Fibroblast-secreted hepatocyte growth factor plays a functional role in esophageal squamous cell carcinoma invasion

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.cancer-associated fibroblasts | esophageal cancer | tumor microenvironment | organotypic culture | c-met

Expression of receptor tyrosine kinases in esophageal carcinosarcoma

“…A recent experimental study indicated that mutant p53 and EGFR expression potentiated HGF/MET signaling (35). The present and previous results suggest that co-expression of MET and EGFR may play a key role in mesenchymal sarcomatous metaplasia of squamous cell carcinoma through mechanisms such as EMT in other type of carcinomas, with subsequent tumor progression.…”

Inhibition of Tumor Growth and Metastasis in Non–Small Cell Lung Cancer by LY2801653, an Inhibitor of Several Oncokinases, Including MET

“…The CAFs surrounding the tumor cells have been shown to be particularly important for regulating migration and invasion of tumor cells (23). HGF was identified as a fibroblast-derived factor which is capable of causing epithelial cell scattering and stimulating the migration and invasion of cancer cells (24)(25)(26). MET is overexpressed in a substantial portion of the NSCLC tumors, ranging from 26% to 51% (27), and has also been associated with advanced cancer stage and poor patient survival (28,29).…”

Growth Factors, Signal Transduction Pathways, and Tumor Suppressor Genes in Esophageal Cancer

“…Secretion of HGF by stromal fibroblasts induces the transformed esophageal epithelial cells to invade extracellular matrix; however, other unidentified factors may also cooperate with HGF in this process, which further highlight the significance of this pathway in esophageal carcinoma invasion and progression [84].…”