Identification and targeting of colon cancer initiating cells

描述（由申请人提供）： 结肠癌是50岁以上男性和女性中第三大最常见的癌症类型，也是癌症相关死亡的第二大常见原因。大多数可用的治疗方法可以有效地杀死大量的癌细胞，但肿瘤可能会从耐药的少数群体中再生，这可能与癌症干细胞相吻合。具有自我更新和分化能力的肿瘤干细胞是肿瘤生长的主要原因，已在人类恶性血液病和几种实体瘤中发现。特异性靶向癌症干细胞可以提供一种新的策略，以根除目前对全身治疗有抵抗力的癌症。ABCB 5是一种新的人类多药耐药介质，最近被证明是由人类黑色素瘤和其他恶性肿瘤，包括结肠癌表达，并负责在体外赋予耐药性化疗。例如，ABCB 5的抑制使正常耐药的黑素瘤细胞对阿霉素、喜树碱和5-FU敏感。随后的工作表明，ABCB 5鉴定了人类恶性黑色素瘤中与临床疾病进展相关的癌症干细胞，并且可以特异性靶向消除肿瘤生长。鉴定在更晚期疾病中具有增强丰度但通过定义化学抗性决定簇对特异性靶向敏感的癌症干细胞对癌症治疗具有重要意义。我们最近的研究确定了临床人类结肠癌中ABCB 5表达细胞的子集，建立了结肠癌细胞系，并显示了ABCB 5表达与临床结肠癌进展之间的相关性。基于这些发现，我们假设化学抗性介质ABCB 5，类似于其在黑色素瘤中的功能，识别结肠癌干细胞，并且特异性靶向表达ABCB 5的结肠癌细胞可能导致消除播散性疾病。本研究拟（1）研究ABCB 5是否可以作为结肠癌的一种新的肿瘤干细胞标志物;（2）检测ABCB 5+结肠癌细胞及相关肿瘤干细胞亚群对5-FU的耐药性，并开发以ABCB 5为靶点的耐药性逆转策略;（3）研究靶向ABCB 5的结肠癌干细胞消融或化学抗性逆转是否可以在体内抑制肿瘤的发生/进展。这将通过研究由小鼠生物测定中的预后和结局数据支持的原发性人类癌症标本来实现，其中肿瘤异种移植物以重现自然发生的疾病的方式发展，并且其中ABCB 5+肿瘤细胞可能是治疗靶向的。所提出的方法将确定新型生物标志物ABCB 5在结肠癌中的临床相关性和治疗重要性，并应为ABCB 5+结肠CSC在人类患者中的成功靶向铺平道路。

DESCRIPTION (provided by applicant): Colon cancer is the third most commonly diagnosed type of cancer in both men and women fifty years of age and older and is the second most common cause of cancer-related death. Most available therapies effectively kill bulk populations of cancer cells, but tumors may regenerate from therapy-resistant minority populations, which may coincide with cancer stem cells. Cancer stem cells capable of self-renewal and differentiation, which are responsible for tumor growth, have been identified in human hematological malignancies and several solid tumors. Specific targeting of cancer stem cells could provide for a novel strategy to eradicate cancers currently resistant to systemic therapy. ABCB5 is a novel human multidrug resistance mediator recently shown to be expressed by human melanomas and additional malignancies including colon cancer and to be responsible for conferring resistance to chemotherapy in vitro. For example, inhibition of ABCB5 renders normally resistant melanoma cells susceptible to doxorubicin, camptothecin and 5-FU. Subsequent work has shown that ABCB5 identifies cancer stem cells in human malignant melanoma that correlate with clinical disease progression and that can be specifically targeted to abrogate tumor growth. Identification of cancer stem cells with enhanced abundance in more advanced disease but susceptibility to specific targeting via a defining chemoresistance determinant has important implications for cancer therapy. Our most recent studies identify a subset of ABCB5-expressing cells in clinical human colon cancers, established colon cancer cell lines, and show a correlation between ABCB5 expression and clinical colon cancer progression. Based on these findings we hypothesize that the chemoresistance mediator ABCB5, similar to its function in melanoma, identifies colon cancer stem cells and that specific targeting of ABCB5-expressing colon cancer cells may result in abrogation of disseminated disease. Here we propose to (1) Study whether ABCB5 can serve as a novel cancer stem cell marker in colon cancer; (2) Examine the chemoresistance of ABCB5+ colon cancer cells and related cancer stem cell subpopulations to 5-FU and develop strategies for ABCB5-targeted chemoresistance reversal; (3) Investigate whether ABCB5- targeted colon cancer stem cell ablation or chemoresistance reversal can inhibit tumor initiation/progression in vivo. This will be accomplished by studying primary human cancer specimens supported by prognostic and outcome data in murine bioassays in which tumor xenografts develop in a manner that recapitulates naturally occurring disease and in which ABCB5+ tumor cells may be therapeutically targeted. The proposed approaches will determine the clinical relevance and therapeutic importance of the novel biomarker ABCB5 in colon cancer, and should pave the way to successful targeting of ABCB5+ colon CSC in human patients.