Cancer associated fibroblast FAK regulates malignant cell metabolism

Abstract: Emerging evidence suggests that cancer cell metabolism can be regulated by cancer-associated fibroblasts (CAFs), but the mechanisms are poorly defined. Here we show that CAFs regulate malignant cell metabolism through pathways under the control of FAK. In breast and pancreatic cancer patients we find that low FAK expression, specifically in the stromal compartment, predicts reduced overall survival. In mice, depletion of FAK in a subpopulation of CAFs regulates paracrine signals that increase malignant cell glycolysis and tumour growth. Proteomic and phosphoproteomic analysis in our mouse model identifies metabolic alterations which are reflected at the transcriptomic level in patients with low stromal FAK. Mechanistically we demonstrate that FAK-depletion in CAFs increases chemokine production, which via CCR1/CCR2 on cancer cells, activate protein kinase A, leading to enhanced malignant cell glycolysis. Our data uncover mechanisms whereby stromal fibroblasts regulate cancer cell metabolism independent of genetic mutations in cancer cells

Cancer associated fibroblast FAK regulates malignant cell metabolism

Abstract: Emerging evidence suggests that cancer cell metabolism can be regulated by cancer-associated fibroblasts (CAFs), but the mechanisms are poorly defined. Here we show that CAFs regulate malignant cell metabolism through pathways under the control of FAK. In breast and pancreatic cancer patients we find that low FAK expression, specifically in the stromal compartment, predicts reduced overall survival. In mice, depletion of FAK in a subpopulation of CAFs regulates paracrine signals that increase malignant cell glycolysis and tumour growth. Proteomic and phosphoproteomic analysis in our mouse model identifies metabolic alterations which are reflected at the transcriptomic level in patients with low stromal FAK. Mechanistically we demonstrate that FAK-depletion in CAFs increases chemokine production, which via CCR1/CCR2 on cancer cells, activate protein kinase A, leading to enhanced malignant cell glycolysis. Our data uncover mechanisms whereby stromal fibroblasts regulate cancer cell metabolism independent of genetic mutations in cancer cells

Dissecting the functions of cancer-associated fibroblasts to therapeutically target head and neck cancer microenvironment

Head and neck cancers (HNC) are a diverse group of aggressive malignancies with high morbidity and mortality, leading to almost half-million deaths annually worldwide. A better understanding of the molecular processes governing tumor formation and progression is crucial to improve current diagnostic and prognostic tools as well as to develop more personalized treatment strategies. Tumors are highly complex and heterogeneous structures in which growth and dissemination is not only governed by the cancer cells intrinsic mechanisms, but also by the surrounding tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) emerge as predominant TME components and key players in the generation of permissive conditions that ultimately impact in tumor progression and metastatic dissemination. Although CAFs were initially considered a consequence of tumor development, it is now well established that they actively contribute to numerous cancer hallmarks i.e., tumor cell growth, migration and invasion, cancer cell stemness, angiogenesis, metabolic reprograming, inflammation, and immune system modulation. In this scenario, therapeutic strategies targeting CAF functions could potentially have a major impact in cancer therapeutics, providing avenues for new treatment options or for improving efficacy in established approaches. This review is focused on thoroughly dissecting existing evidences supporting the contribution of CAFs in HNC biology with an emphasis on current knowledge of the key molecules and pathways involved in CAF-tumor crosstalk, and their potential as novel biomarkers and/or therapeutic targets to effectively interfere the tumor-stroma crosstalk for HNC patients benefit. involved in CAF-tumor crosstalk, and their potential as novel biomarkers and/or therapeutic targets to effec- tively interfere the tumor-stroma crosstalk for HNC patients benefit

Long-term training induces a healthy inflammatory and endocrine emergent biomarker profile in elderly men

The objective of the present study was to investigate the changes in a large panel of emergent geriatric biomarkers in long-term trained elderly men to analyze the effects of long-term exercise on an aged population. We collected blood samples from two groups of male volunteers older than 65 years who maintain a measure of functional independence: one group of sedentary subjects without a history of regular physical activity and the other of subjects who have sustained training, starting during adulthood (mean training time = 49 ± 8 years). We studied morbidity, polypharmacy, cellular and serological inflammatory parameters, and endocrine mediators. After adjusting for confounding factors, we observed reduced medication intake per subject and lower number of diseases per subject with statistical differences nearly significant in the long-term exercise group. We showed that long-term training was associated with lower levels of white blood cell counts, neutrophil counts, interleukin-6, interleukin-10, interleukin-1 receptor antagonist, and soluble TNF receptor-I. Furthermore, we noted an increase in the concentrations of insulin-like growth factor-1 and dehydroepiandrosterone in the long-term training group. We concluded that long-term exercise training from adulthood to old age is clearly associated with a healthy profile of emergent geriatric biomarkers. Long-term training could improve the inflammatory–endocrine imbalance associated with disease, frailty, functional decline, and mortality in elderly men. Our results point to the benefits of prolonged exercise from adulthood to old age