Obesity has been associated with reduced survival in some cancers. A new study headed by scientists at Massachusetts General Hospital (MGH) has now found that obesity may also explain why angiogenesis inhibitor therapy is ineffective against breast cancer (BC). The MGH research, including data from human breast cancer patients and experiments in two mouse models of the disease, suggest that obesity is associated with increased production of inflammatory and angiogenic factors that sustain angiogenesis and promote breast cancer resistance to anti-vascular endothelial growth factor (VEGF) therapy. The results point to new strategies for improving breast cancer response to treatment with antiangiogenic treatments. 

“Collectively, our clinical and preclinical results indicate that obesity fuels resistance to anti-VEGF therapy in breast cancer via production of several inflammatory and proangiogenic factors, depending on the subtype of cancer,” says lead researcher Joao Incio, M.D., Ph.D, at the Edwin L. Steele Laboratories for Tumor Biology in the MGH Department of Radiation Oncology. “Targeting these resistance factors may rejuvenate the use of antiangiogenic therapy in breast cancer treatment.”

The MGH team, and collaborators in the U.S., Portugal, India, Austria, Brazil, China, Germany, and the U.K., report on their findings in Science Translational Medicine, in a paper entitled “Obesity Promotes Resistance to Anti-VEGF Therapy in Breast Cancer by Up-Regulating IL-6 and Potentially FGF-2.”

Promising early studies led to FDA’s accelerated approval of the anti-VEGF antibody bevacizumab (Avastin®) for treating metastatic breast cancer, but a lack of overall survival benefit in Phase III studies subsequently led to the U.S. regulator revoking approval of the drug for the breast cancer indication, the authors explain.

In metastatic colon cancer, obesity has been associated with reduced survival, specifically in patients receiving antiangiogenic therapy, but reports for other cancers have been conflicting, and the effect of obesity on anti-VEGF response in BC patients remains unknown the team adds.

Prior studies have shown that that proinflammatory and angiogenic factors can sustain angiogenesis and tumor progression, despite VEGF blockade. Interestingly, the researchers note, “many of these same factors are also increased in obesity,” when fat tissue expands faster than blood vessel growth, resulting in inadequately vascularized, hypoxic tissue. As a result of hypoxia, cytokines and chemokines are released that cause inflammation and recruit additional proinflammatory and proangiogenesis mediators to boost angiogenesis.

Adipose tissue also makes up a large proportion of breast cancer, and obesity has been shown to increase tumor inflammation, the researchers note. “Therefore, we hypothesized that obesity promotes resistance to anti-VEGF therapy in BCs via systemic as well as local overproduction of inflammatory and alternative angiogenic factors.”

To evaluate their hypothesis, the team first revisited a Phase II clinical trial of neoadjuvant bevacizumab therapy in 99 breast cancer patients. They analyzed the study results, patient data, and computed tomography (CT) scans, and looked at blood vessel density in biopsy samples. Their findings confirmed that the anti-VEGF therapy only benefited a small proportion of patients, while participants who were overweight or obese had tumors that were on average 33% larger at diagnosis, and more hypoxic, than those in patients who weren’t overweight. Circulating levels of the proinflammatory cytokine interleukin 6 (IL-6) and the proangiogenic molecule fibroblast growth factor 2 (FGF-2) were also higher in overweight and obese patients.

Both factors were expressed in adipocyte-rich regions of the patients’ tumors, the investigators note. “Immunohistochemical observation of tumors in obesity revealed that IL-6 and FGF-2 expression in tumors was particularly abundant in adipocyte-rich regions.…These patients also had increasing circulating concentrations of IL-6 and FGF-2, and expression of these factors in tumors was localized in close proximity to adipocyte-rich regions.”

The researchers then evaluated the role of diet-induced obesity on response to anti-VEGF therapy in mouse models of estrogen receptor-positive (ER+) and triple-negative (TN) breast cancer, which mirrorerd the human trial population. The results first showed that obesity accelerated tumor growth, although only in the early stages of tumor development. Significantly, treatment using an anti-mouse VEGF antibody was more effective at inhibiting tumor growth in lean animals than it was in obese animals. Additional assessment showed that it was the animals’ body weight, rather than their diet, that accounted for the reduced sensitivity to anti-VEGF therapy of tumors in the obese animals. “Together, these data indicate that anti-VEGF therapy is less effective in inhibiting BC progression in obese mice,” the team writes.

