Tumorigenic subversion of mural cells in breast cancer

描述（由申请人提供）：肿瘤血管系统的诱导，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、静止的血管系统中起着关键的调节作用。在肿瘤中，壁细胞与内皮的结合减少和异常。先前的工作已经表明，通过血管生成素-1恢复对脉管系统的功能性抑制成熟抑制肿瘤生长，这表明肿瘤血管的稳定可能是癌症治疗中期望的治疗目标。这项工作的假设是，乳腺癌细胞在功能上改变壁细胞和内皮细胞的接触，并颠覆壁细胞从其正常的抗血管生成的作用，血管生成开关的一部分，促进作用。内皮细胞，壁细胞和乳腺癌细胞之间的旁分泌相互作用将使用体外膜和球体模型，模仿血管壁的组织，以及异种移植模型与修改的壁细胞，以解决三个具体的目标。目的1将确定乳腺癌细胞对壁细胞功能的重要改变，这些改变可能导致肿瘤血管系统表现出的成熟缺陷。目的2将研究肿瘤细胞特异性激活壁细胞中基质金属蛋白酶的能力，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活化中起作用。总之，这些研究将i）提供原理证明，即肿瘤可以将正常抑制性壁细胞的功能颠覆为肿瘤促进状态，以及ii）鉴定参与这些活动的关键分子，以作为未来壁细胞定向治疗的靶点，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.