Mesenchymal Stromal Cells and Stromal Fibroblasts in Radiotherapy Resistance

间充质基质细胞和基质成纤维细胞在放射治疗抵抗中的作用

• 批准号: 9381005
• 负责人: Guangwen Ren
• 金额: $ 24.9万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-15 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9381005
• 关键词: Animal Model; Award; Biological Assay; Breast Cancer Model; Breast Cancer Patient; Breast Carcinoma; Breast Melanoma; Breast cancer metastasis; Cancer Model; Cancer Patient; Cancer Relapse; Cellular biology; Chemicals; Clinical; Diagnosis; Failure; Fatty Acids; Fibroblasts; Gene Expression; Genes; Growth Factor; Hypoxia; Immunology; Inflammatory; Ionizing radiation; Knock-out; Knockout Mice; Lead; Malignant Neoplasms; Mediating; Mediator of activation protein; Mentors; Mesenchymal; Mesenchymal Stem Cells; Metabolic; Metastatic Neoplasm to the Lung; Modeling; Molecular; Mus; Neoplasm Metastasis; Pharmacotherapy; Phase; Physiological; Play; Predisposition; Primary Neoplasm; Proteins; Proteomics; Radiation; Radiation Oncology; Radiation therapy; Radiology Specialty; Radioresistance; Recurrence; Relapse; Reporting; Research; Resistance; Role; Stromal Cells; Testing; Training; Treatment Efficacy; Treatment Failure; Work; angiogenesis; cancer cell; cancer recurrence; cancer therapy; chemotherapy; design; improved; in vivo; inhibitor/antagonist; malignant breast neoplasm; melanoma; mortality; mouse model; neoplastic cell; neutralizing antibody; novel; novel strategies; novel therapeutics; osteopontin; overexpression; prevent; public health relevance; radiation response; radioresistant; stem; therapy resistant; tumor; tumor growth; tumor microenvironment; tumor progression

DESCRIPTION (provided by applicant): Cancer recurrence and treatment resistance represent the primary obstacles to current cancer therapies, with the underlying mechanisms largely unclear. In recent years, the hypoxic tumor microenvironment is regarded as one of the major causes mediating the treatment failures. Among the complicated tumor microenvironmental components, mesenchymal stem/stromal cells (MSCs) and their derivative stromal fibroblasts are currently recognized as master regulators in every step of cancer progression including primary tumor growth and secondary metastasis. Moreover, accumulating evidence suggests that MSCs and stromal fibroblasts also play critical roles in chemoresistance through their proteomic or metabolic changes elicited by drug treatments. However, little is known whether MSCs and stromal fibroblasts are involved in radiotherapy resistance. My preliminary results revealed a much less susceptibility of MSCs to ionizing radiation, compared to cancer cells. In mouse models of breast cancer and melanoma, in contrast to untreated MSCs, the irradiated MSCs exerted a robust potential in promoting primary tumor growth and lung metastasis of cancer cells. Through gene expression comparison, irradiated MSCs were shown to express high levels of osteopontin (OPN) and CCL-5. Deficiency of OPN largely abrogated the cancer promoting effects of irradiated MSCs. We therefore hypothesize that MSCs and their derivative stromal fibroblasts are key radiation-responsive stromal components to facilitate cancer progression, through overexpression of OPN, CCL-5 and other mediators. Those stromal features very likely lead to radioresistance or cancer recurrence after radiotherapy. To test this hypothesis, in the mentored phase (K99) of this award, I will first validate the function and molecular mechanisms of radiation-modulated OPN and CCL-5 expression on MSCs in the tumor promoting potential. Furthermore, I will extend the findings in MSCs to their derivative stromal fibroblasts and develop novel stromal markers (OPN, CCL-5 and possibly other factors) to predict the radiotherapy failure in breast cancer patients. All of these endeavors during my mentored phase will contribute to the proposed work in the R00 phase of this award-to develop effective therapeutics to treat clinical relapse/failure of radiotherapy in animal models. During this independent phase, I will attempt to establish radiotherapy resistance model and cancer relapse model in mice, followed by testing potential chemical inhibitors or neutralizing antibodies to prevent and treat these failures. This study combines my previous training in mesenchymal stem cell biology and immunology, and my current training in breast cancer metastasis, treatment resistance and radiation oncology, which brings me to a new field investigating the roles of MSCs and stromal fibroblasts in treatment resistance at my independent stage. The results will not only provide important information for our understanding of the basic stroma radiology, but also help to develop novel therapeutics to target stromal OPN, CCL-5 and possibly other mediators as adjutants to improve the efficacy of radiotherapy.

描述（由申请人提供）：癌症复发和治疗耐药性是目前癌症治疗的主要障碍，其潜在机制基本上不清楚。近年来，缺氧肿瘤微环境被认为是介导治疗失败的主要原因之一。在复杂的肿瘤微环境成分中，间充质干/基质细胞（MSC）及其衍生的基质成纤维细胞是目前公认的肿瘤进展的每个步骤（包括原发性肿瘤生长和继发性转移）的主要调节者。此外，越来越多的证据表明，间充质干细胞和基质成纤维细胞也通过药物治疗引起的蛋白质组学或代谢变化在化学抗性中发挥关键作用。然而，很少有人知道是否骨髓间充质干细胞和基质成纤维细胞参与放疗抵抗。我的初步结果显示，与癌细胞相比，MSC对电离辐射的敏感性要低得多。在乳腺癌和黑色素瘤的小鼠模型中，与未处理的MSC相比，辐照的MSC在促进癌细胞的原发性肿瘤生长和肺转移方面发挥了强大的潜力。通过基因表达比较，显示辐射的MSC表达高水平的骨桥蛋白（OPN）和CCL-5。OPN的缺乏在很大程度上消除了辐射MSC的促癌作用。因此，我们假设MSC及其衍生的基质成纤维细胞是通过OPN、CCL-5和其他介质的过表达促进癌症进展的关键辐射响应性基质组分。这些间质特征很可能导致放射抵抗或放射治疗后的癌症复发。为了验证这一假设，在本奖项的指导阶段（K99），我将首先验证辐射调节的OPN和CCL-5在MSC上表达的功能和分子机制在肿瘤促进潜力中的作用。此外，我将在骨髓间充质干细胞中的发现扩展到其衍生的基质成纤维细胞，并开发新的基质标记物（OPN，CCL-5和可能的其他因素）来预测乳腺癌患者的放疗失败。所有这些努力在我的指导阶段将有助于在R 00阶段的建议工作这个奖项-开发有效的治疗方法来治疗临床复发/失败的放射治疗动物模型。在这个独立的阶段，我将尝试建立小鼠放疗抵抗模型和癌症复发模型，然后测试潜在的化学抑制剂或中和抗体来预防和治疗这些失败。这项研究结合了我以前在间充质干细胞生物学和免疫学方面的培训，以及我目前在乳腺癌转移，治疗抵抗和放射肿瘤学方面的培训，这使我进入了一个新的领域，调查了MSC和基质成纤维细胞在我独立阶段的治疗抵抗中的作用。这些结果不仅为我们理解间质放射学基础提供了重要信息，而且有助于开发新的治疗方法，靶向间质OPN，CCL-5和可能的其他介质作为佐剂，以提高放射治疗的疗效。