrunierC, Ferrand N, et al. c-Jun inhibits transforming growth factor beta -m ediated transcription by repressing Smad3 transcriptional activity [J]. J BiolChem,2000,275(37):28858～28865.
[29] Eunjoo HL, Choun KJ. Role of transforming growth factor-β in transdifferen-tiation and fibrosis of lens epithelial cells[J]. Investigative Ophthalmology and Visual Science, 1999,40(9):2025- 2032.
[30] Yuko, Akihiro K, Yoshiyuki U, et al. triggering the induction of myofi- broblast and fibrogenesis by airway epithelial shedding[J]. Am J Respir Cell Mol Biol, 2001,24(1):1-11.
[31] Eunjoo HL, Choun KJ. Role of transforming growth factor-β in transdifferen-tiation and fibrosis of lens epithelial cells[J]. Investigative Ophthalmology and Visual Science, 1999,40(9):2025- 2032.
[32] Roy SG, Nozaki Y, Phan SH. Regulation of alpha-smooth muscle actin gene expression in myofibroblast differentiation from rat lung fibroblasts[J]. Int J Biochem Cell Biol.2001 ,33(7):723-734
[33] Locci P, Balducci C, Lilli C.Desmoid and fibroma tumors differently respond to TGFbeta(1) stimulus and ECM macromolecule accumulation[J]. Biomed Pharmacother. 2007,61(2-3):131-136.
[34] Buniatian GH. Stages of activation of hepatic stellate cells:effects of ellagic acid, an inhibiter of liver fibrosis, on their differentiation in culture [J].CellProli,2003, 36(6): 307-319.
[35] Cassiman D, Dene fc, Desmet VJ, et al. Human and rat hepatic stellote cell expressn eurotrophins and neurotrophin receptoors[J] Hepatology, 2001, 33(1): 148-158.
[36] Morini S, Carotti S, Carpino G, et a.l GFAP expression in the liver as an early markerofstellate cells activation [J]. Ital JAnat Embryo,l 2005,110(4): 193-207.
[37] Hisataki T, Itoh N, SuzukiK ,et al. Modulation of phenotype of human prostatic stromal cells by transforming growth factor-betas[J]. Prostate, 2004, 58(2): 174-182.
[38] Goumans MJ, Lebrin F, Valdimarsdottir G. Controlling the angiogenic switch: a balance between two distinct TGF-β receptor signaling pathways[J]. Trends Cardiovasc Med 2003;13:301-307.
[39] Johnson DW, Berg JN, Baldwin MA, et al.Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2[J]. Nat Genet. 1996, 3(2):189-195.
[40] Seki T, Yun J, Oh SP.Arterial endothelium-specific activin receptor-like kinase 1 expression suggests its role in arterialization and vascular remodeling[J]. Circ Res. 2003,93(7):682-9.
[41] Goumans MJ, Valdimarsdottir G, Itoh S, et al. Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors[J]. EMBO J. 2002,21(7):1743-53.
[42] Shi-Wen X, Rodriguez-Pascual F, Lamas S, et al.Constitutive ALK5-independent c-Jun N-terminal kinase activation contributes to endothelin-1 overexpression in pulmonary fibrosis: evidence of an autocrine endothelin loop operating through the endothelin A and B receptors [J]. Mol Cell Biol. 2006 ,26(14):5518-5527.
[43] van den Driesche S, Mummery CL, Westermann CJ. Hereditary hemorrhagic telangiectasia: an update on transforming growth factor beta signaling in vasculogenesis and angiogenesis[J]. Cardiovasc Res. 2003 ,58(1):20-31
[44] Rajnoch J, Viklicky O. Angiogenesis and organ transplantation[J]. Folia Microbiol (Praha), 2004,49(5):499-505.
[45] Jung ST, Moon ES, Seo HY, et al. Expression and significance of TGF-beta isoform and VEGF in osteosarcoma[J]. Orthopedics. 2005 ,28(8):755-60
[46] Kim KY, Lee JW, Ahn BW, et al.Loss of endogenous TGF-beta effect induces mouse hepatoma malignancy by correlation with cyclooxygenase -2 and VEGF[J]. Hepatol Res ,2003 ,26(4):302-310.
[47] Toi M, Matsumoto T, Bando H. Vascular endpthelial growth factor :itsprognostic, predictive ,and therapeutic implications [J].Lancet Oncol,2001,2(11):667-673.
[48] Brekken RA, Thorpe PE.Vascular endothelial growth factor and vascular targeting of solid tumors[J].Anticancer Res,2001,21(6B): 4221-4229.
[49] Malik AK, Baldwin ME,Peale F, et al.Redundant roles of VEGF-B and P1GF during selective VEGF-A blockade in mice[J].Blood,2006;107(2):550-557.
[50] Benckert C, Jonas S, Cramer T, et al. Transforming Growth Factor beta 1 Stimulates Vascular Endothelial Growth Factor Gene Transcription in Human Cholangio cellular Carcinoma Cellsl. Cancer Res. 2003,63(5): 1083-1092.
[51] Raymond J, Ogoudikpe C, Salazkin I, et al. Endovascular treatment of aneurysms: gene expression of neointimal cells recruited on the embolic agent and evolution with recurrence in an experimental model [J]. J Vasc Interv Radiol. 2005 ,16 (10) :1355-1363.
