Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth.

Bussolino, Federico; Renzo, Maria Flavia Di; Ziche, Marina; Bocchietto, Elena; Olivero, Martina; Naldini, Luigi; Gaudino, Giovanni; Tamagnone, Luca; Coffer, Arnold I.; Comoglio, Paolo M.

doi:10.1083/jcb.119.3.629

Cited by 1,252 publications

(741 citation statements)

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“…Since previous (Paciucci et al, 1998) and our present results showed that production of HGF in pancreatic cancer cell lines is either undetectable or is low and that HGF mediated fibroblast-dependent invasion of pancreatic cancer cells, HGF is likely to be a stromal mediator which affects invasion and probably subsequent metastasis and dissemination of pancreatic cancer cells. Taken together with the notion that HGF is a potent inducer of angiogenesis (Bussolino et al, 1992;Van Belle et al, 1998;Morishita et al, 1999), the abrogation of functional association between HGF and the Met/HGF receptor would be considerable to suppress malignant behaviour of human pancreatic cancer cells.…”

Section: Discussionmentioning

confidence: 99%

NK4, a four-kringle antagonist of HGF, inhibits spreading and invasion of human pancreatic cancer cells

et al. 2001

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Summary Because of the highly aggressive behaviour, i.e. invasive, disseminative and metastatic properties, the outcome for patients with pancreatic cancer is morbid. A better understanding and interference with the malignant behaviour of pancreatic cancer may provide new directions for treatment. We report here the induction of highly motile and invasive properties in human pancreatic cancer cells by hepatocyte growth factor (HGF) and blockage of these properties by NK4, a newly identified antagonist for HGF. In all of eight human pancreatic cancer cell lines we used (AsPC-1, BxPC-3, H-48N, KP-1N, KP-2, KP-3, MIA PaCa-2 and SUIT-2 cells), the c-Met/HGF receptor was expressed at varying levels. Although weak mitogenic activity of HGF was seen only in SUIT-2 and KP-3 cells, HGF strongly stimulated migration and invasion of these pancreatic cancer cells, except for BxPC-3 and MIA PaCa-2 cells. In contrast, migration and invasion potently induced by HGF in KP-1N, KP-3 and SUIT-2 cells were inhibited by NK4. The invasion of SUIT-2 cells was also potently stimulated with the influence of cocultured pancreatic fibroblasts and by ascitic fluid obtained after pancreatic cancer resection, however, invasiveness of the cancer cells in such conditions was practically abolished by NK4. Consistently, the ascitic fluid in patients who had undergone pancreatic cancer surgery contained high levels of HGF. These findings mean that HGF is probably involved in invasion, dissemination, and metastasis of pancreatic cancer, particularly through tumour-stromal interaction and after resection of the pancreatic cancer. While competitive inhibitory effects of NK4 on HGF and cMet/receptor interaction have been demonstrated in some distinct types of human cancer cells (Date et al, 1998;Hiscox et al, 2000;Kuba et al, 2000;Parr et al, 2000), inhibitory and promising therapeutic effects of NK4 have to be evaluated in cases of highly aggressive pancreatic cancer. In the current study, cancer-stromal interaction through HGF and c-Met coupling and inhibitory effects of NK4 were investigated in human pancreatic cancer cells. The invasion of pancreatic cancer cells was potently stimulated by HGF, cocultivation with fibroblasts, and by ascitic fluid from patients who had undergone pancreatic cancer resection, but this invasion was almost completely inhibited by NK4. The potential inhibition of pancreatic cancer invasion and dissemination by NK4 was thus deemed worthy of investigation. MATERIALS AND METHODS MaterialsHuman recombinant HGF was purified from the conditioned medium of Chinese hamster ovary cells transfected with human HGF cDNA (Nakamura et al, 1989;Seki et al, 1990). Polyclonal antibody against human HGF was prepared from the serum of a rabbit immunized with human recombinant HGF and IgG was purified using protein A-Sepharose (Pharmacia Biotech, Uppsala). Anti-human HGF IgG (1 µg ml -1 ) completely neutralized the biological activities of 1 ng ml -1 human HGF. NK4 was prepared by proteolytic digestion with elastase, as described elsewher...

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Section: Discussionmentioning

confidence: 99%

NK4, a four-kringle antagonist of HGF, inhibits spreading and invasion of human pancreatic cancer cells

et al. 2001

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“…Another important aspect of cancer growth and metastasis is the establishment of neovasculature by angiogenesis (Blood et al, 1990). By inducing endothelial cell proliferation and motility, HGF can stimulate neovascularization in vivo (Bussolino et al, 1992;Grant et al, 1993). These findings suggest that HGF, apart from increasing the invasiveness of cancer cells, may also stimulate primary and secondary tumour growth by modulating the tumour matrix (Jiang et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Serum hepatocyte growth factor as an index of disease status of patients with colorectal carcinoma

