Hepatocyte Growth Factor, a Key Tumor-Promoting Factor in the Tumor Microenvironment

Abstract

The tumor microenvironment plays a key role in tumor development and progression. Stromal cells secrete growth factors, cytokines and extracellular matrix proteins which promote growth, survival and metastatic spread of cancer cells. Fibroblasts are the predominant constituent of the tumor stroma and Hepatocyte Growth Factor (HGF), the specific ligand for the tyrosine kinase receptor c-MET, is a major component of their secretome. Indeed, cancer-associated fibroblasts have been shown to promote growth, survival and migration of cancer cells in an HGF-dependent manner. Fibroblasts also confer resistance to anti-cancer therapy through HGF-induced epithelial mesenchymal transition (EMT) and activation of pro-survival signaling pathways such as ERK and AKT in tumor cells. Constitutive HGF/MET signaling in cancer cells is associated with increased tumor aggressiveness and predicts poor outcome in cancer patients. Due to its role in tumor progression and therapeutic resistance, both HGF and MET have emerged as valid therapeutic targets. Several inhibitors of MET and HGF are currently being tested in clinical trials. Preclinical data provide a strong indication that inhibitors of HGF/MET signaling overcome both primary and acquired resistance to EGFR, HER2, and BRAF targeting agents. These findings support the notion that co-targeting of cancer cells and stromal cells is required to prevent therapeutic resistance and to increase the overall survival rate of cancer patients. HGF dependence has emerged as a hallmark of therapeutic resistance, suggesting that inhibitors of biological activity of HGF should be included into therapeutic regimens of cancer patients.

Macrophage HIF‐2α regulates tumor‐suppressive Spint1 in the tumor microenvironment

“…Interestingly, active c‐Met signaling was also suggested to affect invasive and metastatic properties of tumors instead of enhancing their proliferation . Our observation that HIF‐2α‐dependent elevation of Spint1 contributed to reduced tumor cell proliferation in vitro and correlated with attenuated tumor growth in vivo, corroborates previous reports, proposing that aberrant c‐Met activation by HGF enhanced tumor growth and correlated with poor prognosis, yet, the value of c‐Met expression as a prognostic marker appears limited . Nevertheless, c‐Met was even put forward as a promising candidate for tumor therapeutic interventions .…”

“…Activated HGF exerts its effects on target cells by binding to and activating its receptor c-Met. 46 Activation of c-Met, in turn, enhances proliferation, cell survival, organ morphogenesis, neovascularization, tissue repair, and regeneration. 47 We further provide evidence for a HIF-2α-dependent Spint1 production in TAMs.…”

“…Specifically, Spint1 inhibits HGFA, which is required in the extracellular space to activate pro‐HGF. Activated HGF exerts its effects on target cells by binding to and activating its receptor c‐Met . Activation of c‐Met, in turn, enhances proliferation, cell survival, organ morphogenesis, neovascularization, tissue repair, and regeneration .…”

“…In contrast, pro‐HGF within the tumor microenvironment likely stems from other sources than tumor cells and macrophages. While there is abundant evidence that cancer‐associated fibroblasts are a major source of pro‐HGF in breast carcinomas, adipocytes derived from monocyte/macrophage progenitors were recently shown to provide HGF to enhance migration of tumor cells when coinjected subcutaneously with E0771 cells into mice…”

“…In contrast, pro-HGF within the tumor microenvironment likely stems from other sources than tumor cells and macrophages. While there is abundant evidence that cancer-associated fibroblasts are a major source of pro-HGF in breast carcinomas, 46,[56][57][58] adipocytes derived from monocyte/macrophage progenitors were recently shown to provide HGF to enhance migration of tumor cells when coinjected subcutaneously with E0771 cells into mice. 59 Interestingly, while we found many genes to be differentially expressed between wt and HIF-2α knockout TAMs, only roughly a third showed reduced expression in HIF-2α-deficient macrophages, indicative for a potential direct transcriptional regulation.…”