Obesity is associated with an increased risk of, and a poor prognosis for, postmenopausal (PM) breast cancer (BC). Our goal was to determine whether diet-induced obesity (DIO) promotes 1) shorter tumor latency, 2) an escape from tumor dormancy, and 3) an acceleration of tumor growth and to elucidate the underlying mechanism(s). We have developed in vitro assays and PM breast tumor models complemented by a noninvasive imaging system to detect vascular invasion of dormant tumors and have used them to determine whether obesity promotes the escape from breast tumor dormancy and tumor growth by facilitating the switch to the vascular phenotype (SVP) in PM BC. Obese mice had significantly higher tumor frequency, higher tumor volume, and lower overall survival compared with lean mice. We demonstrate that DIO exacerbates mammary gland hyperplasia and neoplasia, reduces tumor latency, and increases tumor frequency via an earlier acquisition of the SVP. DIO establishes a local and systemic proangiogenic and inflammatory environment via the up-regulation of lipocalin-2 (LCN2), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) that may promote the escape from tumor dormancy and tumor progression. In addition, we show that targeting neovascularization via a multitargeted receptor tyrosine kinase inhibitor, sunitinib, can delay the acquisition of the SVP, thereby prolonging tumor latency, reducing tumor frequency, and increasing tumor-free survival, suggesting that targeting neovascularization may be a potential therapeutic strategy in obesity-associated PM BC progression. This study establishes the link between obesity and PM BC and, for the first time to our knowledge, bridges the dysfunctional neovascularization of obesity with the earliest stages of tumor development.
A contributing risk factor and a byproduct of a hamstrings strain is limited hamstrings range of motion (ROM). Some evidence supports static stretching (SS) and lumbar spinal mobilization therapy (LSMT) as an effective means for increasing hamstrings ROM. However, the efficacy of combining LSMT and SS for increasing hamstrings ROM is unknown. The objective of the study is to quantify the immediate effects of the combination of LSMT and SS compared to LSMT and SS on hamstrings ROM in a healthy population. Thirty participants were randomized by block allocation into one of three intervention groups: (1) LSMT (unilateral lumbar PA mobilization at L-4); (2) SS; or (3) combination of LSMT and SS. Hamstrings ROM was measured pre- and post-intervention by the active knee extension test (AKET). There was no group-by-time interaction effect (p = 0.871). Within group analysis revealed a significant statistical change and a large effect size: LSMT (p = .037, RCI = 3.36, d = 0.771); SS (p = 0.035, RCI = 2.94, d = 0.781); combination (p = .005, RCI = 4.21, d = 1.186. The findings suggest that the combination of LSMT and SS does not have a further effect on hamstrings ROM compared to the individual results of LSMT or SS.
Obesity is associated with a substantially increased risk (~50%) and a poor prognosis of breast cancer (BC) in postmenopausal (PM) women. The mechanism(s) underlying obesity-related BC are not clearly understood and, to date, most studies focus on the systemic effects of subcutaneous or visceral adipocytes on BC. We hypothesize that the increased local presence of ‘obese' mammary adipocytes within the breast microenvironment promotes the acquisition of an angiogenic and invasive breast tumor cell phenotype and thereby markedly accelerates tumor proliferation and progression. We first asked whether local interactions between mammary adipocytes and BC cells might promote tumor growth and if so, what the underlying mechanism(s) might be. Preadipocytes isolated from mammary adipose tissues of overweight/obese pre- (Pre-M; n=7) and post-menopausal (PM; n=9) women were differentiated into mature adipocytes using standard protocols. The effects of both normal (NA) and cancer-associated (CAA) mammary adipocyte secretome from Pre-M and PM obese women were tested on human and mouse BC cell lines respectively. BC cells (MDA-MB-436, MCF-7, M-Wnt), when treated with the secretome of mammary adipocytes from obese women (ObAd-CM), upregulated potent angiogenic factors, including VEGF-A, Angiopoietin-1, Jagged 1, HIF1-α and bFGF and significantly suppressed the angiogenesis inhibitor Tsp-1. ObAd-CM from both Pre-M and PM women significantly stimulated BC cell proliferation, migration and invasion. Importantly, compared to Pre-M patients, CAA Ad-CM from PM patients promoted higher levels of BC cell proliferation, migration and invasion. Pre-treatment with ObAd-CM resulted in increased endothelial cell (EC) recruitment by BC cells, an indispensable step in tumor angiogenesis. This effect was reversed by VEGF neutralization. In addition, ObAd-CM treatment significantly increased EC proliferation and capillary tube formation. Adipokines such as IL-6, IL-8, MCP-1, adiponectin and leptin were highly expressed in ObAd-CM. Of these, IL-6 neutralization alone inhibited the ObAd-CM-induced migratory and invasive phenotype of BC cells. Treatment with ObAd-CM also resulted in significant activation of pSTAT3, pAkt and pErk in BC cells. STAT3 inhibition reversed the ObAd-CM-mediated effects on BC cell proliferation and migration, suggesting that the pro-tumorigenic effects of Ob mammary adipocytes are mediated via IL-6/STAT3 signaling. Taken together, our results indicate that Ob mammary adipocytes promote migration, proliferation, invasion and the angiogenic phenotype in BC cells and suggest that targeting the VEGF/IL-6/STAT3 signaling axis may be a useful strategy in obesity-driven breast tumor growth and metastasis. [Supported by NIH RO1CA185530, the Karp Family Foundation and the Breast Cancer Research Foundation] Citation Format: Roopali Roy, Takaya Shimura, Lauren Merritt, Katherine Gonzalez, Emily Man, Margaret Lotz-Bousvaros, Susan Pories, Marsha A. Moses. Mammary adipocytes drive breast tumor progression and angiogenesis via the VEGF/IL6/STAT3 signaling axis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 121.
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