Abstract 2575: Intermittent calorie restriction reverses the adverse effects of obesity and advanced age on tumor growth in a mouse model of breast cancer

Dalton M. Craven, Laura A. Smith, Michael F. Coleman, Elaine M Glenny, S. Hursting
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Abstract

Advanced age and obesity are two major risk factors for breast cancer (BC) mortality. This presents a significant public health concern as the number of older individuals and incidence of obesity are increasing worldwide. In our mouse models of BC, we have demonstrated that, similar to obesity, advanced age accelerates mammary tumor growth. Mechanistically, obesity and advanced age suppress tumor gene expression relating to antitumor immunity and reduce tumoral abundance of cytotoxic CD8+ T cells. Thus, advanced age- and obesity-related enhancement of mammary tumor growth is explained, in part, through the development of an immunosuppressive tumor microenvironment. Given the aging of our populations and the increasing prevalence of obesity, interventions capable of reversing the tumor-promoting effects of advanced age and obesity are needed. We have previously demonstrated that weight loss by intermittent calorie restriction (ICR), in which mice are placed on a 5:2 calorie restriction (CR) regimen (5 days 14% CR, 2 nonconsecutive days 70% CR per week), attenuates tumor growth and immunosuppression in formerly obese mice. This project tests if ICR will provide similar benefit to aged and aged obese mice. Cohorts of young control (5 mos), young diet-induced obese (DIO; 5 mos), aged control (15 mos), and aged DIO (15 mos) mice were generated and subsequently randomized to either remain on their baseline diet or switch to the ICR intervention. Following 9 weeks on ICR or baseline diet, serum samples were collected and then tumor development induced by orthotopic transplantation of E0771 cancer cells into the 4th mammary fat pad of mice. At tumor endpoint mammary tumors were collected and weighed. To determine if ICR alters systemic inflammation in each experimental group, cytokine levels were measured in serum samples collected prior to tumor inoculation. Multiple inflammatory cytokines were downregulated following ICR intervention in young DIO, aged control, and aged DIO mice, including CCL7, CCL10, and CCL24. Downregulation of inflammatory cytokines was correlated with decreased tumor burden in young DIO, aged control, and aged DIO mice placed on ICR, compared with their respective non-intervention controls. Ongoing analyses are investigating if ICR increases the abundance of cytotoxic CD8+ T cells within the tumor microenvironment of young DIO, aged control, and aged DIO mice. These findings demonstrate that ICR may be effective in reversing obesity- and advanced age-related enhancement of mammary tumor growth in mouse models of breast cancer. More research is needed to test if these preclinical findings translate to obese and aged humans with BC. Identifying dietary interventions that may attenuate obesity- and age-related tumor growth has the potential to improve both patient outcomes and quality of life. This research was supported by R35CA197627 to S. Hursting. Citation Format: Dalton M. Craven, Laura A. Smith, Michael F. Coleman, Elaine M. Glenny, Stephen D. Hursting. Intermittent calorie restriction reverses the adverse effects of obesity and advanced age on tumor growth in a mouse model of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2575.
摘要:在乳腺癌小鼠模型中,间歇性卡路里限制逆转了肥胖和高龄对肿瘤生长的不利影响
高龄和肥胖是乳腺癌(BC)死亡的两个主要危险因素。这引起了一个重大的公共卫生问题,因为世界范围内老年人的数量和肥胖的发病率都在增加。在我们的小鼠BC模型中,我们已经证明,与肥胖相似,高龄会加速乳腺肿瘤的生长。机制上,肥胖和高龄抑制肿瘤抗肿瘤免疫相关基因的表达,降低肿瘤细胞毒性CD8+ T细胞的丰度。因此,高龄和肥胖相关的乳腺肿瘤生长增强部分是通过免疫抑制肿瘤微环境的发展来解释的。考虑到人口老龄化和肥胖的日益流行,需要能够逆转高龄和肥胖对肿瘤促进作用的干预措施。我们之前已经证明,通过间歇性卡路里限制(ICR)减肥,小鼠被放置在5:2的卡路里限制(CR)方案中(每周5天14% CR,非连续2天70% CR),减轻了以前肥胖小鼠的肿瘤生长和免疫抑制。该项目测试ICR是否会对老年和老年肥胖小鼠提供类似的益处。年轻对照组(5个),年轻饮食诱导肥胖(DIO;生成5只(只)、15只(只)老年对照小鼠和15只(只)老年DIO小鼠,随后随机分为两组,一组保持基线饮食,另一组改用ICR干预。在ICR或基线饮食9周后,采集血清样本,然后将E0771癌细胞原位移植到小鼠第4乳腺脂肪垫诱导肿瘤发展。在肿瘤终点收集乳腺肿瘤并称重。为了确定ICR是否改变了每个实验组的全身性炎症,在肿瘤接种前收集的血清样本中测量了细胞因子水平。包括CCL7、CCL10和CCL24在内的年轻DIO、老年对照组和老年DIO小鼠,在ICR干预后,多种炎症细胞因子下调。与各自的非干预对照组相比,接受ICR治疗的年轻DIO小鼠、老年对照组小鼠和老年DIO小鼠的炎症细胞因子下调与肿瘤负荷降低相关。正在进行的分析正在调查ICR是否会增加年轻DIO小鼠、老年对照小鼠和老年DIO小鼠肿瘤微环境中细胞毒性CD8+ T细胞的丰度。这些发现表明,在乳腺癌小鼠模型中,ICR可能有效逆转肥胖和高龄相关的乳腺肿瘤生长增强。需要更多的研究来验证这些临床前研究结果是否适用于肥胖和老年BC患者。确定饮食干预可能减轻肥胖和年龄相关肿瘤的生长,有可能改善患者的预后和生活质量。本研究得到了R35CA197627 to S. Hursting的支持。引文格式:Dalton M. Craven, Laura A. Smith, Michael F. Coleman, Elaine M. Glenny, Stephen D. Hursting。在乳腺癌小鼠模型中,间歇性卡路里限制逆转了肥胖和高龄对肿瘤生长的不利影响[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志,2021;81(13 -增刊):2575。
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