Tumor microenvironment and breast cancer survival: combined effects of breast fat, M2 macrophages and hyaluronan create a dismal prognosis

Abstract

Purpose Tumor microenvironment, including inflammatory cells, adipocytes and extracellular matrix constituents such as hyaluronan (HA), impacts on cancer progression. Systemic metabolism also influences tumor growth e.g. obesity and type 2 diabetes (T2D) are risk factors for breast cancer. Here, in 262 breast cancer cases, we explored the combined impacts on survival of M2-like tumor associated macrophages (TAMs), the abundance of breast fat visualized as low density in mammograms, and tumor HA, and their associations with T2D. Methods Mammographic densities were assessed visually from the diagnostic images and dichotomized into very low density (VLD, density ≤ 10%, “fatty breast”) and mixed density (MID, density > 10%). The amounts of TAMs (CD163+ and CD68+) and tumor HA were determined by immunohistochemistry. The data of T2D was collected from the patient records. Statistical differences between the parameters were calculated with Chi square or Mann–Whitney test and survival analyses with Cox’s model. Results A combination of fatty breasts (VLD), abundance of M2-like TAMs (CD163+) and tumor HA associated with poor survival, as survival was 88–89% in the absence of these factors but only 40–47% when all three factors were present (p < 0.001). Also, an association between T2D and fatty breasts was found (p < 0.01). Furthermore, tumors in fatty breasts contained more frequently high levels of M2-like TAMs than tumors in MID breasts (p = 0.01). Conclusions Our results demonstrate a dramatic effect of the tumor microenvironment on breast cancer progression. We hypothesize that T2D as well as obesity increase the fat content of the breasts, subsequently enhancing local pro-tumoral inflammation.

Folic acid-modified Exosome-PH20 enhances the efficiency of therapy via modulation of the tumor microenvironment and directly inhibits tumor cell metastasis

“…Excessive HA has been related aggressive malignant tumors in patients or preclinical models. In breast cancer patients, the accumulation of HMW-HA is often accompanied by poor prognosis and high mortality [ 29 ]. Moreover, the accumulated HMW-HA can aggregate into cable-like structures that recruit macrophages, which are polarized to the pro-tumorigenic M2-like phenotype [ [30] , [31] , [32] ].…”

Breast Adipocyte Co-culture Increases the Expression of Pro-angiogenic Factors in Macrophages

“…Characterization of breast tissue macrophages showed that macrophages from obese women were similar to TAMs (20). A recent study found that fatty breast tissue combined with a high level of TAMs increased the risk of breast cancer recurrence and mortality (21).…”

T cell immunoglobulin and mucin domain protein 3 inhibits glycolysis in RAW 264.7 macrophages through Hexokinase 2

“…As a crucial component of innate immunity, macrophages are indispensable in tissue homeostasis, coordination of adaptive immune responses, inflammation, resolution and repair 1 . A persistent increase in the inflammatory cytokines released by macrophages is known to induce allergy and autoimmune diseases, 2,3 whereas the anti‐inflammatory phenotype of macrophages releasing IL‐10 and TGF(transforming growth factor)‐β, contributes to progression and metastasis in breast cancer and colon cancer 4,5 . However, most macrophages in the human body display a spectrum of phenotypes between the above‐mentioned opposite phenotypes 6 .…”

“…inflammatory cytokines released by macrophages is known to induce allergy and autoimmune diseases, 2,3 whereas the anti-inflammatory phenotype of macrophages releasing IL-10 and TGF(transforming growth factor)-β, contributes to progression and metastasis in breast cancer and colon cancer. 4,5 However, most macrophages in the human body display a spectrum of phenotypes between the above-mentioned opposite phenotypes. 6 The mechanisms that modulate appropriate functions in macrophages are of great interest but limited information is available.…”