The Kringle 1 Domain of Hepatocyte Growth Factor Has Antiangiogenic and Antitumor Cell Effects on Hepatocellular Carcinoma

Abstract

The kringle 1 domain of human hepatocyte growth factor (HGFK1) was previously shown to inhibit bovine aortic endothelial cell proliferation, suggesting that it might be an antiangiogenic molecule. Here, we evaluated the in vivo efficacy of a recombinant adenoassociated virus carrying HGFK1 (rAAV-HGFK1) for the treatment of hepatocellular carcinoma (HCC) in a rat orthotopic HCC model and explored its molecular mechanisms in vitro in both endothelial and tumor cells. We first showed that rAAV-HGFK1 treatment significantly prolonged the survival time of rats transplanted with tumor cells. Treatment with rAAV-HGFK1 inhibited tumor growth, decreased tumor microvessel density, and completely prevented intrahepatic, lung, and peritoneal metastasis in this in vivo model. In vitro, rAAV-HGFK1 exhibited both antiangiogenic and antitumor cell effects, inhibiting the proliferation of both murine microvascular endothelial cells (MEC) and tumor cells, and inducing apoptosis and G 0 -G 1 phase arrest in these cells. To our surprise, rAAV-HGFK1 did not act through the hepatocyte growth factor/hepatocyte growth factor receptor pathway. Instead, it worked mainly through epidermal growth factor (EGF)/epidermal growth factor receptor (EGFR) signaling, with more minor contributions from vascular endothelial growth factor/vascular endothelial growth factor receptor and B fibroblast growth factor (bFGF)/B fibroblast growth factor receptor (bFGFR) signaling. In both MECs and tumor cells, rAAV-HGFK1 acted through two pathways downstream of EGFR, namely inhibition of extracellular signal-regulated kinase activation and stimulation of p38 mitogen-activated protein kinase/c-Jun-NH 2 -kinase activation. These results suggest for the first time that HGFK1 exerts both antiangiogenic and antitumor cell activities mainly through EGF/EGFR signaling, and may thus be considered as a novel therapeutic strategy for the treatment of HCC. [Cancer Res 2008;68(2):404-14]

MET: A Critical Player in Tumorigenesis and Therapeutic Target

“…In fact, the uncleavable mutant form of HGF/SF (arginine 494 mutated to glutamic acid) can even function as a competitive inhibitor to wild-type HGF/SF (Gherardi et al 2006). In addition, the a chain of HGF/SF is susceptible to proteolysis by coagulation factor Xa (and possibly by other proteases), generating N-domain and kringle fragments that possess their own intrinsic activity in some circumstances (Rubin et al 2001;Pediaditakis et al 2002;Shen et al 2008). HGF/SF also has two shorter splice variants, the amino-terminal domain plus either one or two kringle domains (NK1 and NK2) (Stahl et al 1997), which can act as agonists or antagonists depending on the conditions and assay used (Montesano et al 1998).…”

HGFK1 inhibits bone metastasis in breast cancer through the TAK1/p38 MAPK signaling pathway

“…11 Recently, some researchers demonstrated that EGF-like ligands have the ability to strongly stimulate osteoclastogenesis in an EGFR-dependent manner. 12 We wondered if HGFK1 might be a key regulator during the process of breast cancer metastasis to bone and osteoclastogenesis.…”

“…We previously showed that HGFK1 exerts both antiangiogenic and antitumor activities in hepatocellular carcinoma through the epidermal growth factor (EGF)/epidermal growth factor receptor (EGFR) signaling pathway. 11 A recent report demonstrated that EGF-like ligands have the ability to strongly stimulate osteoclastogenesis in an EGFR-dependent manner. 12 Based on these findings, we wondered if HGFK1 might be a key regulator during the process of breast cancer metastasis to bone and osteoclastogenesis.…”

“…We have previously demonstrated the potentiality of AAV encoding antiangiogenic factors for long-term tumor-free survival with no vector-associated pathogenicity or toxicity. 11 In this study, we constructed an AAV encoding HGFK1 (AAV-HGFK1) and demonstrated the effects of administration of AAV-HGFK1 in treating osteolytic bone damage in a mouse model of bone metastasis. In addition, the effect of AAV-HGFK1 and the mechanism were observed in human breast cancer cell line MDA-MB-231-BO, which is derived from osseous metastases.…”

HGFK1 is Associated with a Better Prognostis and Reverses Inhibition by Gefitinib in NSCLC Cases

“…The inhibition effects on MECs and tumor cell worked mainly through EGF/EGFR signaling, with more minor contributions from VEGF/VEGFR and bFGF/bFGFR signaling. It may thus be considered as a novel therapeutic strategy for the treatment of HCC (Nie et al, 2008;Shen et al, 2008a;Shen et al, 2008b). Certainly, substantial evidence from clinical data is needed to for HGFK1 to be a potential target for anticancer drugs.…”