Tumorigenic subversion of mural cells in breast cancer

描述（由申请人提供）：肿瘤血管的诱导，被称为“血管生成开关”，是肿瘤进展的限速步骤。大多数功能研究都集中在内皮细胞对促血管生成刺激的反应上；然而，越来越多的证据表明，支持壁细胞（平滑肌细胞和周细胞）在维持成熟、静止的脉管系统中起着关键的调节作用。在肿瘤中，壁细胞与内皮的联系减少和异常。先前的研究表明，血管生成素-1对血管功能抑制成熟的恢复可抑制肿瘤生长，这表明肿瘤血管的稳定可能是治疗癌症的理想治疗目标。这项工作的基础假设是，乳腺癌细胞在功能上改变了壁细胞和内皮细胞的接触，并破坏了壁细胞正常的抗血管生成作用，使其成为血管生成开关的一部分，从而促进血管生成。内皮细胞、壁细胞和乳腺癌细胞之间的旁分泌相互作用将通过模拟血管壁组织的体外膜和球形模型以及修饰壁细胞的异种移植模型进行研究，以解决三个具体目标。目的1将确定壁细胞功能的关键变化，以应对乳腺癌细胞，这可能有助于肿瘤血管系统表现出成熟缺陷。目的2将研究肿瘤细胞激活基质金属蛋白酶的能力，特别是在壁细胞中，作为获得促血管生成功能状态的一部分。目的3将探讨特异性鞘氨醇-1-磷酸受体的分化利用是否在肿瘤诱导的壁细胞成熟缺陷和激活中发挥作用。总之，这些研究将i)提供肿瘤可以破坏正常抑制壁细胞功能到肿瘤促进状态的原理证明，ii)确定参与这些活动的关键分子参与者，作为未来壁细胞定向治疗的靶标，以恢复血管系统的静止。

DESCRIPTION (provided by applicant): The induction of tumor vasculature, known as the 'angiogenic switch', is a rate-limiting step in tumor progression. Most functional studies have focused on the responses of endothelial cells to pro-angiogenic stimuli; however, there is mounting evidence that the supporting mural cells (smooth muscle cells and pericytes) play a key regulatory role in maintaining a mature, quiescent vasculature. In tumors, mural cell association with the endothelium is decreased and abnormal. Previous work has shown that restoration of functional inhibitory maturation to vasculature by Angiopoietin-1 inhibits tumor growth, suggesting that stabilization of tumor vessels may be a desirable therapeutic goal in the treatment of cancer. The hypothesis underly this work is that breast cancer cells functionally alter mural cell and endothelial cell contacts and subvert the mural cell from its normal anti-angiogenic role to a vessel-promoting role as part of the angiogenic switch. Paracrine interactions between endothelial cells, mural cells, and breast cancer cells will be studied using in vitro membrane and spheriod models that mimic the organization of the blood vessel wall, as well xenograft models with modified mural cells, in order to address three specific aims. Aim 1 will identify critical alterations in mural cell function in response to breast cancer cells that may contribute to the maturation defect exhibited by the tumor vasculature. Aim 2 will investigate the ability of tumor cells to activate matrix metalloproteases specifically in mural cells as part of the acquisition of a pro-angiogenic functional state. Aim 3 will address whether the differentiation utilization of specific sphingosine-1-phosphate receptors plays a role in the tumor-induced maturation defect and activation of mural cells. Together, these studies will i) provide proof-of-principle that tumors can subvert the function of normally inhibitory mural cells to a tumor-promoting state, and ii) identify pivotal molecular players involved in these activities to serve as targets for future mural cell-directed therapies to restore quiescence to the vasculature.