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

针对癌症干细胞样细胞和炎症进行结肠癌化学预防

基本信息

批准号：
10650910
负责人：
GRACE Y. CHEN
金额：
$ 21.88万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10650910
关键词：
APC gene APC mutation Affect Anti-Inflammatory Agents Biological Availability Biological Markers Breast Cancer Cell Broccoli - dietary Cancer Etiology Cell Count Cells Chemoprevention Chemopreventive Agent Clinical Trials Design Colectomy Colon Colon Carcinoma Colonic Adenoma Colonic Neoplasms Colonic inflammation Colorectal Adenoma Colorectal Cancer Data Development Dose Epithelium Event Familial Adenomatous Polyposis Syndrome Formulation Foundations Future Germ-Line Mutation Goals Growth Histologic Human Immune In Vitro Individual Inflammation Inflammatory Inflammatory Response Isothiocyanates LGR5 gene Malignant - descriptor Malignant Neoplasms Mediating Modeling Mus Mutation Neoplastic Cell Transformation Non-Steroidal Anti-Inflammatory Agents Normal tissue morphology Oncogenic Oral Organoids Pathway interactions Patient Agents Patients Pharmaceutical Preparations Population Pre-Clinical Model Preparation Prevention Prevention strategy Prevention trial Proliferating Publications Reporter Resistance Risk Risk Factors Safety Signal Pathway Signal Transduction Sulforaphane Testing Tissues Toxic effect Tumor Suppressor Genes Tumor Tissue United States WNT Signaling Pathway Woman adenoma analog cancer cell cancer chemoprevention cancer stem cell carcinogenesis carcinogenicity colon cancer prevention colon tumorigenesis colorectal cancer risk cruciferous vegetable cytokine disorder risk efficacy evaluation experimental study high risk in vitro Model in vivo inhibitor malignant breast neoplasm men mortality mouse model mutant novel novel chemoprevention prevent self-renewal single-cell RNA sequencing standard of care stem stem cell biology stem cell biomarkers stem cell function stem cell proliferation stem cells stem-like cell stemness transcriptome sequencing tumor tumor growth tumor initiation tumorigenesis

项目摘要

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.

项目摘要/摘要结直肠癌的标志是腺瘤性息肉病（APC）肿瘤抑制基因的丧失，导致Wnt信号失调和结肠干细胞向癌症的致癌转化细胞。此外，感染是结直肠癌发展的主要危险因素，可以更新可以驱动肿瘤发射细胞形成的细胞因子。那是针对注射和的策略癌症干细胞可能有效降低发生结直肠癌的风险。 Sulforaphane，a 从十字花科蔬菜中得出的天然异硫氰酸盐，在西兰花中特别丰富，具有良好的抗炎和抗肿瘤活动。但是，它抑制的确切机制肿瘤发生及其是否能够降低结直肠癌风险仍有待确定。我们有先前证明磺胺抑制NFκB介导的乳腺癌炎症反应细胞以及乳腺癌干细胞的增殖和自我更新能力。我们现在有初步数据强烈表明磺胺在结肠癌细胞中具有相似的影响，更重要的是，可以抑制由APC突变驱动的人类器官的生长。此外，小鼠喂养西兰花的制剂富含磺胺的富集对结肠感染和腺瘤的发展具有更大的抵抗力形成。在此提案中，我们将研究磺胺硫烷药物制备的效率抑制由失调的Wnt信号驱动的肿瘤发射细胞的建立，并确定其能够使用体内小鼠模型和体外抑制能够恶性转化的结肠干细胞患者衍生的类器官培养物。拟议的研究对于开发一个合成类似物至关重要磺胺硫烷作为患有结直肠癌风险高风险的患者的化学预防剂。