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Hepatocyte Growth Factor Promotes Hepatocarcinogenesis Through C-Met Autocrine Activation and Enhanced Angiogenesis in Transgenic Mice Treated with Diethylnitrosamine

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Hepatocyte Growth Factor Promotes Hepatocarcinogenesis Through C-Met Autocrine Activation and Enhanced Angiogenesis in Transgenic Mice Treated with Diethylnitrosamine Oncogene (2002) 21, 1791 ± 1799 ã 2002 Nature Publishing Group All rights reserved 0950 ± 9232/02 $25.00 www.nature.com/onc ORIGINAL PAPERS Hepatocyte growth factor promotes hepatocarcinogenesis through c-Met autocrine activation and enhanced angiogenesis in transgenic mice treated with diethylnitrosamine Norio Horiguchi1, Hisashi Takayama1, Mitsuo Toyoda1, Toshiyuki Otsuka1, Toshio Fukusato2, Glenn Merlino3, Hitoshi Takagi*,1 and Masatomo Mori1 1The First Department of Internal Medicine, Gunma University School of Medicine, Maebashi, Gunma 371-8511, Japan; 2Division of Diagnostic Pathology, Gunma University School of Medicine, Maebashi, Gunma 371-8511, Japan; 3Laboratory of Molecular Biology, National Cancer Institute, Bethesda, Maryland, MD 20892-4255, USA Hepatocyte growth factor (HGF) is a mitogen for Introduction hepatocytes, but it is not clear whether HGF stimulates or inhibits hepatocarcinogenesis. We previously reported Hepatocyte growth factor (HGF) is a polypeptide that HGF transgenic mice under the metallothionein originally characterized as a highly potent hepatocyte gene promoter developed benign and malignant liver mitogen (Gohda et al., 1988; Nakamura et al., 1989). tumors spontaneously after 17 months of age. To More recent studies have revealed that HGF is a elucidate the role of HGF in hepatocarcinogenesis, multifunctional cytokine and can elicit mitogenic, diethylnitrosamine (DEN) was administered to HGF motogenic, and morphogenic responses in a variety of transgenic mice. HGF overexpression accelerated DEN- cultured epithelial cells expressing the transmembrane induced hepatocarcinogenesis, often accompanied by tyrosine kinase receptor, Met (Brinkmann et al., 1995; abnormal blood vessel formation. In this study, 59% of Zarnegar and Michalopoulos, 1995). HGF is expressed transgenic males (versus 20% of wild-type males) and in a multitude of mesenchymally-derived cells and Met 39% of transgenic females (versus 2% of wild-type expression has been detected in the epithelium of most females) developed either benign or malignant liver tissues, indicating that HGF-Met signal transduction tumors by 48 weeks (P50.005, P50.001, respectively). pathway helps mediate mesenchymal-epithelial interac- Moreover, 33% of males and 23% of female transgenic tions (Rubin et al., 1991; Montesano et al., 1991; mice developed hepatocellular carcinoma (HCC), while Rosen et al., 1994). none of the wild-type mice developed HCC (P50.001, c-met was ®rst cloned as a proto-oncogene through P50.005, respectively). Enhanced kinase activity of the its ability to transform NIH3T3 cells (Park et al., 1986) HGF receptor, Met, was detected in most of these and identi®ed as a HGF receptor (Bottaro et al., 1991). tumors. Expression of vascular endothelial growth factor Robust expression of the c-met proto-oncogene has (VEGF) was up-regulated in parallel with HGF been documented in diverse human and mouse tumors transgene expression. Taken together, our results suggest including hepatocellular carcinomas (HCCs) (Prat et that HGF promotes hepatocarcinogenesis through the al., 1991; Rong et al., 1992, 1993; D'Errico et al., autocrine activation of the HGF-Met signaling pathway 1996), and the c-met gene is ampli®ed in some in association with stimulation of angiogenesis by HGF carcinomas of the gastrointestinal tract (Di Renzo et itself and/or indirectly through VEGF. al., 1995; Kuniyasu et al., 1992). Moreover, activating Oncogene (2002) 21, 1791 ± 