Tumorigenic subversion of mural cells in breast cancer

描述(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；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、静止的血管系统中发挥着关键的调节作用。在肿瘤中，壁细胞与内皮细胞的联系减少和异常。以往的工作表明，血管生成素-1使功能抑制成熟的血管恢复到血管系统可以抑制肿瘤的生长，提示稳定肿瘤血管可能是治疗癌症的理想目标。这项工作背后的假设是，乳腺癌细胞在功能上改变了壁细胞和内皮细胞的联系，并将壁细胞从正常的抗血管生成作用转变为作为血管生成开关的促进血管的作用。为了达到三个特定的目的，我们将使用模拟血管壁组织的体外膜和球体模型以及改良的壁细胞异种移植模型来研究内皮细胞、壁细胞和乳腺癌细胞之间的旁分泌相互作用。目的1将确定响应乳腺癌细胞的壁细胞功能的关键变化，这些变化可能有助于肿瘤血管系统表现出的成熟缺陷。目的2将研究肿瘤细胞激活特定于壁细胞的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将讨论特定的鞘氨醇-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。总而言之，这些研究将：1)提供肿瘤可以颠覆正常抑制的壁细胞的功能到促进肿瘤状态的原理证据；2)确定参与这些活动的关键分子角色，作为未来壁细胞导向治疗的靶点，以恢复血管系统的平静。

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.