Obesity-Activated Adipose-Derived Stromal Cells Promote Breast Cancer Growth and Invasion

Abstract

Obese women diagnosed with breast cancer have an increased risk for metastasis, and the underlying mechanisms are not well established. Within the mammary gland, adipose-derived stromal cells (ASCs) are heterogeneous cells with the capacity to differentiate into multiple mesenchymal lineages. To study the effects of obesity on ASCs, mice were fed a control diet (CD) or high-fat diet (HFD) to induce obesity, and ASCs were isolated from the mammary glands of lean and obese mice. We observed that obesity increased ASCs proliferation, decreased differentiation potential, and upregulated expression of α-smooth muscle actin, a marker of activated fibroblasts, compared to ASCs from lean mice. To determine how ASCs from obese mice impacted tumor growth, we mixed ASCs isolated from CD- or HFD-fed mice with mammary tumor cells and injected them into the mammary glands of lean mice. Tumor cells mixed with ASCs from obese mice grew significantly larger tumors and had increased invasion into surrounding adipose tissue than tumor cells mixed with control ASCs. ASCs from obese mice demonstrated enhanced tumor cell invasion in culture, a phenotype associated with increased expression of insulin-like growth factor-1 (IGF-1) and abrogated by IGF-1 neutralizing antibodies. Weight loss induced in obese mice significantly decreased expression of IGF-1 from ASCs and reduced the ability of the ASCs to induce an invasive phenotype. Together, these results suggest that obesity enhances local invasion of breast cancer cells through increased expression of IGF-1 by mammary ASCs, and weight loss may reverse this tumor-promoting phenotype.

Obesity Promotes Cooperation of Cancer Stem-Like Cells and Macrophages to Enhance Mammary Tumor Angiogenesis

“…Leptin, which is secreted by adipocytes and significantly enhanced in obesity, has been shown to promote CSCs [39], potentially through regulation of Notch signaling [40]. Adipocytes may also induce invasive and aggressive tumor cell behavior through secretion of cytokines [25], and we have previously observed that adipose-derived stromal cells isolated from the mammary glands of obese mice enhanced local invasion of Met-1 and EO771 cells through secretion of insulin-like growth factor-1 [41]. Interestingly, isolated tumor cells from obese mice retained the ability to proliferate at a higher rate through multiple passages, which may suggest that obesity induces epigenetic changes within breast tumors.…”

Single cell transcriptomics reveals involution mimicry during the specification of the basal breast cancer subtype

“…For example, the top pathways of the involution ECM-CAFs that were unique of this ECM subgroup, fatty acid metabolism and peroxisome hallmarks, suggested that these cells may correspond to adipocyte-like fibroblasts arisen through a dedifferentiation process of mature adipocytes 38 or transdifferentiation process of activated fibroblasts 39 . Adipocyte-derived fibroblasts secrete fibronectin and collagen I and have invasive properties 38,40 . Moreover, during the stromal remodelling stage in involution, there is a re-differentiation of the adipocytes 31,41 .…”

Microbiome and morbid obesity increase pathogenic stimulus diversity

“…[127] not shown here). ECM remodeling activated by obesity with its underlying chronic inflammation suggests that obesity or chronic inflammation is not enough as it needs fibrosis, which is subsequently remodeled for aggressive cancer phenotype cells that show enhanced growth and invasiveness [128].…”