Identification and targeting of colon cancer initiating cells

描述(由申请人提供)： 在50岁及以上的男性和女性中，结肠癌是第三种最常见的癌症类型，也是与癌症相关的死亡的第二大常见原因。大多数可用的治疗方法有效地杀死了大量癌细胞，但肿瘤可能会从具有治疗抗性的少数群体再生，这可能与癌症干细胞相吻合。能够自我更新和分化的肿瘤干细胞对肿瘤的生长起作用，已在人类血液系统恶性肿瘤和几种实体瘤中被发现。肿瘤干细胞的特异性靶向可以提供一种新的策略来根除目前对系统治疗耐药的癌症。ABCB5是一种新的人类多药耐药介质，最近发现在人类黑色素瘤和包括结肠癌在内的其他恶性肿瘤中都有表达，并在体外导致化疗耐药。例如，抑制ABCB5使正常耐药的黑色素瘤细胞对阿霉素、喜树碱和5-FU敏感。随后的工作表明，ABCB5在人类恶性黑色素瘤中识别出与临床疾病进展相关的癌症干细胞，并可以专门针对这些干细胞来消除肿瘤的生长。在更晚期的疾病中识别丰度增强的癌症干细胞，但通过一个明确的化疗耐药决定簇对特定靶向的敏感性，对癌症治疗具有重要的意义。我们最新的研究发现，在临床人类结肠癌和已建立的结肠癌细胞系中，ABCB5表达的细胞亚群，并显示ABCB5表达与临床结肠癌进展之间的相关性。基于这些发现，我们假设化疗耐药介质ABCB5，类似于其在黑色素瘤中的功能，识别结肠癌干细胞，并且针对表达ABCB5的结肠癌细胞可能导致消除播散性疾病。在此，我们建议(1)研究ABCB5是否可以作为一种新的结肠癌干细胞标记物；(2)检测ABCB5+结肠癌细胞及其相关肿瘤干细胞亚群对5-FU的化疗耐药性，并开发ABCB5靶向抗药性逆转策略；(3)研究ABCB5靶向结肠癌干细胞消融或抗药性逆转是否可以抑制体内肿瘤的启动/进展。这将通过研究原始人类癌症标本来实现，这些标本得到了小鼠生物检测中预后和结果数据的支持，在这些检测中，肿瘤异种移植的发展方式概括了自然发生的疾病，其中ABCB5+肿瘤细胞可能是治疗靶点。所提出的方法将确定新的生物标记物ABCB5在结肠癌中的临床相关性和治疗重要性，并将为在人类患者中成功靶向ABCB5+结肠CSC铺平道路。 公共卫生相关性： 结肠癌仍然是退伍军人发病率和死亡率的主要原因之一。尽管最近在早期筛查策略和手术切除方法方面取得了重大进展，但许多结肠癌病例仍在目前无法治愈的后期被诊断出来。识别和选择性靶向对全身治疗有抵抗力的肿瘤细胞，最终可能会成功地消除临床上的肿瘤生长，改善退伍军人的生活质量和结肠癌患者的生存。

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. PUBLIC HEALTH RELEVANCE: Colon cancer remains one of the major causes of morbidity and mortality among Veterans. Despite significant recent advances in early screening strategies and surgical resection approaches, many cases of colon cancer are still diagnosed at later currently incurable stages. Identification and selective targeting of tumor cells, which are resistant to systemic therapy, may ultimately lead to successful abrogation of clinical tumor growth and improve quality of life and survival of Veterans suffering from colon cancer.