PROSTATIC VASCULOGENIC MIMICRY: A NEW METASTATIC PATHWAY

我们的实验室描述了一种新的现象，肿瘤血管生成，即肿瘤细胞本身（在没有内皮细胞的情况下）形成血管通道和管状网络，促进肿瘤灌注，而不依赖于传统的血管生成。利用前列腺肿瘤和肿瘤前列腺细胞系进行的初步研究有力地支持了侵袭性前列腺肿瘤也表现出“血管生成拟态”的概念。因此，本研究的总体目标是确定前列腺肿瘤中这种现象的关键分子机制。特异性目的1：表征侵袭性前列腺癌细胞进行血管模拟的细胞和分子表型。假设：侵袭性和转移性前列腺癌细胞（而非正常前列腺上皮细胞）进行血管生成模拟，形成血管通道和小管网络，这些血管通道和小管网络可以独立于血管生成或辅助血管生成而灌注肿瘤。特异性目标2：检查上皮细胞和成纤维细胞样亚群之间的分子相互作用，包括异质前列腺癌，导致血管生成模仿。假设：在异质前列腺肿瘤中，上皮细胞和成纤维细胞样亚群之间高度调控的协同作用对于血管生成模拟是必要的。特异性目的3：确定特异性基质金属蛋白酶（MMPs）在前列腺血管生成模拟中的作用/重要性。假设：特异性MMPs在侵袭性前列腺癌细胞形成血管通道和管状网络中起关键作用。意义：假设存在肿瘤细胞系通道紧密地包裹着前列腺肿瘤，以及它们与肿瘤内皮血管的推定吻合，提供了：1)转移可能扩散到远处部位的潜在新途径，2)提供或补充肿瘤与血管系统之间交换的手段。随着这两个血管室的形成、形态和功能关系的基本细胞和分子机制的确定，很可能会发现新的策略来干扰肿瘤的生长和转移。

Our laboratory has described a new phenomenon, tumor Vasculogenesis, whereby tumor cells themselves (in the absence of endothelial cells), form vascular channels and tubular networks which facilitate tumor perfusion independent of classical angiogenesis. Preliminary studies utilizing prostate tumors and neoplastic prostate cell lines strongly support the concept that "vasculogenic mimicry" is also exhibited by aggressive prostatic neoplasms. The overall objective of this proposed research, therefore, is to determine the key molecular mechanisms underlying this phenomenon in tumors of the prostate. Specific Aim 1: Characterize the cellular and molecular phenotype of the aggressive prostate cancer cells undergoing vasculogenic mimicry. Hypothesis: Invasive and metastatic prostate cancer cells (but not normal prostate epithelium) undergo vasculogenic mimicry and form vascular channels and tubular networks, which can perfuse the tumor independent of or supplemental to angiogenesis. Specific Aim 2: Examine the molecular interactions between the epithelial and fibroblast-like subpopulations comprising heterogeneous prostate cancers, resulting in vasculogenic mimicry. Hypothesis: A highly regulated cooperativity between the epithelial and fibroblast-like subpopulations is necessary for vasculogenic mimicry in heterogeneous prostate tumors. Specific Aim 3: Determine the role/importance of specific matrix metalloproteinases (MMPs) in prostatic vasculogenic mimicry. Hypothesis: Specific MMPs are critical in the formation of vascular channels and tubular networks by aggressive prostate cancer cells. Significance: The hypothesized presence of tumor- cell lined channels intimately investing neoplasms of the prostate gland, together with their presumptive anastomosis with endothelial-lined vessels of the tumor, provides: 1) a potential new route by which metastases may spread to distant sites, and 2) a means of providing, or supplementing exchange between the tumor and the blood vascular system. As the fundamental cell and molecular mechanisms are identified which underlie the formation, morphology, and functional relationships between these two vascular compartments, it is highly likely that novel strategies will be identified for interfering clinically with both tumor growth and metastasis.