PSMAs role in signal transduction pathway switching in prostate cancer

描述（由申请人提供）：前列腺癌（PCa）从一种局部的、基本上可治疗的疾病升级为一种侵袭性、转移性肿瘤，死亡率接近70%，这取决于影响原肿瘤进展、侵袭和转移的因素。在侵袭性和转移性较强的前列腺癌中，跨膜肽酶前列腺特异性膜抗原（PSMA）的表达显著增加，并与患者预后呈负相关[1-3]。虽然前列腺肿瘤进展过程中的加速表达表明这种丰富表达的预后标志物有助于前列腺癌的进展或转移，但这种作用的功能证实仍然难以捉摸。先前有研究表明，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，调节肿瘤和视网膜中的新血管形成[4,5]。最近，PSMA在前列腺肿瘤上皮上的表达促进了体内肿瘤的进展，缺乏PSMA的肿瘤的侵袭性明显降低（未发表的数据）。在机制上，PSMA直接干扰PTEN肿瘤抑制通路，改变关键调控信号通路的激活，改变癌控制受体酪氨酸激酶的表达水平，以及下调雄激素受体的表达，从而驱动促肿瘤、抗凋亡和激素难治表型（未发表的数据）。此外，前列腺癌细胞系的粘附和侵袭完全依赖于PSMA，缺乏PSMA的肿瘤表现出较低的转移率，这表明PSMA也参与了远处转移。因此，我们假设PSMA在前列腺癌肿瘤发生过程中具有双重关键功能：1)调节促肿瘤的关键信号转导途径和受体酪氨酸激酶和雄激素受体的表达；2)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prostate tumor epithelium promotes tumor progression in vivo, where tumors lacking PSMA are markedly less aggressive (unpublished data).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androgen receptor expression, thus driving a pro-tumorigenic, anti-apoptotic and hormone-refractory phenotype (unpublished data).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.