Thrombospondin-4 mediates hyperglycemia- and TGF-beta-induced inflammation in breast cancer

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Abstract Inflammation drives the growth of tumors and is an important predictor of cancer aggressiveness. CD68, a marker of tumor-associated macrophages (TAM), is routinely used as a marker to aid in prognosis and treatment choices for breast cancer. We report that thrombospondin-4 (TSP-4) mediates breast cancer inflammation and growth in mouse models in response to hyperglycemia and TGF-beta by increasing TAM infiltration and production of inflammatory signals in tumors. Analysis of breast cancers and non-cancerous tissue specimens from hyperglycemic patients revealed that levels of TSP-4 and of macrophage marker CD68 are upregulated in diabetic tissues. TSP-4 was co-localized with macrophages in cancer tissues. Bone-marrow-derived macrophages (BMDM) responded to high glucose and TGF-beta by upregulating TSP-4 production and expression, as well as the expression of inflammatory markers. We report a novel function for TSP-4 in breast cancer: regulation of TAM infiltration and inflammation. The results of our study provide new insights into regulation of cancer growth by hyperglycemia and TGF-beta and suggest TSP-4 as a potential therapeutic target. Novelty and Impact Thrombospondin-4 (TSP-4) is a secreted extracellular protein that belongs to the family of matricellular proteins. TSP-4 is one of the top 1% of proteins upregulated in several cancers, including breast cancer. Inflammation and infiltration of macrophages drive cancer progression and metastasis and are clinically important markers of cancer aggressiveness and critical consideration in the process of selection of the appropriate therapeutic approaches. We report that TSP-4 promotes breast cancer inflammation and infiltration of macrophages and mediates the effects of hyperglycemia and TGF-beta on cancer growth and inflammation. Our work describes a role for TSP-4 in cancer inflammation and identifies the pathways, in which increased levels of TSP-4 mediate cancer growth.

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