Forkhead Box F1 Regulates Tumor-Promoting Properties of Cancer-Associated Fibroblasts in Lung Cancer

Abstract

Cancer-associated fibroblasts (CAF) attract increasing attention as potential cancer drug targets due to their ability to stimulate, for example, tumor growth, invasion, angiogenesis, and metastasis. However, the molecular mechanisms causing the tumor-promoting properties of CAFs remain poorly understood. Forkhead box F1 (FoxF1) is a mesenchymal target of hedgehog signaling, known to regulate mesenchymalepithelial interactions during lung development. Studies with FoxF1 gain-and loss-of-function fibroblasts revealed that FoxF1 regulates the contractility of fibroblasts, their production of hepatocyte growth factor and fibroblast growth factor-2, and their stimulation of lung cancer cell migration. FoxF1 status of fibroblasts was also shown to control the ability of fibroblasts to stimulate xenografted tumor growth. FoxF1 was expressed in CAFs of human lung cancer and associated with activation of hedgehog signaling. These observations suggest that hedgehog-dependent FoxF1 is a clinically relevant lung CAF-inducing factor, and support experimentally the general concept that CAF properties can be induced by activation of developmentally important transcription factors. Cancer Res; 70(7); 2644-54. ©2010 AACR.

Forkhead Box F1 represses cell growth and inhibits COL1 and ARPC2 expression in lung fibroblasts in vitro

“…During embryonic and fetal periods, FOXF1 drives migration (26) and myofibroblastic differentiation (38) of lung mesenchyme. In our experiments, FOXF1 did not induce myofibroblast differentiation in adult lung fibroblasts since FOXF1 did not influence ␣-smooth muscle actin expression.…”

JNK1 stress signaling is hyper-activated in high breast density and the tumor stroma: Connecting fibrosis, inflammation, and stemness for cancer prevention

“…More specifically, many of these CAF-markers are functionally related to matrix remodeling, autophagy, senescence, ketone production, hypoxia, oxidative stress, inflammation, DNA damage, and stemness, 22 as well as FGF/EGF/PDGF-signaling. 23,24 These similarities also include molecular markers of the myofibroblast phenotype (such as, actin-binding proteins, the myosins, and other muscle proteins) 22 ( Table 5).…”

Inhibition of ERN1 signaling enzyme affects hypoxic regulation

“…Recently it was shown that the forkhead box transcription factor FOXF1 is a target of the TP53 family and its ectopic expression inhibits cancer cell invasion and migration, whereas the inactivation of FOXF1 stimulated both these processes [28,35]. Furthermore, this transcription factor is a mesenchymal target of hedgehog signaling, known to regulate mesenchymal-epithelial interactions during lung development and contractility of fibroblasts, their production of hepatocyte growth factor and fibroblast growth factor-2 as well as their stimulation of lung cancer cell growth and migration [36].…”