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Fibroblast-secreted hepatocyte growth factor plays a functional role in esophageal squamous cell carcinoma invasion
- Publication Year :
- 2010
- Publisher :
- National Academy of Sciences, 2010.
-
Abstract
- 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.
- Subjects :
- Male
Esophageal Neoplasms
Gene Expression
medicine.disease_cause
Metastasis
Extracellular matrix
medicine
Humans
Neoplasm Invasiveness
Epidermal growth factor receptor
Fibroblast
Cell Line, Transformed
Multidisciplinary
biology
Hepatocyte Growth Factor
Epithelial Cells
Biological Sciences
Fibroblasts
Proto-Oncogene Proteins c-met
medicine.disease
Genes, p53
Extracellular Matrix
ErbB Receptors
medicine.anatomical_structure
Mutation
Cancer research
biology.protein
Carcinoma, Squamous Cell
Hepatocyte growth factor
Female
Signal transduction
Carcinogenesis
medicine.drug
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....aca594d0ad6693d102f52803ca2c8ee1