胰腺癌外周血循环肿瘤细胞的鉴定及其生物学意义研究
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摘要
肿瘤细胞血液播散至远处器官和后来形成的明显转移灶是上皮来源的恶性肿瘤最主要的死亡原因。近年研究表明,播散于血液中的肿瘤细胞可能是实体瘤远处器官转移的早期事件。实体瘤患者外周血中CTCs生物学特性及与临床相关性尚未完全阐明。
很少有文献报道细胞学检测胰腺癌、壶腹癌等实体瘤患者外周血CTCs的生物学特征及临床的相关性。本研究建立了免疫磁珠负性富集和免疫荧光鉴定策略,并和Miltenyi、新芝磁珠进行了比较,发现此方法具有85%左右的回收率。在胰腺癌、食管癌和结肠癌等实体瘤患者外周血中鉴定不同形态的CTCs,结合免疫荧光、FISH和HE染色不但能够鉴定具有完整胞浆结构的CTCs,还能鉴定到胞浆缺失的裸核CTCs。在18例胰腺囊性瘤、7例的胰腺炎和25例健康志愿者没有检测到CTCs,87例胰腺癌患者外周血中CTCs检出率为63.2%(55/87),结合血清CA19-9,能把胰腺癌的诊断率提高到88.1%,CTCs的检出率同胰腺癌患者的分期、肿瘤侵润深度、淋巴结转移、远处器官转移等相关。治疗前检测到胰腺癌患者外周血CTCs提示预后不良(n=59)。在AJCC同一分期中检测到CTCs也提示预后不良。在14例术中/术后进行辅助治疗的患者,发现胰腺癌患者外周血具有不同比率的凋亡CTCs,检测到≥50%的凋亡CTCs或无CTCs患者的预后比较好。39例手术治疗后的患者外周血中检测到CTCs提示预后不良。长期监测1例壶腹周围癌患者在不同治疗阶段的CTCs的动态变化,CTCs动态变化和凋亡的形态改变可能反映了该患者的疾病的进展和治疗的疗效,基本和影像吻合,似乎比影像更早地反映了治疗疗效,有助于对该患者实施个体化治疗,弥补了血清标记物CA19-9、CA24-2等一直处于正常水平的缺陷。
实体瘤患者外周血CTCs的存在可能与肿瘤复发、转移及预后相关,随着CTCs富集的灵敏度和鉴定的特异度的提高,监测胰腺癌等实体瘤外周血CTCs的分子谱或数目的动态变化,有助于在影像发现肿瘤的复发和转移前实施辅助治疗,可能为实体瘤患者的个体化治疗提供有用的工具。
Metastasis is the leading cause of cancer related death.Most deaths from solid tumors are caused by haematogenous spread of cancer cells into distant organs and their subsequent overt metastases.Recent work suggested that dissemination of primary cancer cells to distant sites might be an early event.The biological characteristics and clinical relevance of circulating tumor cells(CTCs) in solid cancer is still not clearly elucidated.But many literatures reported that CTCs in peripheral blood of solid cancer had a relationship with the poor prognosis and tailored therapy.
Few literatures report the biologic characteristics and clinical significance of CTCs in peripheral blood of patients with pancreatic,ampullary cancer by cyotmetric method.We set up immunomagetic negative enrichment together with fluorescence in situ hybridization(FISH) and(Haematoxylin & Eosin) HE to identify CTCs compared with Mitineyi and Xinzhi beads.Moreover,Cell spiking experiment showed the method had about 85%recocvery rate.CTCs would be properly identified CTCs not only the cells with intact structures but also the one with fragmented plasma membrane or nude nucleus.CTCs were detected in 63.2%(55/87) samples of pancreatic cancer patients but not in 18 pancreatic cystic neoplasms patients,7 pancreatitis patients and 25 healthy donors.The rate of detection of CTCs had a relationship with tumor stage,the invasion depth of tumor,lymph node metastasis and the organ metastasis.Patients with CTCs in peripheral blood before treatment predicted a poor prognosis(n=59).The trend persisted in the same AJCC stage.In 14 patients by adjuvant therapy during surgery or after surgery,a different ratio of apoptotic CTCs were found in peripheral blood of pancreatic cancer patients. Moreover,detection of higher ratio of apoptotic CTCs or none CTCs suggests a better prognosis.Detection CTCs in 39 patients after surgery predicted the poor prognosis. One case of patient with periampullary carcinoma was followed up all the time.At the same time,CTCs were monitored in different stage of therapy.CTCs may predict the efficacy of the different therapy and the disease progress,which was in accordance with imaging and make up the the normal level of serum tumor makers of CA19-9 and CA24-2 in this case.
