Novel therapy targeting refractory colon cancer

 描述（由申请人提供）：癌症起始细胞（CIC）表现出独特的标志物，具有高度致瘤性。几个研究小组已经成功地分离出结直肠癌起始细胞（CCIC）的基础上不同的细胞表面标志物。常规疗法，包括化疗和放疗，靶向快速增殖的结直肠癌细胞的大部分群体。虽然大部分肿瘤被根除，但治疗抗性CCIC仍然存在，并且可以分化为非CCIC癌细胞。随着时间的推移，CCIC后代的肿瘤再增殖最终导致比初始预处理的恶性肿瘤更具侵袭性的表型。结直肠癌每年有56，500人死亡，是美国仅次于肺癌的癌症死亡原因。每年有150，000至160，000例新病例被诊断出来，其中10%至20%已经有肝转移。大约70%的结直肠癌患者最终会发生肝转移。肝切除术是目前唯一提供长期生存的治疗形式，5年生存率为25%至39%。根据目前肝切除术的选择标准，只有10%至20%的患者适合进行根治性手术。其余患者的预后是严峻的姑息化疗和对症治疗是唯一可用的选择。没有可靠的治疗方法来控制化疗后的癌症复发。本实验室发现，配对免疫球蛋白样受体B（PIRB）及其同源物白细胞免疫球蛋白样受体B（LILRB）在控制结肠癌起始细胞（CIC）的“干性”和诱导上皮-间质转化（EMT）中起重要作用。近年来，血管生成素样蛋白（Angptls）被鉴定为PIRB/LILRB的天然高亲和力配体。我们发现，通过其高亲和力配体，血管生成素样蛋白2（Angptl-2，小鼠）和Angptl-2和-5（人），PIRB活化促进骨髓来源的抑制细胞获得M2（替代）巨噬细胞功能表型，诱导结肠肿瘤细胞的CIC表型，并增强转移。我们推测，通过连接Angptl的PIRB/LILRB信号传导可以诱导结肠癌起始细胞和EMT的表型，从而促进化疗耐药性的发展。因此，阻断PIRB/LILRB信号传导可以预防化疗后结肠癌复发。提出了三个具体目标。在目的1中，我们将基于PIRB/LILRB的表达确定Angptls对结肠肿瘤细胞系的增殖和“干性”维持的作用。在目的2中，我们将评估化疗诱导的Angptl表达对CIC和EMT表型的影响。在目标3中，我们将评估阻断PIRB/LILRB信号传导单独或与化疗疗法联合对结肠癌起始细胞和骨髓分化的作用。我们的研究将确定控制CCIC和EMT表型的Angptl受体介导的信号传导的分子决定因素，并为设计难治性结直肠癌的新治疗方式提供新的信息。

 DESCRIPTION (provided by applicant): Cancer initiating cells (CICs) exhibit distinct markers and are highly tumorigenic. Several research groups have successfully isolated colorectal cancer initiating cells (CCICs) based on distinct cell-surface markers. Conventional therapies, including chemotherapies and radiotherapies, target the bulk population of rapidly proliferating colorectal cancer cells. Although a large proportion of tumor mass is eradicated, therapy-resistant CCICs remain and can differentiate into non-CCIC cancer cells. Repopulation of the tumor over time by the progenies of CCICs ultimately results in a more aggressive phenotype than the initial pretreated malignancy. With 56,500 fatalities per year, colorectal cancer is second only to lung cancer as a cause of cancer deaths in the USA. Each year, 150,000 to 160,000 new cases are diagnosed of which 10 to 20% already have liver metastases. About 70% of all colorectal cancer patients eventually develop liver metastases. Hepatic resection is currently the only form of treatment that offers long-term survival, with 5-year survival rates ranging from 25% to 39%. Using the current selection criteria for hepatectomy, only 10% to 20% of all patients are candidates for curative operation. The prognosis for the remaining patients is grim with palliative chemotherapy and symptomatic treatments being the only available options. There are no reliable treatment modalities for controlling cancer recurrence after chemotherapy. Our laboratory has found that paired immunoglobulin-like receptor B (PIRB) and its human ortholog leukocyte Ig-like receptor B (LILRB) play an important role in controlling the "stemness" of colon cancer initiating cells (CIC) and induction of epithelial-mesenchymal transition (EMT). Recently, Angiopoietin-like proteins (Angptls) have been identified as a nature high affinity ligand for PIRB/LILRBs. We found that PIRB activation, through its high affinity ligands, angiopoietin like protein 2 (Angptl-2, mouse) and Angptl-2 and -5 (human), promoted acquisition of an M2 (alternative) macrophage functional phenotype by myeloid-derived suppressor cell, induced CIC phenotypes of colon tumor cells, and enhanced metastases. We hypothesize that PIRB/LILRB signaling through ligation of Angptl can induce the phenotype of colon cancer initiating cell and EMT, thereby facilitating the development of chemotherapy resistance. Thus, blockade of PIRB/LILRB signaling may prevent colon cancer relapse after chemotherapy. Three specific aims are proposed. In Aim 1, we will determine the effect of Angptls on proliferation and maintenance of "stemness" of colon tumor cell lines, based on the expression of PIRB/LILRB. In Aim 2, we will assess the effect of Angptl expression induced by chemotherapy on CIC and EMT phenotypes. In Aim 3, we will evaluate the effect of blocking PIRB/LILRB signaling, alone or in conjunction with chemothrapy therapy, on colon cancer initiating cells and myeloid differentiation. Our study will identify the molecular determinants of Angptl receptor-mediated signaling in control of CCIC and EMT phenotypes, and provide new information for devising a novel therapeutic modality for refractory colorectal cancer.