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是当前癌症治疗的主要障碍，其潜在机制尚不清楚。近年来，缺氧的肿瘤微环境被认为是导致治疗失败的主要原因之一。在复杂的肿瘤微环境成分中，间充质干细胞/基质细胞（MSC）及其衍生的基质成纤维细胞目前被认为是癌症进展每个步骤（包括原发性肿瘤生长和继发性转移）的主要调节因子。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或代谢变化在化疗耐药中发挥关键作用。然而，间充质干细胞和基质成纤维细胞是否参与放疗抵抗尚不清楚。我的初步结果显示，与癌细胞相比，间充质干细胞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，与未经处理的间充质干细胞相比，经过辐照的间充质干细胞在促进原发性肿瘤生长和癌细胞肺转移方面发挥了强大的潜力。通过基因表达比较，受辐射的间充质干细胞显示出高水平的骨桥蛋白（OPN）和CCL-5表达。 OPN 的缺乏在很大程度上消除了受辐射的 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关键的辐射响应基质成分，通过 OPN、CCL-5 和其他介质的过度表达来促进癌症进展。这些基质特征很可能导致放射抗性或放射治疗后癌症复发。为了验证这一假设，在本次奖项的指导阶段（K99），我将首先验证辐射调节的 OPN 和 CCL-5 在 MSC 上表达的促肿瘤潜力的功能和分子机制。此外，我将把 MSC 的研究结果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 和可能的其他因子）来预测乳腺癌患者的放疗失败。我指导阶段的所有这些努力都将有助于该奖项 R00 阶段的拟议工作——开发有效的疗法来治疗动物模型中放疗的临床复发/失败。在这个独立阶段，我将尝试在小鼠中建立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。这项研究结合了我之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，研究间充质干细胞和基质成纤维细胞在我的独立研究中的治疗抵抗中的作用。阶段。该结果不仅将为我们了解基础基质放射学提供重要信息，而且有助于开发针对基质 OPN、CCL-5 和可能的其他介质作为辅助剂的新疗法，以提高放射治疗的疗效。