CTCs in peripheral blood of patients with solid cancers may predicate the tumor recurrence and metastasis.As the increasing of sensitivity and specificity of enrichment and identification of CTCs,adjuvant therapy may be necessary before tumor relapse and metastasis can be detected by radiography,and monitoring the dynamic CTCs and its molecular spectrum may predict individualized therapy for patients with solid cancers.
很少有文献报道细胞学检测胰腺癌、壶腹癌等实体瘤患者外周血CTCs的生物学特征及临床的相关性。本研究建立了免疫磁珠负性富集和免疫荧光鉴定策略,并和Miltenyi、新芝磁珠进行了比较,发现此方法具有85%左右的回收率。在胰腺癌、食管癌和结肠癌等实体瘤患者外周血中鉴定不同形态的CTCs,结合免疫荧光、FISH和HE染色不但能够鉴定具有完整胞浆结构的CTCs,还能鉴定到胞浆缺失的裸核CTCs。在18例胰腺囊性瘤、7例的胰腺炎和25例健康志愿者没有检测到CTCs,87例胰腺癌患者外周血中CTCs检出率为63.2%(55/87),结合血清CA19-9,能把胰腺癌的诊断率提高到88.1%,CTCs的检出率同胰腺癌患者的分期、肿瘤侵润深度、淋巴结转移、远处器官转移等相关。治疗前检测到胰腺癌患者外周血CTCs提示预后不良(n=59)。在AJCC同一分期中检测到CTCs也提示预后不良。在14例术中/术后进行辅助治疗的患者,发现胰腺癌患者外周血具有不同比率的凋亡CTCs,检测到≥50%的凋亡CTCs或无CTCs患者的预后比较好。39例手术治疗后的患者外周血中检测到CTCs提示预后不良。长期监测1例壶腹周围癌患者在不同治疗阶段的CTCs的动态变化,CTCs动态变化和凋亡的形态改变可能反映了该患者的疾病的进展和治疗的疗效,基本和影像吻合,似乎比影像更早地反映了治疗疗效,有助于对该患者实施个体化治疗,弥补了血清标记物CA19-9、CA24-2等一直处于正常水平的缺陷。
实体瘤患者外周血CTCs的存在可能与肿瘤复发、转移及预后相关,随着CTCs富集的灵敏度和鉴定的特异度的提高,监测胰腺癌等实体瘤外周血CTCs的分子谱或数目的动态变化,有助于在影像发现肿瘤的复发和转移前实施辅助治疗,可能为实体瘤患者的个体化治疗提供有用的工具。
Metastasis is the leading cause of cancer related death.Most deaths from solid tumors are caused by haematogenous spread of cancer cells into distant organs and their subsequent overt metastases.Recent work suggested that dissemination of primary cancer cells to distant sites might be an early event.The biological characteristics and clinical relevance of circulating tumor cells(CTCs) in solid cancer is still not clearly elucidated.But many literatures reported that CTCs in peripheral blood of solid cancer had a relationship with the poor prognosis and tailored therapy.
Few literatures report the biologic characteristics and clinical significance of CTCs in peripheral blood of patients with pancreatic,ampullary cancer by cyotmetric method.We set up immunomagetic negative enrichment together with fluorescence in situ hybridization(FISH) and(Haematoxylin & Eosin) HE to identify CTCs compared with Mitineyi and Xinzhi beads.Moreover,Cell spiking experiment showed the method had about 85%recocvery rate.CTCs would be properly identified CTCs not only the cells with intact structures but also the one with fragmented plasma membrane or nude nucleus.CTCs were detected in 63.2%(55/87) samples of pancreatic cancer patients but not in 18 pancreatic cystic neoplasms patients,7 pancreatitis patients and 25 healthy donors.The rate of detection of CTCs had a relationship with tumor stage,the invasion depth of tumor,lymph node metastasis and the organ metastasis.Patients with CTCs in peripheral blood before treatment predicted a poor prognosis(n=59).The trend persisted in the same AJCC stage.In 14 patients by adjuvant therapy during surgery or after surgery,a different ratio of apoptotic CTCs were found in peripheral blood of pancreatic cancer patients. Moreover,detection of higher ratio of apoptotic CTCs or none CTCs suggests a better prognosis.Detection CTCs in 39 patients after surgery predicted the poor prognosis. One case of patient with periampullary carcinoma was followed up all the time.At the same time,CTCs were monitored in different stage of therapy.CTCs may predict the efficacy of the different therapy and the disease progress,which was in accordance with imaging and make up the the normal level of serum tumor makers of CA19-9 and CA24-2 in this case.
CTCs in peripheral blood of patients with solid cancers may predicate the tumor recurrence and metastasis.As the increasing of sensitivity and specificity of enrichment and identification of CTCs,adjuvant therapy may be necessary before tumor relapse and metastasis can be detected by radiography,and monitoring the dynamic CTCs and its molecular spectrum may predict individualized therapy for patients with solid cancers.
引文
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