Endothelial Transdifferentiation of Invasive Tumor Cells

描述(申请人提供)：在胚胎发育期间， 初级血管网络的形成是通过血管生成实现的--原位 祖细胞向内皮细胞分化，内皮细胞组织成 原始网络。随后血管生成网络的重塑成为 功能上有效的血管形成是通过血管生成--萌芽 来自已有网络的新毛细血管。我们引入了这个术语 “血管生成拟态”描述侵袭性黑色素瘤的独特能力 肿瘤细胞在三维培养中形成管状结构和图案化网络， 它“模仿”胚胎血管生成网络的模式，并重塑 在患者侵袭性肿瘤中看到的花纹网络--与 预后不良。这些侵袭性肿瘤细胞的分子图谱表明 他们有一个不受管制的基因，能够表达一种 内皮样表型。我们的初步研究表明：1) 侵袭性黑色素瘤细胞表达VE-钙粘附素(由 内皮细胞)；2)侵袭性肿瘤细胞产生细胞外基质 (ECM)诱导侵袭性差的黑色素瘤细胞形成血管生成 网络；3)侵袭性黑色素瘤细胞参与血管重建 缺血肢体模型，从而说明了他们的内皮干细胞 可塑性。拟议的研究推进了在当前 侵袭性黑色素瘤胚胎样表型的资助期 细胞：目的1：确定VE-钙粘附素表达的功能意义 在人黑色素瘤细胞中进行内皮转分化和 血管生成拟态。目标2：确定由 侵袭性黑色素瘤细胞诱导侵袭性较差的黑色素瘤细胞 形成血管生成网络并模拟内皮细胞。目标3：调查 侵袭性黑色素瘤细胞的干细胞可塑性 在创面愈合和缺血的动物模型中重新血管化组织。数据 这些新的研究产生的基因将为 关于血管内皮细胞的临床诊断和新概念 侵袭性黑色素瘤细胞及其干细胞的分化 可塑性。

DESCRIPTION (provided by applicant): During embryonic development, the formation of primary vascular networks occurs by vasculogenesis -- the in situ differentiation of progenitor cells to endothelial cells that organize into a primitive network. The subsequent remodeling of the vasculogenic network into a functionally efficient vasculature occurs through angiogenesis -- the sprouting of new capillaries from a preexisting network. We have introduced the term "vasculogenic mimicry" to describe the unique ability of aggressive melanoma tumor cells to form tubular structures and patterned networks in 3-D culture, which "mimics" the pattern of embryonic vasculogenic networks and recapitulates the patterned networks seen in patients' aggressive tumors -- correlating with poor prognosis. The molecular profile of these aggressive tumor cells suggests that they have a deregulated genotype, capable of expressing an endothelial-like phenotype. Our preliminary studies indicate that: 1) aggressive melanoma cells express VE-cadherin (exclusively expressed by endothelial cells); 2) aggressive tumor cells produce an extracellular matrix (ECM) that induces poorly aggressive melanoma cells to form vasculogenic networks; and 3) aggressive melanoma cells participate in the revascularization of an ischemic limb model, thus illustrating their endothelial stem cell plasticity. The proposed studies advance observations made during the current funding period regarding the embryonic-like phenotype of aggressive melanoma cells: Aim 1: Determine the functional significance of VE-cadherin expression in human melanoma tumor cells engaged in endothelial transdifferentiation and vasculogenic mimicry. Aim 2: Identify the key molecular components produced by aggressive melanoma tumor cells that induce poorly aggressive melanoma cells to form vasculogenic networks and mimic endothelial cells. Aim 3: Investigate the stem cell plasticity of aggressive melanoma tumor cells for their potential to re-vascularize tissues in animal models of wound healing and ischemia. The data generated from these novel studies will provide new molecular markers for clinical diagnosis and new concepts regarding the trarisendothelial differentiation of aggressive melanoma tumor cells and their stem cell plasticity.