Obesity and Cancer: An Angiogenic and Inflammatory Link

Fukumura, Dai; Incio, João; Shankaraiah, Ram C.; Jain, Rakesh K.

doi:10.1111/micc.12270

Cited by 55 publications

(48 citation statements)

References 190 publications

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“…Similar to the enlarged adipocytes that form in adipose tissue during obesity, CAAs are associated with increased production of proangiogenic growth factors and proinflammatory cytokines (15, 16, 21). These growth factors and cytokines, when present in the tumor microenvironment, can sustain angiogenesis and tumor progression despite blockade of VEGF signaling (1, 9–11, 28, 29).…”

Section: Resultsmentioning

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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Section: Resultsmentioning

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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“…In general, obesity is associated with tumor progression and poor prognosis in various cancers [38]. Fujiwara et al [15] reported that high visceral adiposity was independently associated with poor prognosis, but the incidence of advanced HCC was too small (61 of 1,257 patients, 4.8%), with various treatments being performed in their study.…”

Section: Discussionmentioning

confidence: 99%

No Muscle Depletion with High Visceral Fat as a Novel Beneficial Biomarker of Sorafenib for Hepatocellular Carcinoma

et al. 2018

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Background: Sorafenib is a standard therapy for patients with advanced hepatocellular carcinoma (HCC). However, no predictive biomarkers of sorafenib efficacy have been discovered. Herein, we investigated the impact of body composition, such as skeletal muscle and visceral fat, on the prognosis of advanced HCC patients treated with sorafenib. Methods: We enrolled 100 patients with advanced HCC treated with sorafenib. Prior to receiving sorafenib therapy, skeletal muscle index (SMI) and visceral fat area (VFA) were measured using computed tomography at the third lumbar vertebra and umbilical level, respectively. Muscle depletion was defined as an SMI value < 42 cm²/m² in men and < 38 cm²/m² in women. High VFA (H-VFA) was defined as a value ≥100 cm². In addition to SMI and VFA, we also analyzed various clinical parameters as potential prognostic factors. Results: Multivariate analysis showed that having a tumor number < 7 (hazard ratio [HR] = 0.409, p < 0.001), absence of extrahepatic spread (EHS) (HR = 0.562, p < 0.001), absence of muscle depletion (HR = 0.498, p = 0.006), and H-VFA (HR = 0.556, p = 0.031) were significant factors for long-term survival. Therefore, we evaluated the prognosis of those with no muscle depletion with H-VFA. The no muscle depletion with H-VFA group showed significantly longer survival than the other group (median survival time 15.6 vs. 11.0 months, p = 0.003). Multivariate analysis showed that having a tumor number < 7 (HR = 0.454, p = 0.001), absence of EHS (HR = 0.511, p = 0.008), and no muscle depletion with H-VFA (HR = 0.454, p = 0.002) were significant predictors of survival. Conclusions: We identified no muscle depletion with H-VFA as a novel biomarker for advanced HCC patients treated with sorafenib.

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“…Obesity is associated with an unfavourable prognosis across multiple types of cancer 114 . Notably, an increased severity of adverse effects has been observed in obese versus nonobese mice following immunotherapy 115 ; however, the mechanisms underlying this increase are not understood.…”

Section: Perspectivesmentioning

confidence: 99%

Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges

et al. 2018

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Immunotherapy has emerged as a major therapeutic modality in oncology. Currently, however, the majority of patients with cancer do not derive benefit from these treatments. Vascular abnormalities are a hallmark of most solid tumours and facilitate immune evasion. These abnormalities stem from elevated levels of proangiogenic factors, such as VEGF and angiopoietin 2 (ANG2); judicious use of drugs targeting these molecules can improve therapeutic responsiveness, partially owing to normalization of the abnormal tumour vasculature that can, in turn, increase the infiltration of immune effector cells into tumours and convert the intrinsically immunosuppressive tumour microenvironment (TME) to an immunosupportive one. Immunotherapy relies on the accumulation and activity of immune effector cells within the TME, and immune responses and vascular normalization seem to be reciprocally regulated. Thus, combining antiangiogenic therapies and immunotherapies might increase the effectiveness of immunotherapy and diminish the risk of immune-related adverse effects. In this Perspective, we outline the roles of VEGF and ANG2 in tumour immune evasion and progression, and discuss the evidence indicating that antiangiogenic agents can normalize the TME. We also suggest ways that antiangiogenic agents can be combined with immune-checkpoint inhibitors to potentially improve patient outcomes, and highlight avenues of future research.

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Obesity and Cancer: An Angiogenic and Inflammatory Link

Cited by 55 publications

References 190 publications

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

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

No Muscle Depletion with High Visceral Fat as a Novel Beneficial Biomarker of Sorafenib for Hepatocellular Carcinoma

Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges

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