Analysis of Homing Receptors in Prostate Cancer

描述（申请人提供）：前列腺肿瘤转移多发生于骨，常导致患者预后差。不幸的是，目前还没有针对骨转移的分子发病机制的治疗方法。最近的研究表明，前列腺肿瘤细胞对骨髓内皮（BMEC）的亲和力比对其他组织血管内膜的粘附性强。我们的实验室已经证明骨转移性前列腺肿瘤细胞和BMEC之间最初的粘附相互作用是由内皮(E)选择素介导的。我们已经确定了一种候选前列腺肿瘤细胞e -选择素配体，称为p -选择素糖蛋白配体1 （PSGL-1）。值得注意的是，PSGL-1在正常前列腺上皮以及局部和转移性前列腺肿瘤组织的组织微阵列（TMA）上的表达分析显示，PSGL-1几乎只存在于转移性前列腺肿瘤细胞上，包括骨肿瘤细胞。我们假设PSGL-1促进前列腺肿瘤转移，包括前列腺癌的骨向性行为。本研究的目的是阐明前列腺肿瘤转移的分子发病机制，并鉴定促进转移行为和/或具有结构基序的肿瘤细胞受体，以靶向新的抗癌疗法。具体目的是：1)分析e -选择素配体和PSGL-1对转移性前列腺肿瘤细胞的糖生物学调控；2)探讨e -选择素结合的PSGL-1在前列腺肿瘤转移中的功能作用。实验将包括创新的Western blotting、印迹滚动和细胞粘附测定，以及PSGL-1 +和-转移性前列腺肿瘤细胞的体内滚动测定。我们将采用人骨- nod - scid小鼠模型来探讨PSGL-1在人前列腺肿瘤进展和转移中的作用。PSGL-1 +或-人转移性前列腺肿瘤细胞将分析其进入人骨异种移植物的能力。将发生自发性前列腺腺癌和远处转移的TRAMP小鼠与PSGL-1缺失的小鼠杂交，在体内直接检测PSGL-1在前列腺肿瘤进展和转移中的作用。这些分析结果将为前列腺肿瘤转移的分子发病机制提供新的见解，并可能为开发靶向归巢受体的新疗法提供理论依据。

DESCRIPTION (provided by applicant): Prostate tumor metastasis characteristically occurs in bone and often results in the poor prognosis of patients. Unfortunately, there are no treatments that specifically target the molecular pathogenesis of bone metastasis. Recent studies have indicated that prostate tumor cells exhibit an enhanced avidity for bone marrow endothelium (BMEC) compared with adhesion to blood vessel linings in other tissues. Our laboratory has shown that initial adhesive interactions between bone-metastatic prostate tumor cells and BMEC is mediated by endothelial (E)-selectin. We have identified a candidate prostate tumor cell E-selectin ligand known as P-selectin glycoprotein ligand-1 (PSGL-1). Remarkably, expression analysis of PSGL-1 on tissue micro-arrays (TMA) of normal prostate epithelium and of localized and metastatic prostate tumor tissue has revealed that PSGL-1 is almost exclusively found on metastatic prostate tumor cells, including tumor cells in bone. We hypothesize that PSGL-1 facilitates prostate tumor metastasis, including the bone tropic behavior of prostate cancer. The objective of studies outlined in this proposal is to elucidate the molecular pathogenesis of prostate tumor metastasis and identify tumor cell receptors that promote metastatic behavior and/or possess structural motif(s) for targeting of novel anti-cancer therapies. The specific aims are: 1) To analyze the glycobiological regulation of E-selectin ligand and PSGL-1 on metastatic prostate tumor cells and 2) To investigate the functional role of E-selectin-binding PSGL-1 in prostate tumor metastasis. Experimentation will include innovative Western blotting, blot rolling and cell adhesion assays as well as in vivo rolling assays of PSGL-1 + and - metastatic prostate tumor cells. We will employ a hu-bone-NOD-SCID mouse model to explore the role of PSGL-1 in human prostate tumor progression and metastasis. PSGL-1 + or - human metastatic prostate tumor cells will be analyzed for their capacity to home into human bone xenografts. TRAMP mice, which develop spontaneous prostate adenocarcinoma and distant metastases, will be crossed into PSGL-1 null mice to directly test the role of PSGL-1 in prostate tumor progression and metastasis, in vivo. Results from these analyses will offer new insights into the molecular pathogenesis of prostate tumor metastasis and may provide rationale for development of new therapies targeting homing receptors.