[52] Bisson C, Blacher S, PoletteM, et al.Restricted expression of membrane type-I-matrix metalloproteinase by myofibroblasts adjacent to human breast cancer cells[J]. Int J Cancer, 2003,105: 7-13.
[53] Offersen BV, Nielsen BS, HansenGH, etal. The myofibroblast is the predominant plasminogen activator inhibitor-1 expressing cell type in human breast carcinomas [ J]. Ann J Pathol ,2003,163 (5): 1887-1899.
[54] Givant- Horwitz V, Davidson B, Van de Putte G, et al. Epression of the 67 kDa laminin receptor and the alpha6 intergrinsubunit in serous ovarian carcinoma [J]. Clin Exp Metastasis, 2003,20(7):599- 609.
[1]Spano F, Raugei G, Palla E, et al. Characterization of the human lipocortin-2-encoding multigene family: its structure suggests the existence of a short amino acid unit undergoing duplication[J]. Gene,1990,95(2):243-251.
[2]Deier R, Schmid KW, Gerke V, et al. Differential expression of annexins I, II and IV in human tissues: an irnmunohistochemical study. Histochem Cell Biol, 1998 Aug; 110(2): 137-148.
[3]Tanaka T, Akatsuka S, Ozeki M, et al. Redox regulation of annexin 2 and its implications for oxidative stress-induced renal carcinogenesis and metastasis[J]. Oncogene, 2004 ,23(22):3980-3989.
[4]Xu TR, Rumsby MG. Phorbol ester-induced translocation of PKC epsilon to the nucleus in fibroblasts: identification of nuclear PKC epsilon-associating proteins[J]. FEBS Lett, 2004,570(1-3):20-4.
[5]Rengifo-Cam W, Umar S, Sarkar S, et al. Antiapoptotic effects of progastrin on pancreatic cancer cells are mediated by sustained activation of nuclear factor -{kappa}B[J]. Cancer Res,2007,67(15):7266-7274.
[6] Choi KS, Fogg DK, Yoon CS, et al.p11 regulates extracellular plasmin production and invasiveness of HT1080 fibrosarcoma cells[J]. FASEB , 2003 , 17 (2): 235 - 246.
[7] Esposito I, Penzel R, Chaib-Harrireche M, et al. Tenascin C and annexin II expression in the process of pancreatic carcinogenesis[J] J Pathol, 2006, 208 (5):673-685.
[8]Hayes MJ, Shao D, Bailly M, et al. Regulation of actin dynamics by annexin 2[J]. EMBO J,2006,25(9): 1816-1826.
[9]Semov A, Moreno MJ, Onichtchenko A, et al. Metastasis-associated protein S100A4 induces angiogenesis through interaction with Annexin II and accelerated plasmin formation[J]. J Biol Chem,2005, 280(21):20833-20841.
[10]Domoto T, Miyama Y, Suzuki H,et al. Evaluation of S100A10, annexin II and B-FABP expression as markers for renal cell carcinoma[J]. Cancer Sci, 2007, 98(1):77-82.
[11]Ito Y, Arai K, Nozawa R, et al. S100A10 expression in thyroid neoplasms originating from the follicular epithelium: contribution to the aggressive characteristic of anaplastic carcinoma [J]. Anticancer Res, 2007, 27 (4C):2679-2683.
[12]Sharma MR, Koltowski L, Ownbey RT,et al. Angiogenesis-associated protein annexin II in breast cancer: selective expression in invasive breast cancer and contribution to tumor invasion and progression [J]. Expe Mol Pathol,2006, 81(2):146-156.
[13]Pei H, Zhu H, Zeng S,et al. Proteome analysis and tissue microarray for profiling protein markers associated with lymph node metastasis in colorectal cancer [J]. J Proteome Res, 2007, 6(7):2495-2501.
[14]Liu JW, Shen JJ , Angela TS , et al. Annexin II expression is reduced or lost in prostate cancer cells and its re-expression inhibits prostate cancer cell migration [J]. Oncogene ,2003 ,22 (10) :1475-1485.
[15]Yee DS, Narula N, Ramzy I, et al . Reduced annexin II protein expression in high-grade prostatic intraepithelial neoplasia and prostate cancer[J]. Arch Pathol Lab Med,2007 ,131(6):902-908.
[16]Qi YJ, Wang LD, Jiao XY, et al. Dysregulation of Annexin II expression in esophageal squamous cell cancer and adjacent tissues from a high-incidence area for esophageal cancer in Henan province [J]. Ai Zheng, 2007,26 (7): 730-736.
[17] Dowling P, Meleady P, Dowd A, et al. Proteomic analysis of isolated membrane fractions from superinvasive cancer cells[J]. Biochim Biophys Acta , 2007 , 1774(1):93-101.
[18] Kreunin P, Yoo C, Urquidi V, et al. Proteomic profiling identifies breast tumor metastasis-associated factors in an isogenic model[J]. Proteomics, 2007 , 7 (2):299-312.
[19] Katayama M, Nakano H, Ishiuchi A, et al. Protein pattern difference in the colon cancer cell lines examined by two-dimensional differential in-gel electrophoresis and mass spectrometry[J]. Surg Today, 2006,36(12):1085-1093.
[20] Qi YJ, Wang LD, Jiao XY, et al. Dysregulation of Annexin II expression in esophageal squamous cell cancer and adjacent tissues from a high-incidence area for esophageal cancer in Henan province[J]. Ai Zheng, 2007 ,26(7):730-736.