Melanoma Stem Cells, Vasculogenesis and Neoplastic Progression

摘要： 人类黑色素瘤是一种高度侵袭性和抗药性的癌症，对系统治疗一次耐药。 散播的。恶性肿瘤中具有胚胎样可塑性的未分化亚群的发现 已经指出黑色素瘤干细胞的存在。最近，我们的实验室发现了黑色素瘤干细胞 以表达化疗耐药介质ABCBS为特征的细胞，负责 黑色素瘤的进展和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的分子和细胞机制 肿瘤进展目前尚不清楚。血管生成和转移是公认的现象 对肿瘤生长和肿瘤进展至关重要。尽管有关于分子的重要知识 涉及的途径，癌症干细胞与这些过程的特定关系尚未被证明。 到目前为止。我们假设黑色素瘤干细胞能够自我更新和分化，这是 负责肿瘤生长，可能与与肿瘤密切相关的癌症亚群重合 血管生成和转移以及该细胞群体和相关分子特异性靶向 因此，通路可以提供新的策略来根除目前对常规药物耐药的癌症 心理治疗。这项建议的具体目的如下：(1)调查ABCBS+ 明确黑色素瘤干细胞与肿瘤血管生成的分子机制； ABCBS+黑色素瘤干细胞在转移性肿瘤进展中的作用；以及(3)发展新的黑色素瘤 干细胞靶向治疗。因此，该提案与旨在开发小说的努力高度相关 基于选择性靶向肿瘤干细胞重要分子通路的肿瘤治疗策略 细胞。

Abstract: 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.