Hepatocyte Growth Factor from a Clinical Perspective: A Pancreatic Cancer Challenge

Abstract

Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States and incidence rates are rising. Both detection and treatment options for pancreatic cancer are limited, providing a less than 5% five-year survival advantage. The need for new biomarkers for early detection and treatment of pancreatic cancer demands the efficient translation of bench knowledge to provide clinical benefit. One source of therapeutic resistance is the pancreatic tumor microenvironment, which is characterized by desmoplasia and hypoxia making it less conducive to current therapies. A major factor regulating desmoplasia and subsequently promoting chemoresistance in pancreatic cancer is hepatocyte growth factor (HGF), the sole ligand for c-MET (mesenchymal-epithelial transition), an epithelial tyrosine kinase receptor. Binding of HGF to c-MET leads to receptor dimerization and autophosphorylation resulting in the activation of multiple cellular processes that support cancer progression. Inhibiting activation of c-MET in cancer cells, in combination with other approaches for reducing desmoplasia in the tumor microenvironment, might significantly improve the success of chemotherapy. Therefore, HGF makes a potent novel target for developing therapeutic strategies in combination with existing drugs for treating pancreatic adenocarcinoma. This review provides a comprehensive analysis of HGF and its promising potential as a chemotherapeutic target for pancreatic cancer.

Cancer-associated fibroblasts modulate growth factor signaling and extracellular matrix remodeling to regulate tumor metastasis

“…HGF, also called scatter factor (SF/HGF), is primarily secreted by stromal cells and regulates various cell functions, such as differentiation, proliferation, and migration in epithelial cells, which express its cell-surface receptor c-Met [16]. CAFs secrete high levels of HGF and the ECM glycoprotein tenascin-C, which were necessary for invasion of colon cancer cells into Matrigel and type I collagen gels [17].…”

“…The ability of CAFs to promote HNSCC cell migration and invasion was attributed to increased secretion of HGF [21], suggesting that targeting HGF signaling in cancers is beneficial in inhibiting tumor progression. Phase I clinical trials are currently underway using the anti-HGF antibody ficlatuzumab for the treatment of HNSCC and non-small-cell lung cancers [16]. …”

c‑Met affects gemcitabine resistance during carcinogenesis in a mouse model of pancreatic cancer

“…A previous study associated the MET proto-oncogene receptor tyrosine kinase (c-MET), which functions in epithelial-mesenchymal transition (EMT), with PDAC. c-MET encodes for a membrane-bound receptor tyrosine kinase that is predominantly expressed by epithelial cells (4). Activation of c-Met occurs following its phosphorylation in response to the binding of its ligand, hepatocyte growth factor (HGF; also referred to as scatter factor), which results in the induction of a downstream signaling cascade (4).…”

“…c-MET encodes for a membrane-bound receptor tyrosine kinase that is predominantly expressed by epithelial cells (4). Activation of c-Met occurs following its phosphorylation in response to the binding of its ligand, hepatocyte growth factor (HGF; also referred to as scatter factor), which results in the induction of a downstream signaling cascade (4). c-Met activating ligands are secreted by cells of mesenchymal origin (4).…”

“…Activation of c-Met occurs following its phosphorylation in response to the binding of its ligand, hepatocyte growth factor (HGF; also referred to as scatter factor), which results in the induction of a downstream signaling cascade (4). c-Met activating ligands are secreted by cells of mesenchymal origin (4). The resulting HGF/c-Met pleiotropic signaling pathway activates mediators of cell proliferation and motility (4).…”