AGING AS A SELECTIVE PRESSURE THAT DRIVES TUMOR PROGRESSION

项目摘要 衰老是癌症发病的主要危险因素，超过60%的癌症诊断发生在老年人中 65岁及以上。此外，轶事观察表明，年龄影响预后和结果。然而， 很少有实验数据剖析衰老、癌症进展和抗癌敏感性之间的联系 治疗事实上，绝大多数指导新治疗靶点发现的临床前研究 导致FDA批准的抗癌治疗的临床试验忽视了年龄的影响， 普通病人对衰老在癌症中的作用缺乏了解尤其令人不安， 新的癌症病例在全球范围内呈上升趋势，这一事实与以下因素的比例增加有关： 世界上的老年人口。从生物学上讲，衰老过程会影响生物体中每个细胞的功能 这表明在老年宿主中发展的癌症与在年轻宿主中发展的癌症是不同的疾病， 一个.我最近用人类血清样本证明了肿瘤的进展和转移的形成 至少部分地作为老年宿主的整体代谢失调的表现而发生。这支持了 衰老在癌症中的作用远远超出了暴露于诱变剂的时间增加， 在中心阶段协调恶性表型演变所需的不同方面的过程。 因此，为了有效地治疗癌症，我们必须超越目前忽视癌症的框架。 癌症患者的年龄。在这里，我们提出，老年宿主肿瘤微环境发挥不同的作用， 达尔文主义的压力与宿主抗癌防御能力的下降相结合，定义了肿瘤细胞如何 在原发性肿瘤内演变，进展为转移性疾病并对抗癌疗法作出反应。 采用尖端的散装和单细胞技术相结合，我们希望系统地描绘 衰老如何影响癌细胞的表型和基因型，以及表征衰老的影响。 衰老过程对肿瘤微环境不同组分的组成和相互作用的影响。 最后，我们将直接评估老年是否影响FDA批准的化疗方案的反应 和免疫疗法，并评估是否已知的策略，以振兴旧组织可以影响这些反应 治疗干预。通过这些研究，我们的目标是建立设计所需的知识基础设施 治疗策略，解释了随着衰老发生的重新编程。

PROJECT SUMMARY Aging is the major risk factor for cancer incidence, with more than 60% of cancer diagnoses occurring in those aged 65 and above. In addition, anecdotal observations indicate that age affects prognosis and outcome. Yet, very little experimental data dissect the connection of aging, cancer progression and sensitivity to anti-cancer therapies. In fact, the vast majority of preclinical research that guide the discovery of novel therapeutic targets and clinical trials that lead to anti-cancer treatments approved by the FDA neglect to account for the age of the average patient. This lack of understanding of how aging plays a role in cancer is especially troubling considering that the number of new cancer cases is on the rise globally, a fact that is tied to the increase in the proportion of the older population in the world. Biologically the aging process affects the function of every cell in an organism suggesting that a cancer developing in an aged host is a different disease than a cancer developing in a young one. Using human serum samples, I recently demonstrated that tumor progression and metastasis formation occur, at least in part, as a manifestation of global metabolic deregulation of the aged host. This supports the idea that the role of aging in cancer goes far beyond increased exposure time to mutagens and puts the aging process at the center stage coordinating the different aspects required for the evolution of malignant phenotypes. Therefore, in order to effectively treat cancer, we must look beyond the current framework which neglects the role of the cancer patient’s age. Here, we propose that the aged host tumor microenvironment exerts distinct Darwinian pressures that combined with the decline of the host anti-cancer defenses define how tumor cells evolve within the primary tumor, progress into metastatic disease and respond to anti-cancer therapies. Employing a combination of cutting-edge bulk and single cell technologies we expect to systematically delineate how aging affects the phenotypes and genotypes of cancer cells as well as to characterize the effects of the aging process on the composition and interactions of the different components of the tumor microenvironment. Finally, we will directly evaluate if old age affects the response to FDA-approved chemotherapeutic regiments and immunotherapies, and evaluate if strategies known to rejuvenate old tissues can affect the response to these therapeutic interventions. Through these studies, we aim to build the knowledge infrastructure required to design therapeutic strategies that account for the reprogramming that occurs with aging.