Epigenetic Reprogramming of Cancer-Associated Fibroblasts Deregulates Glucose Metabolism and Facilitates Progression of Breast Cancer.

The mechanistic contributions of cancer-associated fibroblasts (CAFs) in breast cancer progression remain to be fully understood. While altered glucose metabolism in CAFs could fuel cancer cells, how such metabolic reprogramming emerges and is sustained needs further investigation. Studying fibroblasts isolated from patients with benign breast tissues and breast cancer, in conjunction with multiple animal models, we demonstrate that CAFs exhibit a metabolic shift toward lactate and pyruvate production and fuel biosynthetic pathways of cancer cells. The depletion or suppression of the lactate production of CAFs alter the tumor metabolic profile and impede tumor growth. The glycolytic phenotype of the CAFs is in part sustained through epigenetic reprogramming of HIF-1α and glycolytic enzymes. Hypoxia induces epigenetic reprogramming of normal fibroblasts, resulting in a pro-glycolytic, CAF-like transcriptome. Our findings suggest that the glucose metabolism of CAFs evolves during tumor progression, and their breast cancer-promoting phenotype is partly mediated by oxygen-dependent epigenetic modifications.

Naviculocuneiform and Second and Third Tarsometatarsal Articulations: Underappreciated Normal Anatomy and How It May Affect Fluoroscopy-Guided Injections.

OBJECTIVE: Because the second and third tarsometatarsal (TMT) and naviculocuneiform joints normally communicate, the least arthritic or technically most straightforward joint was injected when a fluoroscopically guided therapeutic injection was ordered for one or both joints. We hypothesized that pain relief would be equivalent regardless of the joint injected and would result in less radiation and a lower steroid dose compared with patients who had both articulations injected. MATERIALS AND METHODS: Seventy-eight patients were divided into four joint groups: naviculocuneiform requested and injected (n = 15), nonrequested naviculocuneiform or second and third TMT injected (n = 25), both injected (n = 23), and TMT requested and injected (n = 15). Variables recorded included patient age and sex, fluoroscopy time, steroid dose, pre- and postprocedural pain, osteoarthrosis (OA) grade, and confidence of intraarticular injection. Statistical analysis compared mean pain level change before and after injection, mean fluoroscopy time, and mean steroid dose between groups. The mean OA grade of the nonrequested joint was compared with that of the requested joint in patients whose injected and requested joints did not match (group 2). RESULTS: Pre- and postinjection pain reduction (p = 0.630) and postinjection pain (p = 0.935) were not significantly different. Mean steroid dose (p < 0.001) and fluoroscopy time (p = 0.0001) were significantly increased for the both joint injection group. Within the nonrequested naviculocuneiform or second and third TMT injection group, there was a significant difference in OA grade between injected (least arthritic) and requested joints (p = 0.001). CONCLUSION: When faced with challenging naviculocuneiform or second and third TMT joint injections, choosing the technically most straightforward joint may result in less radiation and steroid dose without compromising quality of care or pain reduction.