Obesity is correlated with worsened prognosis and treatment resistance in breast cancer. Macrophage-targeted therapies are currently in clinical trials, however, little is known about how obesity may impact treatment efficacy. Within breast adipose tissue, obesity leads to chronic, macrophage-driven inflammation, suggesting that obese breast cancer patients may benefit from these therapies. Using a high fat diet model of obesity, we orthotopically transplanted cancer cell lines into the mammary glands of obese and lean mice. We quantified changes in tumor invasiveness, angiogenesis and metastasis, and examined the efficacy of macrophage depletion to diminish tumor progression in obese and lean mice. Mammary tumors from obese mice grew significantly faster, were enriched for cancer stem-like cells (CSCs) and were more locally invasive and metastatic. Tumor cells isolated from obese mice demonstrated enhanced expression of stem cell-related pathways including Sox2 and Notch2. Despite more rapid growth, mammary tumors from obese mice had reduced necrosis, higher blood vessel density, and greater macrophage recruitment. Depletion of macrophages in obese tumor-bearing mice resulted in increased tumor necrosis, reduced endothelial cells, and enhanced recruitment of CD8+ T cells compared to IgG-treated controls. Macrophages may be an important clinical target to improve treatment options for obese breast cancer patients.

Women with obesity who develop breast cancer have a worsened prognosis with diminished survival rates and increased rates of metastasis. Obesity is also associated with decreased breast cancer response to endocrine and chemotherapeutic treatments. Studies utilizing multiple in vivo models of obesity as well as human breast tumors have enhanced our understanding of how obesity alters the breast tumor microenvironment. Changes in the complement and function of adipocytes, adipose-derived stromal cells, immune cells, and endothelial cells and remodeling of the extracellular matrix all contribute to the rapid growth of breast tumors in the context of obesity. Interactions of these cells enhance secretion of cytokines and adipokines as well as local levels of estrogen within the breast tumor microenvironment that promote resistance to multiple therapies. In this review, we will discuss our current understanding of the impact of obesity on the breast tumor microenvironment, how obesity-induced changes in cellular interactions promote resistance to breast cancer treatments, and areas for development of treatment interventions for breast cancer patients with obesity.

Obesity is correlated with increased incidence of breast cancer metastasis; however, the mechanisms underlying how obesity promotes metastasis are unclear. In a diet-induced obese mouse model, obesity enhanced lung metastasis in both the presence and absence of primary mammary tumors and increased recruitment of myeloid lineage cells into the lungs. In the absence of tumors, obese mice demonstrated increased numbers of myeloid lineage cells and elevated collagen fibers within the lung stroma, reminiscent of premetastatic niches formed by primary tumors. Lung stromal cells isolated from obese tumor-naïve mice showed increased proliferation, contractility, and expression of extracellular matrix, inflammatory markers and transforming growth factor beta-1 (TGFβ1). Conditioned media from lung stromal cells from obese mice promoted myeloid lineage cell migration in vitro in response to colony-stimulating factor 2 (CSF2) expression and enhanced invasion of tumor cells. Together, these results suggest that prior to tumor formation, obesity alters the lung microenvironment, creating niches conducive to metastatic growth.

Obesity is a risk factor for breast cancer in postmenopausal and high‐risk premenopausal women. Changes within the obese breast microenvironment may increase breast cancer risk. Transforming growth factor beta‐1 (TGFβ1) is a major regulator of mammary epithelial stem/progenitor cells, and its activity is dysregulated under conditions of obesity. Using a high‐fat diet model of obesity in mice and breast tissue from women, we observed that TGFβ1 activity is reduced in breast epithelial cells in obesity. Breast ducts and lobules demonstrated increased decorin in the extracellular matrix (ECM) surrounding epithelial cells, and we observed that decorin and latent TGFβ1 complexed together. Under conditions of obesity, macrophages expressed higher levels of decorin and were significantly increased in number surrounding breast epithelial cells. To investigate the relationship between macrophages and decorin expression, we treated obese mice with either IgG control or anti‐F4/80 antibodies to deplete macrophages. Mice treated with anti‐F4/80 antibodies demonstrated reduced decorin surrounding mammary ducts and enhanced TGFβ1 activity within mammary epithelial cells. Given the role of TGFβ1 as a tumor suppressor, reduced epithelial TGFβ1 activity and enhanced TGFβ1 within the ECM of obese mammary tissue may enhance breast cancer risk.

