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Effect of the aged microenvironment on tumor dormancy

衰老微环境对肿瘤休眠的影响

基本信息

批准号：
9324629
负责人：
Ashani T Weeraratna
金额：
$ 43.46万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-02 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9324629
关键词：
Address Affect Age Aggressive behavior Aging Animal Model Animals Apoptosis Blood Vessels CD8-Positive T-Lymphocytes Cancer Biology Cancer Patient Cells Cessation of life Clinical Clustered Regularly Interspaced Short Palindromic Repeats Data Diagnosis Disease Disease remission Elements Endothelial Cells Equilibrium Excision Genetic Goals Growth Immune Immune system Implant In Vitro Individual Iodine Lead Lesion Lung Malignant Neoplasms Mediating Melanoma Cell Micrometastasis Modeling Mus Myelogenous Nature Neoplasm Metastasis Organism Pathway interactions Patients Pharmacology Play Population Primary Neoplasm Process Prognostic Factor Prognostic Marker Proteins Recurrence Role Sampling Signal Transduction Skin Suppressor-Effector T-Lymphocytes Testing Therapeutic Time Vascularization Visceral WNT Signaling Pathway Wild Type Mouse Wnt proteins age effect age related aged angiogenesis design effective therapy experimental study in vivo melanoma migration mouse model neoplastic cell novel novel marker older patient overexpression progression marker tumor tumor microenvironment

项目摘要

Tumor dormancy presents a barrier to effective therapy. Tumor dormancy is thought to be comprised of three key elements: cellular dormancy, where tumor cells maintain a quiescent, slow-cycling state, angiogenic dormancy, where the growth of the overall micro-metastasis is kept in check by apoptosis due to lack of vascularization, and immune-mediated dormancy, where the immune system continues to edit the tumor population, keeping it in equilibrium. The equilibrium of these dormant subpopulations is maintained until microenvironmental conditions favor their outgrowth. To date, it is unclear what those exact micro- environmental conditions are. Understanding why tumor cells leave this dormant state and become aggressive is a critical unmet need in cancer biology. One indisputable fact about tumor dormancy is that in cases where a tumor is dormant, a significant lapse of time occurs between the diagnosis and removal of a primary tumor, and the recurrence of metastasis. During this lapse of time, an organism ages, and age is a poor prognostic factor for multiple tumor types, including melanoma. We hypothesize that changes in the aging microenvironment can contribute to an emergence from dormancy. Our long-term goal is to understand how the aged microenvironment contributes to an emergence from dormancy. Our data implicate the Wnt signaling pathway in melanoma dormancy. We have identified Wnt5A and sFRP2 (secreted frizzled related protein 2), as two Wnt pathway modulators whose level and activity we hypothesize play roles in the emergence from tumor dormancy. We have shown that aging accelerates melanoma metastasis, partly mediated by Wnt5A and sFRP2, which are increased during aging. Our data indicate that sFRP2 enhances angiogenesis, potentially regulating angiogenic dormancy. sFRP2-mediated angiogenesis has been shown to require endothelial cell expression of Wnt5A and we will test this in the context of tumor dormancy. Immune-mediated dormancy relies in part on the activity of myeloid derived suppressor cells (MDSCs), and their ability to regulate CD8+ cells. Our data show that MDSCs are increased in the aged tumor microenvironment, and further, that MDSCs in the tumor microenvironment begin to express their own Wnt5A. Using novel animal models we have created, we will test the hypothesis that non-canonical Wnt signaling can regulate immune-mediated dormancy of micrometastases, via effects on angiogenesis and MDSCs.

肿瘤休眠是有效治疗的障碍。肿瘤休眠被认为是由