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. ? ? ?
Human malignant melanoma is a highly metastatic cancer that is markedly resistant to conventional therapy (Chin et al., 2006;Helmbach et al., 2003;Soengas and Lowe, 2003). Although the survival rate of patients diagnosed with melanoma has improved considerably over the past decades (Beddingfield, 2003), the lifetime risk and overall mortality due to melanoma escalate yearly (Thompson et al., 2005) and increase more rapidly than in most adult onset cancers (Jemal et al., 2001). While primary melanomas are largely (>95%) curable by surgical excision when diagnosed early (Breslow, 1978), the 5-year survival of patients with regional lymph node infiltrations decreases to 50% (Balch et al., 2001). Melanoma prognosis is particularly poor for patients with visceral metastases as evidenced by a median survival rate of only a few months (Balch et al., 2001). The minimal therapeutic benefit of current treatment regimens in this group of patients (Soengas and Lowe, 2003) indicates the urgency for novel therapeutic strategies targeted at therapy-resistant melanoma cell populations, which may coincide with cancer stem cells (CSC). Tumor initiation and growth resulting from the formation of CSC, which may comprise only a minority of cells within a tumor but are nevertheless critically involved in its propagation, is an intriguing concept that is being increasingly validated experimentally (Schatton and Frank, 2008). Furthermore, cancer growth and metastasis driven by chemoresistant CSC has been proposed to contribute to the failure of existing chemotherapies to consistently eradicate malignant tumors (Dean et al., 2005;Reya et al., 2001;Schatton et al., 2008). ABCB5 (ATP-binding cassette, sub-family B (MDR/TAP), member 5) is a novel human multidrug resistance (MDR) mediator first cloned and characterized in our laboratory (Frank et al., 2003), which is principally expressed by cells of the melanocytic lineage (Chen et al., 2005;Frank et al., 2005; Frank et al., 2003;Heimerl et al., 2007;Huang et al., 2004;Szakacs et al., 2004) and is responsible for conferring resistance to chemotherapy in vitro (Frank et al., 2005;Huang et al., 2004). Subsequent work by our laboratory has demonstrated that ABCB5 identifies CSC in human malignant melanoma (malignant melanoma stem cells, MMSC) that correlate with clinical disease progression and that can be specifically targeted to abrogate tumor growth (Schatton et al., 2008). Consistent with these findings, the ABCB5 gene is also preferentially expressed by in vitro self-renewing melanoma minority populations (Keshet et al., 2008) and by melanoma cell lines of metastatic as opposed to primary, radial growth phase tumor origin (Sousa and Espreafico, 2008). The specific molecular and cellular mechanisms by which MMSC 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 CSC to these processes has not been demonstrated to date. In this regard, further preliminary results from our laboratory detailed in this proposal reveal specific gene expression profiles, functional differentiation plasticity, and tumor distribution patterns of ABCB5+ MMSC strongly suggestive of a specific contribution of this cell subset to tumor vasculogenesis through vasculogenic mimicry and to melanoma progression through enhanced metastatic potential. We hypothesize that ABCB5+ MMSC, capable of self-renewal and differentiation and responsible for tumor growth, contribute to tumor vasculogenesis and are responsible for melanoma metastasis, and that specific targeting of ABCB5+ MMSC and MMSC-specific molecular pathways could therefore provide for novel strategies to eradicate cancers currently resistant to conventional therapy. The specific aims of this proposal are the following: Specific Aim 1: Investigate the relationship between ABCB5+ melanoma stem cells and tumor vasculogenesis and define the molecular mechanisms involved. Specific Aim 2: Define the role of ABCB5+ melanoma stem cells in metastatic neoplastic progression. Specific Aim 3: Develop novel melanoma stem cell-targeted therapies.
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