Further analyses showed that tumors in the obese ER+ breast cancer model mice were also characterized by higher adipocyte size and number, while adipocyte-rich tumor areas had lower vessel density and were hypoxic. When the tumor-bearing animals were treated using the anti-VEGF antibody, tumor tissue in adipocyte-rich regions remained viable, whereas adipocyte-poor areas became necrotic, “suggesting a protective effect of adipose stroma in tumors,” the authors write.

Consistent with observations of higher concentrations of IL-6 in both the plasma and adipocyte-rich tumor regions of obese breast cancer patients, the authors also found that expression of IL-6 was elevated in the tumors of obese ER+ model mice, “possibly reflecting the baseline increase in tumor hypoxia, because hypoxia can increase IL-6 production,” they write.

The authors postulated that IL-6 may represent “a rational target to overcome obesity-induced resistance to anti-VEGF therapy.” Tests in the ER+ mouse model showed that combining the anti-VEGF antibody therapy with pharmacological inhibition of IL-6 reduced tumor growth in obese mice to rates similar to those in lean mice receiving just the anti-VEGF treatment. IL-6 inhibition alone wasn’t effective in obese mice.

In contrast, IL-6 inhibition had no added benefit to anti-VEGF therapy in the lean ER+ model mice, “indicating that IL-6 specifically mediates obesity-induced resistance to antiangiogenic therapy,” the team suggests. 

Tests in the TN breast cancer mouse model showed that FGF-2, rather than IL-6, was associated with obesity. Similar to the observation of increased levels if IL-6 expression in the ER+  model of breast cancer, the TN breast cancer model demonstrated increased tumor expression of FGF-2 in obese animals, particularly in adipocyte-rich areas of the tumor. “Considering that FGF-2 has previously been implicated in resistance to antiangiogenic therapy, this poses yet another potential mechanism of resistance to anti-VEGF therapy induced by obesity,” the authors comment. And mirroring results in the ER+ breast cancer model, anti-VEGF antibody therapy was less effective at reducing vessel density in obese TN breast cancer mice than in lean animals. However, adding metformin therapy to anti-VEGF treatment in obese TN mice reduced gene and protein expression of FGF-2 and also led to reduced vessel density, and “ultimately resensitized tumors to anti-VEGF treatment,” the team reports.

“Our work reveals strategies to improve the clinical outcome of BC,” the authors conclude. “Overall, we identified two complementary strategies to overcome BC resistance to anti-VEGF therapy in obesity by targeting IL-6 and/or FGF-2.…Previous studies have reported the role of IL-6 or FGF-2 in the context of resistance to antiangiogenic therapies. This study, however, suggests that these molecules mediate obesity-induced resistance to anti-VEGF therapy.”

The authors also point out that because inflammation and angiogenesis can affect responses to conventional and other targeted therapies, “the findings of this work may extend beyond anti-VEGF treatment in BC.”   

“This is the first study to propose that markers such as body mass index could help personalize anti-VEGF therapy, with blockade of molecules like IL-6 or FGF-2 for overweight or obese cancer patients,” says Incio. “Identifying and validating predictive biomarkers of treatment response and gaining the ability to classify patients regarding which of the more than a dozen currently available antiangiogenic therapies would be most beneficial remain major priorities in oncology.”

Co-senior author Dai Fukumura, M.D., Ph.D, deputy director of the Steele Labs, adds, “Although the role of systemic adipokines—signaling molecules derived from adipose tissues—has been studied in multiple obesity-associated diseases, studies dissecting their role in cancer have been limited. Our studies are the first to demonstrate the role of the adipokines IL-6 and FGF-2 in both breast cancer patients and clinically relevant animal models and that these adipokines are derived from adipocytes within tumors. There are many different adipokines, and we found that different factors mediate anti-VEGF resistance in different subsets of breast cancers. Investigations of the crosstalk between cancer-associated adipocytes and the tumor microenvironment are needed to develop novel strategies to overcome obesity-induced aggravation of breast cancer.”

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