PSMAs role in signal transduction pathway switching in prostate cancer

PSMA 在前列腺癌信号转导通路切换中的作用

基本信息

批准号：
8907977
负责人：
LESLIE ANN CAROMILE
金额：
$ 10.04万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-07 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8907977
关键词：
Adhesions Affect Androgen Receptor Animals Apoptotic Archives Automobile Driving Blood Blood Circulation Bone Marrow Cancer Control Cell Line Cessation of life Data Diagnosis Disease Distant Endothelial Cells Epithelium Extracellular Matrix Glutamate Carboxypeptidase II Health Hormones Human In Vitro Incidence Individual Integrins Knockout Mice Link Lymphatic MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of prostate Mediating Metastatic Prostate Cancer Molecular Molecular Biology Mus Mutation Neoplasm Circulating Cells Neoplasm Metastasis PI3K/AKT PTEN gene Pathway interactions Patients Peptide Hydrolases Phenotype Play Prevention Prognostic Marker Prostate Prostatic Neoplasms Receptor Protein-Tyrosine Kinases Refractory Regulation Retinal Neoplasms Role Sampling Signal Pathway Signal Transduction Signal Transduction Pathway Site Small Interfering RNA Specimen Testing Testosterone Tumor Suppressor Proteins Vascularization advanced disease autocrine base cancer therapy deprivation in vivo in vivo Model male mortality mouse model neoplastic cell novel outcome forecast prostate cancer cell prostate cancer cell line receptor expression therapeutic development tumor tumor progression tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): The escalation of prostate cancer(PCa) from a localized, largely treatable disease to an invasive, metastatic tumor with a nearly 70% mortality rate depends on factors affecting the progression, invasion and metastasis of the original tumor. Expression of the transmembrane peptidase Prostate Specific Membrane Antigen (PSMA) is markedly increased in more aggressive and metastatic prostate carcinomas where it correlates negatively with patient prognosis[1-3]. While this accelerating expression during progression of prostate tumors suggests this abundantly expressed prognostic marker contributes to PCa progression or metastasis, functional confirmation of such a role remains elusive. It has previously been shown that PSMA regulates neovessel formation in tumors and the retina by facilitating integrin 1-mediated endothelial adhesion to the extracellular matrix and resultant signal transduction mechanisms[4, 5]. More recently, PSMA expression on the prostate tumor epithelium promotes tumor progression in vivo, where tumors lacking PSMA are markedly less aggressive (unpublished data). Mechanistically, PSMA directly interferes with the PTEN tumor-suppressor pathway, alters activation of critical regulatory signaling pathways and modifies expression levels of cancer- controlling receptor tyrosine kinases as well as down regulating androgen receptor expression, thus driving a pro-tumorigenic, anti-apoptotic and hormone-refractory phenotype (unpublished data). Furthermore, adhesion and invasion of PCa cell lines is exquisitely PSMA dependent and tumors lacking PSMA show reduced rates of metastasis, suggesting its participation in metastasis to distant sites as well. Therefore, it is hypothesized that PSMA performs dual pivotal functions during prostate cancer tumorigenesis by: i) modulating critical tumor- promoting signal transduction pathways and receptor tyrosine kinase and androgen receptor expression and ii) regulating integrin adhesion of circulating tumor cells to bone marrow endothelial cells to promote metastasis.

描述（由申请人提供）：前列腺癌（PCa）从一种局部的、很大程度上可治疗的疾病升级为一种死亡率接近 70% 的侵袭性、转移性肿瘤，取决于影响原发肿瘤的进展、侵袭和转移的因素。跨膜肽酶前列腺特异性膜抗原 (PSMA) 的表达在更具侵袭性和转移性的前列腺癌中显着增加，与患者预后呈负相关[1-3]。虽然前列腺肿瘤进展过程中这种加速表达表明这种大量表达的预后标志物有助于前列腺癌进展或转移，但这种作用的功能确认仍然难以捉摸。先前已表明，PSMA 通过促进整合素 1 介导的内皮细胞与细胞外基质的粘附以及由此产生的信号转导机制来调节肿瘤和视网膜中的新生血管形成 [4, 5]。最近，前列腺肿瘤上皮上的 PSMA 表达促进体内肿瘤进展，其中缺乏 PSMA 的肿瘤的侵袭性明显较低（未发表的数据）。从机制上讲，PSMA 直接干扰 PTEN 肿瘤抑制通路，改变关键调节信号通路的激活，改变控癌受体酪氨酸激酶的表达水平，并下调雄激素受体表达，从而驱动促肿瘤、抗凋亡的作用。和激素难治性表型（未发表的数据）。此外，PCa 细胞系的粘附和侵袭完全依赖于 PSMA，缺乏 PSMA 的肿瘤显示出转移率降低，表明其也参与了向远处部位的转移。因此，假设 PSMA 在前列腺癌肿瘤发生过程中发挥双重关键功能：i) 调节关键的肿瘤促进信号转导途径以及受体酪氨酸激酶和雄激素受体表达，ii) 调节循环肿瘤细胞与骨髓内皮细胞的整合素粘附以促进转移。