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

Abstract

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.

Macrophages induce malignant traits in mammary epithelium via IKKε/TBK1 kinases and the serine biosynthesis pathway

“…Because this observation is recapitulated in a diet‐induced model of obesity in mice (Arendt et al , ), we tested the invasive behaviour of mouse primary mammary organoids derived from animals on normal diet (ND) vs. high‐fat diet (HFD) (Fig EV4A). As expected, animals on HFD were heavier than the ones on ND (average body weight: 27.2 ± 1.48 g vs. 21.3 ± 1.27 g, respectively), adipocytes in the mammary fat pad were on average larger (major adipocyte diameter: 74.4 ± 17.1 μm vs. 42.5 ± 7.7 μm), and we could observe a higher number of infiltrating macrophages (Fig EV4B–F), as previously reported (Subbaramaiah et al , ; Incio et al , ). When organoids were seeded in collagen, a substrate which promotes collective invasion (Nguyen‐Ngoc et al , ), organoids derived from mice on HFD were more invasive than the ones derived from mice of ND (Fig D–F), suggesting that the environment created by HFD affects the invasive properties of the cells, via a mechanism that is conserved when the cells are cultured in vitro .…”

Decreased Efficacy of Doxorubicin Corresponds With Modifications in Lipid Metabolism Markers and Fatty Acid Profiles in Breast Tumors From Obese vs. Lean Mice

“…Similar to previous findings (33)(34)(35) we successfully establish weight gain in our animal model. Body weight of animals in the HFD group was significantly higher than those in the LFD group, before (Figure 2A) and after tumor induction irrespective of treatment (Figure 3A), which was corroborated by mammary adipose tissue weight.…”

“…It has previously been shown that these elevated circulating cytokines (i.e., IL-6 and IL-8) exerted effects at distant sites (47,48), this favors the progression of breast cancer by upregulating the secretion of pro-inflammatory adipokines as well as exacerbates immune cell infiltration, which in turn promoted cancer progression through cellular proliferation, angiogenesis and the inhibition of apoptosis (38,39,49). Evidence also supports the role of obesity-induced inflammation (IL-6, TNF-α, and leptin) in Tamoxifen R and anti-VEGF acquired breast cancer drug resistance (33,50).…”

“…In addition, poor treatment outcomes are also reported in overweight and obese breast cancer patients evident by larger tumor sizes and poor clinical outcomes (7,18,42,43) especially those treated with doxorubicin (42,44). It was also reported that DIO decreased the efficacy of breast cancer treatment protocols in pre-clinical animal models (33,45).…”

“…Additionally, Cowen et al (39) reported a higher body weight in female MMTV-PyMT mice on a HFD (35.7% energy from fat) compared to mice on a LFD (10% energy from fat), even after adjusting for tumor weight and tumor volume. Others reported that DIO promotes tumor growth, progression, and metastasis in animal models (40,41), specifically in breast cancer (16,17,33). In addition, poor treatment outcomes are also reported in overweight and obese breast cancer patients evident by larger tumor sizes and poor clinical outcomes (7,18,42,43) especially those treated with doxorubicin (42,44).…”