Gajeton, J. | bioRxiv Science

bioRxiv2020

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

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 ImpactThrombospondin-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.

cancer biology↗

bioRxiv2019

miR-467 Prevents Inflammation And Insulin Resistance In Response To Hyperglycemia

Obesity is associated with inflammation and insulin resistance (IR), but the regulation of insulin sensitivity (IS) and connections between IS and inflammation remain unclear. We investigated the role of miR-467a-5p, a miRNA induced by hyperglycemia, in regulating inflammation and blood glucose handling. We previously demonstrated that miR-467a-5p is induced by hyperglycemia and inhibits the production of thrombospondin-1 (TSP-1), a protein implicated in regulating inflammation. To investigate the role of miR-467 in blood glucose handling and tissue inflammation, WT C57/BL6 mice were fed chow or Western diet from 5 to 32 weeks of age and injected weekly with miR-467a-5p antagonist. Inhibiting miR-467a-5p resulted in 47% increase in macrophage infiltration and increased Il6 levels in adipose tissue, higher plasma insulin levels (98 vs 63 ng/mL), and 17% decrease in glucose clearance without increase in weight or HDL/LDL. The antagonist effect was lost in mice on Western diet. Mice lacking TSP-1 lost some but not all of the miR-467 effects, suggesting Thbs1-/- (and other unknown transcripts) are targeted by miR-467 to regulate inflammation. miR-467a-5p provides a physiological feedback when blood glucose is elevated to avoid inflammation and increased blood glucose and insulin levels, which may prevent IR.

physiology↗