Fukuura

Miki²,

Inoue³

et al. 1998

Br J Cancer

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Summary To evaluate the clinical significance of serum levels of hepatocyte growth factor (HGF) in colorectal cancer patients, we measured the venous and portal concentrations of HGF in 60 patients. The tissue concentrations in the tumour and adjacent normal mucosa were also determined. The serum HGF concentration for the peripheral venous blood of the patients was significantly higher than that in normal controls. The content of HGF in cancer tissue was also significantly higher than that in normal mucosa, and it was correlated with the serum HGF concentration for the peripheral venous blood. The serum concentration of HGF reflected pathological features, including tumour size and lymph node or liver metastasis, and it showed an association with various preoperative nutritional parameters and the preoperative haemoglobin level. The serum HGF concentration was also correlated with the serum concentrations of immunosuppressive acidic protein and interleukin-6, indices of the host's immunological condition. Serum HGF seems to be a useful index of the disease status of patients with colorectal carcinoma.Keywords: hepatocyte growth factor; nutritional status; immunological status; colorectal cancer Hepatocyte growth factor (HGF) is a multifunctional cytokine that is the most potent known stimulator of hepatocyte growth and DNA synthesis Kaneko et al, 1992). HGF has also been recognized as a tumour-disseminating factor (Weidner et al, 1991;Mayer et al, 1993;Tannapfel et al, 1994). In several experimental studies, evidence has been acquired of a relation of HGF to the progression of tumour cells . Among the particularly important biological activities of HGF in tumour cells is its capacity to increase epithelial cell proliferation and motility (Gherardi et al, 1990). In clinical studies, a relationship between the concentration of HGF in serum or cancer tissue and the progression of disease has been noted in patients with gastric cancer (Taniguchi et al, 1997), oesophageal cancer (Takada et al, 1995) and breast cancer (Yamashita et al, 1994;Taniguchi et al, 1995). However, there are no reports regarding the clinical relevance of HGF in patients with colorectal carcinoma.Malnutrition or immunosuppression are involved in the development of life-threatening complications in patients with malignancies (Braga et al, 1988;Nishi et al, 1988;Dannhauser et al, 1995;Triantafillidis et al, 1995;Windsor et al, 1995;Goransson et al, 1996). Patients with advanced cancer and cachexia typically demonstrate modestly increased rates of energy expenditure with concomitant diminished food intake. These metabolic changes may be due to mediators released by the tumour or by the host (Keller, 1993). Recently, the role of cytokines in these metabolic changes was emphasized (Gambardella et al, 1997). In addition, the relationship between cytokines and an immunosuppressive substance has also been highlighted (Tanaka et al, 1993 The objective of this study was to evaluate the relationship between serum HGF concentration and clinicopathological ...

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“…HGF/SF is a cytokine with unique properties (exerting multiple functions), such as mitogenic and motogenic effects on a variety of normal and transformed cells, and angiogenic (Bussolino et al, 1992;Grant et al, 1993) and morphogenic activity (Montesano et al, 1991). These diverse activities are mediated via a single receptor encoded by the c-MET protooncogene (Naldini et al, 1991;Weidner et al, 1993) al., 1986).…”

Section: Discussionmentioning

confidence: 99%

Overexpression and activation of hepatocyte growth factor/scatter factor in human non-small-cell lung carcinomas

Olivero¹,

et al. 1996

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Summary Hepatocyte growth factor/scatter factor (HGF/SF) stimulates the invasive growth of epithelial cells via the c-MET oncogene-encoded receptor. In normal lung, both the receptor and the ligand are detected, and the latter is known to be a mitogenic and a motogenic factor for both cultured bronchial epithelial cells and non-small-cell carcinoma lines. Here, ligand and receptor expression was examined in 42 samples of primary human non-small-cell lung carcinoma of different histotype. Each carcinoma sample was compared with adjacent normal lung tissue. The MetlHGF receptor was found to be 2 to 10-fold increased in 25% of carcinoma samples (P=0.0113). The ligand, HGF/SF, was found to be 10 to 100-fold overexpressed in carcinoma samples (P<0.0001). Notably, while HGF/SF was occasionally detectable and found exclusively as a single-chain inactive precursor in normal tissues, it was constantly in the biologically-active heterodimeric form in carcinomas. Immunohistochemical staining showed homogeneous expression of both the receptor and the ligand in carcinoma samples, whereas staining was barely detectable in their normal counterparts. These data show that HGF/SF is overexpressed and consistently activated in non-small-cell lung carcinomas and may contribute to the invasive growth of lung cancer.

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Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth.

Cited by 1,252 publications

References 69 publications

NK4, a four-kringle antagonist of HGF, inhibits spreading and invasion of human pancreatic cancer cells

NK4, a four-kringle antagonist of HGF, inhibits spreading and invasion of human pancreatic cancer cells

Serum hepatocyte growth factor as an index of disease status of patients with colorectal carcinoma

Overexpression and activation of hepatocyte growth factor/scatter factor in human non-small-cell lung carcinomas

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