Melanoma Stem Cells, Vasculogenesis and Neoplastic Progression

描述(申请人提供)：人类黑色素瘤是一种高度侵袭性和抗药性的癌症，一旦扩散就对系统治疗产生抗药性。这种恶性肿瘤中具有胚胎样可塑性的未分化亚群的发现表明存在黑色素瘤干细胞。最近，我们的实验室已经鉴定出黑色素瘤干细胞，其特征是表达化疗耐药介质ABCBS，它与黑色素瘤的进展有关，并可作为实验性肿瘤异种移植模型的治疗靶点。黑色素瘤干细胞触发肿瘤发生和促进肿瘤进展的分子和细胞机制目前尚不清楚。血管生成和转移是公认的对肿瘤生长和肿瘤进展至关重要的现象。尽管对所涉及的分子途径有重要的了解，但到目前为止还没有证明癌症干细胞与这些过程的具体关系。我们假设，能够自我更新和分化的黑色素瘤干细胞可能与参与肿瘤血管生成和转移的癌症亚群重合，因此，针对这一细胞群体和相关分子途径的特异性靶向可能为根除目前对常规治疗耐药的癌症提供新的策略。这项建议的具体目的如下：(1)研究ABCBS+黑色素瘤干细胞与肿瘤血管生成的关系，并确定所涉及的分子机制；(2)确定ABCBS+黑色素瘤干细胞在转移性肿瘤进展中的作用；(3)开发新的黑色素瘤干细胞靶向治疗。因此，该提案与旨在开发基于选择性靶向癌症干细胞中的重要分子通路的癌症治疗的新治疗策略的努力高度相关。

DESCRIPTION (provided by applicant): Human melanoma is a highly aggressive and drug resistant cancer and resistant to systemic therapy once disseminated. Findings of undifferentiated subpopulations with embryonic-like plasticity within this malignancy have pointed to the presence of melanoma stem cells. Recently our laboratory has identified melanoma stem cells characterized by expression of the chemoresistance mediator ABCBS, which are responsible for melanoma progression and can be therapeutically targeted in experimental tumor xenotransplantation models. The molecular and cellular mechanisms by which melanoma stem cells trigger tumorigenesis and promote neoplastic progression are currently unknown. Vasculogenesis and metastasis are phenomena recognized to be critical for tumor growth and neoplastic progression. Despite the significant knowledge about the molecular pathways involved, a specific relationship of cancer stem cells to these processes has not been demonstrated to date. We hypothesize that melanoma stem cells capable of self-renewal and differentiation, which are responsible for tumor growth, may coincide with cancer subpopulations critically involved in tumor vasculogenesis and metastasis and that specific targeting of this cell population and of related molecular pathways could thus provide for novel strategies to eradicate cancers currently resistant to conventional therapy. The specific aims of this proposal are the following: (1) Investigate the relationship between ABCBS+ melanoma stem cells and tumor vasculogenesis and define the molecular mechanisms involved; (2) Define the role of ABCBS+ melanoma stem cells in metastatic neoplastic progression; and (3) Develop novel melanoma stem cell-targeted therapies. Thus, the proposal is highly relevant to efforts directed at developing novel therapeutic strategies to cancer therapy based on selectively targeting vital molecular pathways in cancer stem cells.