Senescence, Proliferation and Invasion- What is the link?

衰老、增殖和入侵——有何联系？

• 批准号: 7963978
• 负责人: Ashani Weeraratna
• 金额: $ 25.14万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7963978
• 关键词: Aging; Cells; Cessation of life; Coculture Techniques; Complex; Fibroblasts; Gene Expression Profiling; Genes; Immunity; Individual; Invaded; Lead; Link; Malignant Neoplasms; Melanoma Cell; Modeling; Neoplasm Metastasis; Nutrient; Oncogenes; Outcome; Patients; Physiological Processes; Process; Skin; System; age effect; base; interest; melanoma; neoplastic cell; normal aging; outcome forecast; release factor; senescence; tumor; tumor progression

It has become abundantly clear that the phenomenon of senescence in cancer is a very complex one. While senescence of the tumor cell is a desired outcome for tumor therapy, senescence of normal fibroblasts in the microenvironment may promote progression of nearby tumor cells. In aging patients, an increasing percentage of skin fibroblasts become senescent, thus we are interested in the effects of the aging microenvironment on tumor progression. Older individuals who present with melanoma have a worse prognosis, and this could be due to factors such as decreased immunity, or changes in the microenvironment. Klotho is a gene that interacts with Wnts, and whose knockdown can lead to accelerated aging. We are studying the relationship between klotho and Wnt5A using melanoma as a model, and normal, aging skin. We are in the process of determining whether older skin fibroblasts have an increase in Wnt5a, and a loss of klotho. If this is so, we will ask if we can make melanoma cells more invasive if we co-culture them with old vs young fibroblasts. Further, we will knock klotho out of the younger fibroblasts, and see what effects that has on secretion of different factors from these fibroblasts, and if we can accelerate senescence, and if those senescing fibroblasts make melanoma cells more invasive. On a long term basis we will also ask if oncogene induced senescence can influence surrounding cells in a co-culture system- eg, skin fibroblasts, and make them senesce and in turn, release factors that then cause tumor cells to invade. Gene expression profiling studies will also be performed to obtain a global overview of thes studies.

已经很清楚的是，癌症中衰老的现象是非常复杂的。虽然肿瘤细胞的衰老是肿瘤治疗的预期结果，但微环境中正常成纤维细胞的衰老可能会促进附近肿瘤细胞的进展。 在衰老的患者中，越来越多的皮肤成纤维细胞变得衰老，因此我们对衰老微环境对肿瘤进展的影响感兴趣。出现黑色素瘤的老年人的预后较差，这可能是由于免疫力降低或微环境变化等因素所致。克洛托（Klotho）是一种与WNT相互作用的基因，其敲低可以导致加速衰老。我们正在使用黑色素瘤作为模型以及正常的衰老皮肤研究Klotho和Wnt5a之间的关系。我们正在确定较旧的皮肤成纤维细胞是否增加了Wnt5a，而Klotho的丧失。如果是这样，我们将询问如果我们与旧的成纤维细胞共同培养，是否可以使黑色素瘤细胞更具侵入性。此外，我们将从年轻的成纤维细胞中敲出Klotho，并查看这些成纤维细胞中不同因素的分泌的影响，如果我们可以加速衰老，以及那些衰老的成纤维细胞会使黑色素瘤细胞更具侵入性。从长远来看，我们还将询问癌基因诱导的衰老是否会影响共培养系统中的细胞 - 例如皮肤成纤维细胞，并使它们使它们延伸，然后释放因导致肿瘤细胞侵袭的释放因子。还将进行基因表达分析研究，以获取有关这些研究的全球概述。