Analysis of Homing Receptors in Prostate Cancer

描述(申请人提供)：前列腺癌转移以骨转移为特征，常导致患者预后不良。不幸的是，目前还没有专门针对骨转移分子发病机制的治疗方法。最近的研究表明，与其他组织中的血管衬里相比，前列腺肿瘤细胞对骨髓内皮细胞(BMEC)的亲和力增强。我们的实验室已经证明，骨转移前列腺癌细胞与BMEC之间最初的黏附作用是由内皮(E)-选择素介导的。我们已经确定了一个候选的前列腺癌细胞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在正常前列腺上皮组织微阵列(TMA)以及局部和转移性前列腺癌组织中的表达分析表明，PSGL-1几乎仅在转移性前列腺癌细胞上发现，包括骨中的肿瘤细胞。我们假设PSGL-1促进前列腺癌的转移，包括前列腺癌的趋骨行为。这项研究的目的是阐明前列腺癌转移的分子机制，并寻找促进转移行为和/或具有结构基序的肿瘤细胞受体(S)，用于靶向新的抗癌治疗。其具体目的是：1)分析E-选择素配体和PSGL-1对前列腺癌转移细胞的糖生物学调节作用；2)探讨E-选择素结合PSGL-1在前列腺癌转移中的功能作用。实验将包括创新的Western blotting、印迹滚动和细胞黏附分析，以及PSGL-1+和转移性前列腺癌细胞的体内滚动分析。我们将使用人-骨-NOD-SCID小鼠模型来探索PSGL-1在人类前列腺癌进展和转移中的作用。PSGL-1+或-人转移性前列腺癌细胞将被分析其植入人骨移植的能力。将发生自发性前列腺癌和远处转移的TRAMP小鼠与PSGL-1基因缺失的小鼠杂交，在体内直接测试PSGL-1在前列腺癌进展和转移中的作用。这些分析的结果将为前列腺癌转移的分子机制提供新的见解，并可能为开发针对归巢受体的新疗法提供理论基础。

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.