PSMAs role in signal transduction pathway switching in prostate cancer

描述（由申请人提供）：前列腺癌（PCa）从局部的、基本上可治疗的疾病升级为侵袭性、转移性肿瘤，死亡率接近70%，这取决于影响原始肿瘤进展、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著增加，其中其与患者预后呈负相关[1-3]。虽然这种在前列腺肿瘤进展过程中的加速表达表明这种大量表达的预后标志物有助于PCa进展或转移，但这种作用的功能确认仍然难以捉摸。先前已经表明，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）。在机制上，PSMA直接干扰PTEN肿瘤抑制途径，改变关键调节信号传导途径的活化并改变癌症控制受体酪氨酸激酶的表达水平以及下调雄激素受体表达，从而驱动促肿瘤发生、抗凋亡和肿瘤难治性表型（未发表的数据）。此外，PCa细胞系的粘附和侵袭是精确地PSMA依赖性的，并且缺乏PSMA的肿瘤显示出降低的转移率，这表明其也参与向远处部位的转移。因此，假设PSMA通过以下方式在前列腺癌肿瘤发生期间执行双重关键功能：i）调节关键的肿瘤促进信号转导途径和受体酪氨酸激酶和雄激素受体表达，以及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。

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prostate tumor epithelium promotes tumor progression in vivo, where tumors lacking PSMA are markedly less aggressive (unpublished data).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androgen receptor expression, thus driving a pro-tumorigenic, anti-apoptotic and hormone-refractory phenotype (unpublished data).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.