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，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，促进肿瘤的灌注，而不是经典的血管生成。对前列腺癌和前列腺癌细胞系的初步研究有力地支持了侵袭性前列腺癌也表现出“血管生成拟态”的概念。因此，这项拟议研究的总体目标是确定前列腺癌这种现象背后的关键分子机制。具体目的1：研究侵袭性前列腺癌血管生成拟态的细胞和分子表型。假设：侵袭性和转移性前列腺癌细胞(但不是正常前列腺上皮)经历血管生成拟态，形成血管通道和管状网，可独立于血管生成或补充血管生成而向肿瘤灌流。具体目标2：研究构成异质性前列腺癌的上皮细胞和成纤维细胞样亚群之间的分子相互作用，导致血管生成拟态。假设：异质性前列腺癌的血管生成拟态需要上皮细胞和成纤维细胞样亚群之间高度调节的协同性。具体目标3：确定特定的基质金属蛋白酶(MMPs)在前列腺血管生成拟态中的作用/重要性。假设：特定的MMPs在侵袭性前列腺癌细胞的血管通道和管状网络的形成中起关键作用。意义：假设存在与前列腺癌紧密相连的肿瘤细胞通道，以及它们与肿瘤内皮细胞血管的假定吻合，提供了：1)转移可能扩散到远处的潜在新途径，2)提供或补充肿瘤和血管系统之间的交换的方法。随着这两个血管之间形成、形态和功能关系的基本细胞和分子机制的确定，很有可能找到新的策略来同时干预肿瘤的生长和转移。

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.