Fibroblast-secreted hepatocyte growth factor plays a functional role in esophageal squamous cell carcinoma invasion.
Squamous cell cancers comprise the most common type of human epithelial cancers. One subtype, esophageal squamous cell carcinoma (ESCC), is an aggressive cancer with poor prognosis due to late diagnosis and metastasis. Factors derived from the extracellular matrix (ECM) create an environment conducive to tumor growth and invasion. Specialized cancer-associated fibroblasts (CAFs) in the ECM influence tumorigenesis. We have shown previously that the nature and activation state of fibroblasts are critical in modulating the invasive ability of ESCC in an in vivo-like organotypic 3D cell culture, a form of human tissue engineering. Dramatic differences in invasion of transformed esophageal epithelial cells depended on the type of fibroblast in the matrix. We hypothesize that CAFs create an environment primed for growth and invasion through the secretion of factors. We find that fibroblast secretion of hepatocyte growth factor (HGF) fosters the ability of transformed esophageal epithelial cells to invade into the ECM, although other unidentified factors may cooperate with HGF. Genetic modifications of both HGF in fibroblasts and its receptor Met in epithelial cells, along with pharmacologic inhibition of HGF and Met, underscore the importance of this pathway in ESCC invasion and progression. Furthermore, Met activation is increased upon combinatorial overexpression of epidermal growth factor receptor (EGFR) and p53(R175H), two common genetic mutations in ESCC. These results highlight the potential benefit of the therapeutic targeting of HGF/Met signaling in ESCC and potentially other squamous cancers where this pathway is deregulated.
Gastroenterology Division, Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
Katharine D
KD
Grugan
Charles G
CG
Miller
Yao
Y
Yao
Carmen Z
CZ
Michaylira
Shinya
S
Ohashi
Andres J
AJ
Klein-Szanto
J Alan
JA
Diehl
Meenhard
M
Herlyn
May
M
Han
Hiroshi
H
Nakagawa
Anil K
AK
Rustgi
D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D002461:Cell Line, Transformed; D004847:Epithelial Cells / Q000473:pathology / Q000502:physiology; D066246:ErbB Receptors / Q000235:genetics; D004938:Esophageal Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D005109:Extracellular Matrix / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000473:pathology / Q000502:physiology; D015870:Gene Expression; D016158:Genes, p53; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction
C066855:HGF protein, human; D017228:Hepatocyte Growth Factor; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met