Targeting cancer stem-like cells and inflammation for colon cancer chemoprevention

项目总结/摘要 结肠直肠癌的一个标志是腺瘤性结肠息肉病（APC）肿瘤抑制基因的丢失， 导致Wnt信号转导失调和结肠干细胞向癌干细胞的致癌转化 细胞此外，炎症是结直肠癌发展的主要危险因素， 这些细胞因子可以驱动肿瘤起始细胞的形成。因此，针对炎症和炎症的策略， 癌症干细胞可能有效降低患结肠直肠癌的风险。萝卜硫烷a 衍生自十字花科蔬菜并且在花椰菜中特别丰富的天然存在的异硫氰酸酯， 具有良好的抗炎和抗肿瘤活性。然而，它抑制的确切机制 肿瘤发生以及它是否能够降低结直肠癌的风险仍有待确定。我们有 先前的研究表明，萝卜硫素可抑制乳腺癌中NFκ B介导的炎症反应， 细胞以及乳腺癌干细胞的增殖和自我更新能力。我们现在有了初步的 数据有力地表明萝卜硫素在结肠癌细胞中具有类似的作用，更重要的是， 抑制由APC突变驱动的人类类器官的生长。此外，给小鼠喂食西兰花制剂， 富含萝卜硫素的人更能抵抗结肠炎症和腺瘤的发展 阵在本提案中，我们将研究莱菔硫烷的药物制剂在以下方面的功效： 抑制由失调的Wnt信号传导驱动的肿瘤起始细胞的建立，并确定其 使用体内小鼠模型和体外实验抑制能够恶性转化的结肠干细胞的能力 患者来源的类器官培养物。所提出的研究将是至关重要的，在开发一个合成类似物的 萝卜硫素作为结直肠癌高危患者的化学预防剂。

PROJECT SUMMARY/ABSTRACT A hallmark of colorectal cancers is the loss of the adenomatous polyposis coli (APC) tumor suppressor gene, resulting in dysregulated Wnt signaling and the oncogenic transformation of colon stem cells into cancer stem cells. In addition, inflammation, a major risk factor for the development of colorectal cancer, can upregulate cytokines that can drive the formation of tumor-initiating cells. Thus, strategies that target both inflammation and cancer stem cells may be effective in decreasing the risk of developing colorectal cancer. Sulforaphane, a naturally-occurring isothiocyanate derived from cruciferous vegetables and particularly abundant in broccoli, has well-established anti-inflammatory and anti-tumor activities. However, the precise mechanism by which it inhibits tumorigenesis and whether it is capable of reducing colorectal cancer risk remain to be determined. We have previously demonstrated that sulforaphane inhibits NFκB-mediated inflammatory responses in breast cancer cells as well as the proliferation and self-renewal capacity of breast cancer stem cells. We now have preliminary data strongly suggesting that sulforaphane has similar effects in colon cancer cells and more importantly, can inhibit the growth of human organoids driven by an APC mutation. Furthermore, mice fed a preparation of broccoli that is enriched in sulforaphane are more resistant to the development of colonic inflammation and adenoma formation. In this proposal, we will examine the efficacy of a pharmaceutical preparation of sulforaphane in suppressing the establishment of tumor-initiating cells driven by dysregulated Wnt signaling and determine its ability to inhibit colon stem cells capable of malignant transformation using in vivo mouse models and in vitro patient-derived organoid cultures. The proposed studies will be critical in developing a synthetic analog of sulforaphane as a chemopreventive agent in patients at high risk for developing colorectal cancer.