Obesity-associated NLRC4 inflammasome activation drives breast cancer progression

Kolb, Ryan; Phan, Liem; Borcherding, Nicholas; Liu, Yanping; Fang, Yuan; Janowski, Ann M.; Xie, Qing; Markan, Kathleen R.; Li, Wei; Potthoff, Matthew J.; Fuentes‐Mattei, Enrique; Ellies, Lesley G.; Knudson, C. Michael; Lee, Mong Hong; Yeung, Sai Ching Jim; Cassel, Suzanne L.; Sutterwala, Fayyaz S.; Zhang, Weizhou

doi:10.1038/ncomms13007

Cited by 204 publications

(210 citation statements)

References 59 publications

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“…Our results indicate correlation between the infiltration of neutrophils in the primary tumor and the acquisition of a more mesenchymal phenotype by tumor cells. In contrast, Kolb and collaborators found that the inflammasome of macrophages in primary tumors in obese mice is responsible for triggering angiogenesis through expression of vascular endothelial growth factor A (VEGFA), consequently boosting primary tumor growth [10]. Our results differ in that we did not see increased macrophage content in tumors from obese mice, and we observed a reduction in vessel density with a concomitant increase in hypoxia.…”

Section: Discussioncontrasting

confidence: 99%

Obesity promotes the expansion of metastasis-initiating cells in breast cancer

et al. 2018

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BackgroundObesity is a strong predictor of poor prognosis in breast cancer, especially in postmenopausal women. In particular, tumors in obese patients tend to seed more distant metastases, although the biology behind this observation remains poorly understood.MethodsTo elucidate the effects of the obese microenvironment on metastatic spread, we ovariectomized C57BL/6 J female mice and fed them either a regular diet (RD) or a high-fat diet (HFD) to generate a postmenopausal diet-induced obesity model. We then studied tumor progression to metastasis of Py230 and EO771 grafts. We analyzed and phenotyped the RD and HFD tumors and the surrounding adipose tissue by flow cytometry, qPCR, immunohistochemistry (IHC) and western blot. The influence of the microenvironment on tumor cells was assessed by performing cross-transplantation of RD and HFD tumor cells into other RD and HFD mice. The results were analyzed using the unpaired Student t test when comparing two variables, otherwise we used one-way or two-way analysis of variance. The relationship between two variables was calculated using correlation coefficients.ResultsOur results show that tumors in obese mice grow faster, are also less vascularized, more hypoxic, of higher grade and enriched in CD11b+Ly6G+ neutrophils. Collectively, this favors induction of the epithelial-to-mesenchymal transition and progression to claudin-low breast cancer, a subtype of triple-negative breast cancer that is enriched in cancer stem cells. Interestingly, transplanting HFD-derived tumor cells in RD mice transfers enhanced tumor growth and lung metastasis formation.ConclusionsThese data indicate that a pro-metastatic effect of obesity is acquired by the tumor cells in the primary tumor independently of the microenvironment of the secondary site.Graphical abstractEffects of postmenopausal obesity on primary breast cancer tumoursᅟElectronic supplementary materialThe online version of this article (10.1186/s13058-018-1029-4) contains supplementary material, which is available to authorized users.

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Section: Discussioncontrasting

confidence: 99%

Obesity promotes the expansion of metastasis-initiating cells in breast cancer

et al. 2018

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“…The link between IL-6 and obesity is well-established (60–62). In addition, transcriptomic analysis revealed marked up-regulation of IL-6 inflammatory pathway in the tumors of BC patients with obesity in comparison to those without obesity (63). In our study, we found that IL-6 increased with BW in BC patients and mice, was particularly expressed in adipose-rich regions of tumors, and was associated with worse response to anti-VEGF therapy.…”

Section: Discussionmentioning

confidence: 99%

Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2

et al. 2018

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Anti–vascular endothelial growth factor (VEGF) therapy has failed to improve survival in patients with breast cancer (BC). Potential mechanisms of resistance to anti-VEGF therapy include the up-regulation of alternative angiogenic and proinflammatory factors. Obesity is associated with hypoxic adipose tissues, including those in the breast, resulting in increased production of some of the aforementioned factors. Hence, we hypothesized that obesity could contribute to anti-VEGF therapy’s lack of efficacy. We found that BC patients with obesity harbored increased systemic concentrations of interleukin-6 (IL-6) and/or fibroblast growth factor 2 (FGF-2), and their tumor vasculature was less sensitive to anti-VEGF treatment. Mouse models revealed that obesity impairs the effects of anti-VEGF on angiogenesis, tumor growth, and metastasis. In one murine BC model, obesity was associated with increased IL-6 production from adipocytes and myeloid cells within tumors. IL-6 blockade abrogated the obesity-induced resistance to anti-VEGF therapy in primary and metastatic sites by directly affecting tumor cell proliferation, normalizing tumor vasculature, alleviating hypoxia, and reducing immunosuppression. Similarly, in a second mouse model, where obesity was associated with increased FGF-2, normalization of FGF-2 expression by metformin or specific FGF receptor inhibition decreased vessel density and restored tumor sensitivity to anti-VEGF therapy in obese mice. Collectively, our data indicate that obesity fuels BC resistance to anti-VEGF therapy via the production of inflammatory and angiogenic factors.

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“…For example, adipocyte-secreted vascular endothelial growth factor (VEGF)-A and interleukin (IL)-1β promote tumor angiogenesis and recruitment of immunosuppressive neutrophils to the tumor microenvironment, respectively. 37,38 Given the impact of adiposity on breast cancer development and progression and the complexity of the tumor microenvironment, it is important to understand the tumor-adipose network better.…”

Section: Introductionmentioning

confidence: 99%

Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer

Sun

Gupta

et al. 2018

OncoImmunology

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Programmed death-ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) modulate antitumor immunity and are major targets of checkpoint blockade immunotherapy. However, clinical trials of anti-PD-L1 and anti-PD-1 antibodies in breast cancer demonstrate only modest efficacy. Furthermore, specific PD-L1 contributions in various tissue and cell compartments to antitumor immunity remain incompletely elucidated. Here we show that PD-L1 expression is markedly elevated in mature adipocytes versus preadipocytes. Adipocyte PD-L1 prevents anti-PD-L1 antibody from activating important antitumor functions of CD8+ T cells in vitro. Adipocyte PD-L1 ablation obliterates, whereas forced preadipocyte PD-L1 expression confers, these inhibitory effects. Pharmacologic inhibition of adipogenesis selectively reduces PD-L1 expression in mouse adipose tissue and enhances the antitumor efficacy of anti-PD-L1 or anti-PD-1 antibodies in syngeneic mammary tumor models. Our findings provide a previously unappreciated approach to bolster anticancer immunotherapy efficacy and suggest a mechanism for the role of adipose tissue in breast cancer progression.

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Obesity-associated NLRC4 inflammasome activation drives breast cancer progression

Cited by 204 publications

References 59 publications

Obesity promotes the expansion of metastasis-initiating cells in breast cancer

Obesity promotes the expansion of metastasis-initiating cells in breast cancer

Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2

Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer

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