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：
8464658
负责人：
PAUL J CHIAO
金额：
$ 29.89万
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/8464658
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 neoplasm pancreatic tumorigenesis perineural public health relevance 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）：胰腺癌是美国成人癌症死亡率的第四大原因，其 5 年生存率在过去 25 年中一直保持在 1-3%。诊断时，大约 80% 的胰腺癌患者患有局部晚期或转移性耐药疾病，中位生存期不到 6 个月。即使 I 期或 II 期胰腺癌明显局限于胰腺并通过手术切除，70% 的患者在术后 2 年内仍会出现肝转移。目前转移性胰腺癌的治疗基本上无效。因此，胰腺癌是癌症研究中最大的挑战之一。尽管胰腺癌的基因谱正在出现，但引发和介导其局部侵袭性生长、转移和化疗耐药等主要临床特征的特定基因改变的作用仍未得到解决。胰腺癌细胞侵袭和转移的潜在机制仍有待阐明。识别胰腺肿瘤发生和转移中标志性遗传和分子改变的功能将为设计新的治疗方法提供分子基础。因此，拟议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，这些模型携带在该疾病中发现的标志性遗传改变，并研究这些遗传改变诱导的表型。我们最近的研究结果表明，原肌球蛋白相关激酶 BT1 (TrkBT1) 是蛋白酪氨酸激酶受体家族的成员，在转移性胰腺癌细胞系 Colo357L3.6pl 中过度表达，但在非转移性亲代细胞系 Colo357FG 中不过度表达。 TrkBT1的过度表达与人胰腺腺癌肝转移的发生有关。 TrkBT1 也是其他转移性胰腺癌细胞系中 TrkB 的主要过表达形式。通过 shRNA 敲低 TrkBT1 诱导失巢凋亡。 TrkBT1在非转移性Colo357FG细胞中的过度表达诱导了软琼脂中的集落形成和裸鼠的肝转移，但缺乏激酶结构域的TrkBT1变体如何诱导胰腺癌转移仍有待进一步确定。 TrkBT1 变体通过激活 RhoA 在胰腺癌转移中发挥关键作用的假设将得到进一步测试。具体目的是确定GDI1、RhoA以及GDI1和RhoA的shRNA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。更好地了解诱导转移表型的遗传改变机制将为开发有效的胰腺癌治疗策略奠定基础。针对胰腺癌中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。