Tumor epithelial cells within a tumor coexist with a complex microenvironment in which a variety of interactions between its various components determine the behavior of the primary tumors. Cancer- associated fibroblasts (CAF) and M2 macrophages, characterized by high expression of different markers, including a-SMA, FSP1 and FAP, or CD163 and DCSIGN, respectively, are involved in the malignancy of different tumors. In the present study, expression of the above markers in CAF and M2 macrophages was analyzed using RT-PCR and immunohistochemistry in the normal mucosa and tumor tissue from a cohort of 289 colorectal cancer patients. Expression of CAF and M2 markers is associated with the clinical outcome of colorectal cancer patients. Moreover, the combination of CAF and M2 markers identifies three groups of patients with clear differences in the progression of the disease. This combined variable could be a decisive factor in the survival of advanced-stage patients. Taken together, these analyses demonstrate the prognostic involvement of interrelationships between DCSIGN, CD163, a-SMA, FSP1 and FAP markers in the survival of colon cancer patients.This work has been supported by Fundación Científica AECC, SAF2010-20750, S2010 ⁄BMD-2344, RTICC-RD06 ⁄ 0020 ⁄ 0020, PI12 ⁄ 02037 and Fundación Banco Santander. A.G.H. laboratory was supported by RD06 ⁄ 0020 ⁄ 0040. C.P. is the recipient of a Miguel Servet Contract from the Instituto de Salud Carlos III (CP09 ⁄ 00294) and V.G. is the recipient of a Fundación Científica AECC fellowshi

The mitochondrial H(+)-ATP synthase synthesizes most of cellular ATP requirements by oxidative phosphorylation (OXPHOS). The ATPase Inhibitory Factor 1 (IF1) is known to inhibit the hydrolase activity of the H(+)-ATP synthase in situations that compromise OXPHOS. Herein, we demonstrate that phosphorylation of S39 in IF1 by mitochondrial protein kinase A abolishes its capacity to bind the H(+)-ATP synthase. Only dephosphorylated IF1 binds and inhibits both the hydrolase and synthase activities of the enzyme. The phosphorylation status of IF1 regulates the flux of aerobic glycolysis and ATP production through OXPHOS in hypoxia and during the cell cycle. Dephosphorylated IF1 is present in human carcinomas. Remarkably, mouse heart contains a large fraction of dephosphorylated IF1 that becomes phosphorylated and inactivated upon in vivo β-adrenergic stimulation. Overall, we demonstrate the essential function of the phosphorylation of IF1 in regulating energy metabolism and speculate that dephosho-IF1 might play a role in signaling mitohormesis.