TFF3 GENE EXPRESSION IN METASTATIC COLON CANCER

转移性结肠癌中的 TFF3 基因表达

• 批准号: 6377141
• 负责人: STEVEN H. ITZKOWITZ
• 金额: $ 30.64万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-15 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6377141
• 关键词: athymic mouse; cell line; colon neoplasms; gene deletion mutation; gene expression; gene therapy; genetic promoter element; lethal genes; liver neoplasms; metastasis; neoplasm /cancer genetics; neoplasm /cancer transplantation; nonhuman therapy evaluation; reporter genes

Colorectal cancer is the second most common cause of cancer-related mortality in the United States, and 80 percent of patients who die of colorectal cancer have liver metastases. Since current treatments for metastatic colon cancer have achieved only limited success, there is an important need to develop novel and more effective treatment strategies. Our group has used suicide gene therapy based on the herpes simplex virus thymidine kinase gene plus ganciclovir to successfully treat colon cancer liver metastases in a syngeneic animal model. We have also demonstrated that placing the suicide gene under the control of the carcinoembryonic antigen (CEA) promoter affords greater tissue specificity. In addition, we have developed a binary gene expression construct in which the GAL4/VP16 transcription factors are placed under the control of the CEA promoter. This permitted the delivery of a higher dose of suicide gene-containing vector with better tumor cell killing and less toxicity. Although CEA is a useful prototype tumor-associated gene, its expression by many normal cells, particularly biliary epithelium, may result in unacceptable toxicity and limit its clinical utility. The identification of a gene that is more intestine-specific, while maintaining tumor-specificity, should offer the opportunity for greater therapeutic efficacy. Trefoil factor family 3 (TFF3; formerly called intestinal trefoil factor, ITF) is a promising candidate in this regard. TFF3 is primarily expressed by cells of the small and large intestine with no expression in the liver and very restricted expression in other normal organs. Evidence to date indicates that TFF3 expression is highly conserved during the progression from adenoma to carcinoma in the colon. TFF3 has been shown to phosphorylate b-catenin, thereby disrupting cell-cell adhesion and enabling cells to become motile which may explain the role of TFF3 in normal cell migration to heals mucosal wounds, but also for cancer cell invasion and metastasis. We have shown that all human colon cancer liver metastases studied express the TFF3 gene. Therefore, TFF3 appears to be an ideal candidate gene that has both tumor- and intestinal-specificity. The aims of this study are to: 1) Identify elements in the TFF3 promoter that confer colon-specific gene expression; 2) Create and test suicide gene constructs driven by the TFF3 promoter in vitro; and 3) Test the anti-tumor efficacy and toxicity of TFF3-suicide gene constructs in vivo. The use of the TFF3 gene to drive expression of suicide genes offers a novel approach which should result in more targetted, safer gene therapy for metastatic colon cancer.

结直肠癌是美国与癌症相关死亡率的第二大最常见原因，而死于大肠癌的患者中有80％患有肝转移。由于目前对转移性结肠癌的治疗只取得了有限的成功，因此有一个重要的需要开发新颖，更有效的治疗策略。 我们的小组使用了基于单纯疱疹病毒胸苷激酶基因和ganciclovir的自杀基因治疗来成功治疗合成动物模型中的结肠癌肝转移。 我们还证明，将自杀基因置于癌胚抗原（CEA）启动子的控制之下具有更大的组织特异性。 此外，我们开发了一种二元基因表达构建体，其中GAL4/VP16转录因子置于CEA启动子的控制之下。 这允许递送更高剂量的含自杀基因的载体，具有更好的肿瘤细胞杀伤和毒性较小。 尽管CEA是一种有用的原型肿瘤相关基因，但其许多正常细胞（尤其是胆道上皮）的表达可能导致不可接受的毒性并限制其临床实用性。 鉴定更特定于肠道的基因，同时保持肿瘤特异性，这应该为更大的治疗功效提供机会。 Trefoil因子家族3（TFF3；以前称为肠Trefoil因子ITF）是这方面有前途的候选人。 TFF3主要由小肠和大肠的细胞表达，在肝脏中没有表达，在其他正常器官中表达非常有限。 迄今为止的证据表明，在结肠中从腺瘤到癌的进展过程中，TFF3表达是高度保守的。 TFF3已被证明可磷酸化B-catenin，从而破坏细胞 - 细胞粘附并使细胞变成运动，这可能解释了TFF3在正常细胞迁移到愈合的粘膜伤口中的作用，也可以解释癌细胞侵袭和转移。 我们已经表明，所有研究的人类结肠癌肝转移研究了TFF3基因。 因此，TFF3似乎是具有肿瘤特异性和肠道特异性的理想候选基因。这项研究的目的是：1）确定赋予结肠特异性基因表达的TFF3启动子中的元素； 2）创建和测试由TFF3启动子在体外驱动的自杀基因构建体； 3）测试体内TFF3-suicide基因构建体的抗肿瘤功效和毒性。 使用TFF3基因驱动自杀基因的表达提供了一种新颖的方法，该方法应导致对转移性结肠癌的靶向更安全，更安全的基因治疗。

项目成果

A rat model to study the role of STn antigen in colon cancer.

研究 STn 抗原在结肠癌中作用的大鼠模型。

• DOI: 10.1023/a:1022248408857
• 发表时间: 2001
• 期刊: Glycoconjugate journal
• 影响因子: 3
• 作者: Ogata,S;Ho,I;Maklansky,J;Chen,A;Werther,JL;Reddish,M;Longenecker,BM;Sigurdson,E;Iishi,S;Zhang,JY;Itzkowitz,SH
• 通讯作者: Itzkowitz,SH

Early colonic carcinoma with extensive lymph node metastases: case report and review of literature.

早期结肠癌伴广泛淋巴结转移：病例报告及文献复习。

• DOI: 10.1007/s003840000273
• 发表时间: 2001
• 期刊: International journal of colorectal disease
• 影响因子: 2.8
• 作者: Lien,GS;Chen,CN;Cheng,YS;Chen,SH;Pan,S;Hsieh,MC;Fang,CL;Itzkowitz,S
• 通讯作者: Itzkowitz,S

Intestinal trefoil factor: a marker of poor prognosis in gastric carcinoma.

• 发表时间: 2002-05
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: T. Yamachika;J. Werther;C. Bodian;M. Babyatsky;M. Tatematsu;Y. Yamamura;Anli Chen;S. Itzkowitz;Biomathematical Sciences