Forkhead box F1 regulates tumor-promoting properties of cancer-associated fibroblasts in lung cancer.
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 mesenchymal-epithelial 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.
Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.
Roy-Akira
RA
Saito
Patrick
P
Micke
Janna
J
Paulsson
Martin
M
Augsten
Cristina
C
Peña
Per
P
Jönsson
Johan
J
Botling
Karolina
K
Edlund
Leif
L
Johansson
Peter
P
Carlsson
Karin
K
Jirström
Kohei
K
Miyazono
Arne
A
Ostman
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D053823:Hedgehog Proteins / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D041681:NIH 3T3 Cells; D015398:Signal Transduction; D014162:Transfection
C098521:FOXF1 protein, human; D051858:Forkhead Transcription Factors; C486293:Foxf1 protein, mouse; D053823:Hedgehog Proteins; D016222:Fibroblast Growth Factor 2; D017228:Hepatocyte Growth Factor