Melanoma Stem Cells, Vasculogenesis and Neoplastic Progression

描述（由申请人提供）：人类黑色素瘤是一种高度侵袭性和耐药的癌症，一旦播散，对全身治疗有抵抗力。在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黑色素瘤干细胞的存在。最近，我们的实验室发现了以表达化疗耐药介质ABCBS为特征的黑色素瘤干细胞，ABCBS负责黑色素瘤的进展，可以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。血管发生和转移是肿瘤生长和肿瘤进展的关键现象。尽管对所涉及的分子途径有重要的了解，但迄今为止尚未证明癌症干细胞与这些过程的特定关系。我们假设黑色素瘤干细胞能够自我更新和分化，负责肿瘤的生长，可能与肿瘤血管发生和转移的关键癌症亚群一致，并且特异性靶向这些细胞群和相关分子途径可以因此提供新的策略来根除目前对传统治疗无效的癌症。本课题的具体目的是：(1)研究ABCBS+黑色素瘤干细胞与肿瘤血管发生的关系，明确其分子机制；(2)明确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方法。因此，该建议与开发基于选择性靶向癌症干细胞中重要分子通路的新型癌症治疗策略高度相关。

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.