Mechanisms of Overexpressed TrkB in Inducing Pancreatic Cancer Metastasis

过表达TrkB诱导胰腺癌转移的机制

基本信息

批准号：
8676697
负责人：
PAUL J CHIAO
金额：
$ 30.85万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-06 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8676697
关键词：
Adult Agar Amino Acids Anoikis Basic Science Binding Cancer Etiology Cancer Patient Cancer cell line Cell Culture Techniques Cell Line Cells Clinical Cytoplasm Development Diagnosis Disease Dissociation Dominant-Negative Mutation Ductal Epithelial Cell Epithelial Family Family member Genes Goals Growth Guanine Nucleotide Dissociation Inhibitors Guanosine Triphosphate Health Human Malignant neoplasm of pancreas Mediating Mesenchymal Metastatic Neoplasm to the Liver Modeling Molecular Molecular Genetics Mus Mutation Neoplasm Metastasis Nonmetastatic Nude Mice Operative Surgical Procedures Outcome Pancreas Pancreatic Adenocarcinoma Patients Peritoneal Phenotype Phosphotransferases Play Protein Tyrosine Kinase Publications Receptor Protein-Tyrosine Kinases Research Resistance Retroperitoneal Space Role Signal Pathway Signal Transduction Specimen Staging Survival Rate Testing Therapeutic Translational Research Tropomyosin Tumor Cell Line United States Variant Xenograft procedure anticancer research base chemotherapy design effective therapy genetic profiling in vivo kinase inhibitor knock-down member mortality mouse model mutant novel novel therapeutic intervention overexpression pancreatic cancer cells pancreatic cell line pancreatic neoplasm pancreatic tumorigenesis perineural rho rhoB p20 GDI small hairpin RNA therapy resistant treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer mortality in adults in the United States, with a 5- year survival rate that has remained at 1-3% for the past 25 years. At diagnosis, approximately 80% of pancreatic cancer patients have therapy-resistant locally advanced or metastatic disease with a median survival of less than 6 months. Even when stage I or II pancreatic cancer is apparently localized to the pancreas and surgically removed, 70% of those patients still develop liver metastases within 2 years after surgery. Current treatments of metastatic pancreatic cancer are largely ineffective. Pancreatic cancer thus poses one of the greatest challenges in cancer research. Although a genetic profile for pancreatic caner is emerging, the role of specific genetic alterations that initiate and mediate its cardinal clinical features of locally aggressive growth, metastasis, and chemotherapy resistance, remains unresolved. The underlying mechanisms, by which pancreatic cancer cells become invasive and metastatic, remain to be elucidated. Identification of the functions of the signature genetic and molecular alterations in pancreatic tumorigenesis and metastasis will provide a molecular basis for designing novel therapeutic approaches. Therefore, the long-term objective of the proposed research is to study the molecular basis of pancreatic metastasis using mouse models, which carry the signature genetic alterations found in this disease, and study the phenotypes induced by these genetic alterations. Our recent findings show that tropomyosin-related kinase BT1 (TrkBT1), which is a member of the protein tyrosine kinase receptor family, is overexpressed in metastatic pancreatic cancer cell line, Colo357L3.6pl, but not in the nonmetastatic parental cell line, Colo357FG. The overexpression of TrkBT1 has been related to occurrence of liver metastasis in human pancreatic adenocarcinoma. TrkBT1 was also the predominant overexpressed form of TrkB in other metastatic pancreatic cancer cell lines. Knock down of TrkBT1 by its shRNA induced anoikis. Overexpression of TrkBT1 in nonmetastatic Colo357FG cells induced colony formation in soft agar and liver metastasis in nude mice, but how the TrkBT1 variant, which lacks kinase-domain, induces pancreatic cancer metastasis remain to be further established. The hypothesis, the TrkBT1 variant play a key role in pancreatic cancer metastasis by activation of RhoA will be further tested. The specific aims are to determine whether the expression of GDI1, RhoA, and shRNA for GDI1 and RhoA will alter the metastatic potential of the pancreatic cancer cells, and to elucidate the mechanism by which the TrkBT1 induced the liver metastasis. A better understanding of the mechanisms of genetic alterations in induction of metastatic phenotypes will provide a basis for developing effective treatment strategies for pancreatic cancer. Targeting specific mutations and signaling pathways in pancreatic cancer may be one of the novel therapeutic interventions to treat cancer metastasis.

描述（由申请人提供）：胰腺癌是美国成年人癌症死亡率的第四个主要原因，在过去25年中，其生存率为5年的生存率一直保持在1-3％。诊断时，大约80％的胰腺癌患者患有耐药性局部晚期或转移性疾病，中位生存期少于6个月。即使I或II期胰腺癌显然位于胰腺并通过外科手术去除时，这些患者中有70％仍在手术后2年内发展出肝转移。转移性胰腺癌的当前治疗方法在很大程度上无效。因此，胰腺癌是癌症研究中最大的挑战之一。尽管出现了胰腺癌的遗传特征，但特定的遗传改变的作用启动和介导了其局部侵略性生长，转移和耐化学疗法的局部临床特征，但仍未解决。胰腺癌细胞变得侵入性和转移的基本机制仍有待阐明。胰腺癌发生和转移的特征性遗传和分子改变功能的鉴定将为设计新型治疗方法提供分子基础。因此，提出的研究的长期目标是使用小鼠模型研究胰腺转移的分子基础，这些模型带有该疾病中发现的特征性遗传变化，并研究这些遗传改变引起的表型。我们最近的发现表明，与蛋白质酪氨酸激酶受体家族的成员，与肌动蛋白相关的激酶BT1（TRKBT1）在转移性胰腺癌细胞系中过表达Colo357L3.6PL，但在非移动性良好细胞系列中，Colo357fg。 TRKBT1的过表达与人类胰腺腺癌中的肝转移有关。 TRKBT1也是其他转移性胰腺癌细胞系中TRKB的主要表达形式。 shrna诱导的厌食症击倒trkbt1。在非转移性COLO357FG细胞中TRKBT1的过表达诱导裸鼠的软琼脂和肝转移诱导菌落形成，但是如何缺乏激酶域的TRKBT1变体诱导胰腺癌转移，以进一步建立胰腺癌转移。假设TRKBT1变体通过激活RhoA在胰腺癌转移中起关键作用。具体目的是确定GDI1，RhoA和ShRNA的GDI1和RhoA的表达是否会改变胰腺癌细胞的转移潜力，并阐明TRKBT1诱导肝转移的机制。更好地理解转移性表型诱导遗传改变的机制将为制定有效的胰腺癌治疗策略提供基础。靶向胰腺癌的特定突变和信号通路可能是治疗癌症转移的新型治疗干预措施之一。