No abstract

Bladder inflammation is associated with several lower urinary tract symptoms that greatly reduce quality of life, yet contributing factors are not completely understood. Environmental chemicals are plausible mediators of inflammatory reactions within the bladder. Here, we examine whether developmental exposure to polychlorinated biphenyls (PCBs) leads to changes in immune cells within the bladder of young mice. Female mice were exposed to an environmentally relevant mixture of PCBs through gestation and lactation, and bladders were collected from offspring at postnatal day (P) 28–31. We identify several dose- and sex-dependent PCB effects in the bladder. The lowest concentration of PCB (0.1 mg/kg/d) increased CD45+ hematolymphoid immune cells in both sexes. While PCBs had no effect on CD79b+ B cells or CD3+ T cells, PCBs (0.1 mg/kg/d) did increase F4/80+ macrophages particularly in female bladder. Collagen density was also examined to determine whether inflammatory events coincide with changes in the stromal extracellular matrix. PCBs (0.1 mg/kg/d) decreased collagen density in female bladder compared to control. PCBs also increased the number of cells undergoing cell division predominantly in male bladder. These results implicate perturbations to the immune system in relation to PCB effects on the bladder. Future study to define the underlying mechanisms could help understand how environmental factors can be risk factors for lower urinary tract symptoms.

Obesity is a growing health concern worldwide and increases the incidence of multiple types of cancer, including breast cancer. Obese breast cancer patients often develop more aggressive tumors than lean patients and have increased risk for metastasis, tumor recurrence and mortality. Here, we sought to address how obesity alters the biology of breast cancer to promote aggressive tumors. To induce obesity, we fed mice either a control diet (CD) or high fat diet (HFD) for 16 weeks, then transplanted Met-1 tumor cells into mammary fat pads and monitored tumor growth. At end stage, tumors from HFD-fed mice were significantly larger than tumors from CD-fed mice, suggesting obesity promotes tumor growth. To investigate how obesity promotes tumor aggression, we dissociated the tumors from CD- and HFD-fed mice and plated isolated tumor cells in tumorsphere and invasion assays to test for cells with cancer stem-like cell (CSC) properties. Tumor cells from HFD-fed mice demonstrated increased tumorsphere formation and increased capacity for invasion compared to tumor cells from CD-fed mice, suggesting that obesity selects for tumor cells with CSC properties. Next, to address how obesity impacts the tumor microenvironment, we evaluated tumor necrosis and blood vessel formation through CD31 staining. Tumors from HFD-fed mice had significantly less necrosis and greater CD31 staining than those from CD-fed mice, suggesting that obesity promotes tumor angiogenesis. Since obesity promotes chronic, macrophage-driven inflammation within adipose tissue of the mammary gland, we stained tumors for the macrophage marker, F4/80. As with obese mammary glands, tumors from HFD-fed mice had significantly greater macrophage recruitment than tumors from CD-fed mice, together suggesting that obesity alters the tumor microenvironment. To determine how obesity stimulates tumor angiogenesis, we performed an in vitro assay by culturing dissociated tumor cells from HFD or CD-fed mice alone or with macrophages. Conditioned media (CM) isolated from tumor cells from HFD-fed mice cultured with macrophages enhanced the ability of endothelial cells to form networks in vitro. In contrast, CM from HFD tumor cells alone, macrophages alone, or those from CD-fed mice did not promote network formation. Together, these results suggest that cooperation between macrophages and tumor cells from HFD-fed mice promotes angiogenesis. Next, to investigate how macrophages and tumor cells interacting in obesity, we depleted macrophages using anti-F4/80 antibodies in CD-fed and HFD-fed tumor-bearing mice. In HFD-fed mice, macrophage depletion significantly reduced tumor volume and CD31 staining while increasing tumor necrosis compared to controls. Obesity promotes interactions between tumor cells and macrophages to enhance tumor angiogenesis and progression.

SUMMARYObesity is correlated with increased incidence of breast cancer metastasis, however the mechanisms underlying how obesity promotes metastasis are unclear. In a diet-induced obesity mouse model, obesity enhanced lung metastases in both the presence and absence of primary mammary tumors and increased recruitment of myeloid lineage cells into the lungs. In the absence of tumors, obese mice demonstrated increased numbers of myeloid lineage cells and elevated collagen fibers within the lung stroma, reminiscent of pre-metastatic niches formed by primary tumors. Lung stromal cells isolated from obese non-tumor-bearing mice showed increased proliferation, contractility, and expression of extracellular matrix, inflammatory markers, and TGFβ1. Conditioned media from lung stromal cells from obese mice promoted myeloid lineage cell migration in vitro in response to CSF2 expression and enhanced invasion of tumor cells. Together, these results suggest that prior to tumor formation, obesity alters the lung microenvironment, creating niches conducive for metastatic growth.