Hyperglycemia-Induced miR-467 Drives Tumor Inflammation and Growth in Breast Cancer.

The tumor microenvironment contains the parenchyma, blood vessels, and infiltrating immune cells, including tumor-associated macrophages (TAMs). TAMs affect the developing tumor and drive cancer inflammation. We used mouse models of hyperglycemia and cancer and specimens from hyperglycemic breast cancer (BC) patients to demonstrate that miR-467 mediates the effects of high blood glucose on cancer inflammation and growth. Hyperglycemic patients have a higher risk of developing breast cancer. We have identified a novel miRNA-dependent pathway activated by hyperglycemia that promotes BC angiogenesis and inflammation supporting BC growth. miR-467 is upregulated in endothelial cells (EC), macrophages, BC cells, and in BC tumors. A target of miR-467, thrombospondin-1 (TSP-1), inhibits angiogenesis and promotes resolution of inflammation. Systemic injections of a miR-467 antagonist in mouse models of hyperglycemia resulted in decreased BC growth (p < 0.001). Tumors from hyperglycemic mice had a two-fold increase in macrophage accumulation compared to normoglycemic controls (p < 0.001), and TAM infiltration was prevented by the miR-467 antagonist (p < 0.001). BC specimens from hyperglycemic patients had increased miR-467 levels, increased angiogenesis, decreased levels of TSP-1, and increased TAM infiltration in malignant breast tissue in hyperglycemic vs. normoglycemic patients (2.17-fold, p = 0.002) and even in normal breast tissue from hyperglycemic patients (2.18-fold increase, p = 0.04). In malignant BC tissue, miR-467 levels were upregulated 258-fold in hyperglycemic patients compared to normoglycemic patients (p < 0.001) and increased 56-fold in adjacent normal tissue (p = 0.008). Our results suggest that miR-467 accelerates tumor growth by inducing angiogenesis and promoting the recruitment of TAMs to drive hyperglycemia-induced cancer inflammation.

miR-467 regulates inflammation and blood insulin and glucose.

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 hyperglycaemia, in regulating inflammation and blood glucose handling. We previously demonstrated that miR-467a-5p is induced by hyperglycaemia 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 C57BL/6 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 ng/mL 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.

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 to aid in prognosis and treatment choices for breast cancer patients. 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 noncancerous tissue specimens from hyperglycemic patients revealed that levels of TSP-4 and of macrophage marker CD68 are upregulated in diabetic tissues. TSP-4 was colocalized 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.

Thrombospondins and remodeling of the tumor microenvironment.

Vascular remodeling defines cancer growth and aggressiveness. Although cancer cells produce pro-angiogenic signals, the fate of angiogenesis critically depends on the cancer microenvironment. Composition of the extracellular matrix (ECM) and tumor inflammation determine whether a cancer will remain dormant, will be recognized by the immune system and eliminated, or whether the tumor will develop and lead to the spread and metastasis of cancer cells. Thrombospondins (TSPs), a family of ECM proteins that has long been associated with the regulation of angiogenesis and cancer, regulate multiple physiological processes that determine cancer growth and spreading, from angiogenesis to inflammation, metabolic changes, and properties of ECM. Here, we sought to review publications that describe various functions of TSPs that link these proteins to regulation of cancer growth by modulating multiple physiological and pathological events that prevent or support tumor development. In addition to its direct effects on angiogenesis, TSPs have important roles in regulation of inflammation, immunity, ECM properties and composition, and glucose and insulin metabolism. Furthermore, TSPs have distinct roles as regulators of remodeling in tissues and tumors, such that the pathways activated by a single TSP can interact and influence each other. The complex nature of TSP interactions and functions, including their different cell- and tissue-specific effects, may lead to confusing results and controversial conclusions when taken out of the context of interdisciplinary and holistic approaches. However, studies of TSP functions and roles in different systems of the organism offer an integrative view of tumor remodeling and a potential for finding therapeutic targets that would modulate multiple complementary processes associated with cancer growth.

The lncRNA CASC15 regulates SOX4 expression in RUNX1-rearranged acute leukemia.

BACKGROUND: Long non-coding RNAs (lncRNAs) play a variety of cellular roles, including regulation of transcription and translation, leading to alterations in gene expression. Some lncRNAs modulate the expression of chromosomally adjacent genes. Here, we assess the roles of the lncRNA CASC15 in regulation of a chromosomally nearby gene, SOX4, and its function in RUNX1/AML translocated leukemia. RESULTS: CASC15 is a conserved lncRNA that was upregulated in pediatric B-acute lymphoblastic leukemia (B-ALL) with t (12; 21) as well as pediatric acute myeloid leukemia (AML) with t (8; 21), both of which are associated with relatively better prognosis. Enforced expression of CASC15 led to a myeloid bias in development, and overall, decreased engraftment and colony formation. At the cellular level, CASC15 regulated cellular survival, proliferation, and the expression of its chromosomally adjacent gene, SOX4. Differentially regulated genes following CASC15 knockdown were enriched for predicted transcriptional targets of the Yin and Yang-1 (YY1) transcription factor. Interestingly, we found that CASC15 enhances YY1-mediated regulation of the SOX4 promoter. CONCLUSIONS: Our findings represent the first characterization of this CASC15 in RUNX1-translocated leukemia, and point towards a mechanistic basis for its action.