1799. DOI: 10.1038/sj/ mutations within the tyrosine kinase domain of c-met onc/1205248 have been reported in human renal papillary carcino- mas and childhood HCCs (Schmidt et al., 1997; Park Keywords: HGF transgenic; hepatocellular carcinoma; et al., 1999). In addition, coexpression of HGF-Met c-Met; diethylnitrosamine; VEGF has been identi®ed in a variety of transformed cultured cells and in some tumors (Bellusci et al., 1994; Tuck et al., 1996; Rahimi et al., 1996). Taken together, these studies suggest that activation of HGF-Met signaling can be intimately associated with neoplastic transfor- mation. Paradoxically, however, HGF has also been reported to inhibit the growth of certain carcinoma cells. With *Correspondence: H Takagi, The First Department of Internal respect to HCC, HGF was ®rst reported to show anti- Medicine, Gunma University School of Medicine, Showa-machi proliferative eects on some HCC cell lines, whereas it 3-39-15, Maebashi, Gunma 371-8511, Japan; had a mitogenic eect on others (Tajima et al., 1991; E-mail: [email protected] Received 6 September 2001; revised 4 December 2001; accepted 12 Shiota et al., 1992; Miyazaki et al., 1992). Further- December 2001 more, both stimulatory and inhibitory eects of HGF overexpression promotes hepatocarcinogenesis N Horiguchi et al 1792 exogenous administration of HGF on carcinogen- described previously (Takayama et al., 1997a, 2001). treated rats have been reported (Liu et al., 1995; Nonetheless, 39% (12/31) of HGF transgenic females Yaono et al., 1995; Ogasawara et al., 1998). There are developed liver tumors by 40 weeks. In contrast, only also con¯icting reports in HGF transgenic mice. We 2% (1/42) of wild-type females developed liver tumors previously reported that transgenic mice harboring a by 48 weeks (P50.001). Liver tumors in HGF full-length mouse HGF cDNA under the control of the transgenic mice were larger in size and more numerous mouse metallothionein (MT) gene promoter induced compared to those arising in wild-type mice. This liver tumors, which arose spontaneously in six dierence was extremely evident at 48 weeks male independent transgenic lines after 17 months (Sakata mice. 100% (4/4) of HGF transgenic mice had a et al., 1996). In contrast, overexpression of a human number of (6+1.8 per mouse) frank liver tumors which HGF cDNA under the regulation of the albumin are more than 5 mm in diameter, whereas none (0/5) of promoter in transgenic mice did not induce HCC wild-type developed such tumors (P50.001). (Shiota et al., 1994). Moreover, the HGF transgene With respect to progression to malignancy, 33% (9/ appeared to inhibit hepatocarcinogenesis in bitrans- 27) and 23% (7/31) of male and female HGF genic mice overexpressing c-myc (Santoni-Rugiu et al., transgenic mice developed HCCs, respectively (Table 1996) or transforming growth factor alpha (TGF-a) 2). In contrast, no HCC was found in male or female (Shiota et al., 1995). Therefore, whether HGF wild-type mice (P50.001, P50.005, respectively). participates in hepatocarcinogenesis remains to be Several studies reported that cells expressing both resolved. HGF and c-met show enhanced metastasis in vivo Here we report the promoting eect of HGF on (Bellusci et al., 1994; Rong et al., 1994; Jeers et al., diethylnitrosamine (DEN)-induced hepatocarcinogen- 1996), but in the present study, only one HCC showed esis in MT-HGF transgenic mice, and provide multiple metastasis to the lung by 48 weeks. Prolonged characterization of these liver tumors at histopatholo- observation might be necessary for the study of gical and molecular levels. metastasis in this model. Liver growth over the course of this study was determined by measuring liver weight relative to total body weight. Table 3 shows that transgenic mouse liver weight was much greater than Results that of wild-type mice at each time point. The liver weight in 40-week-old HGF transgenic females with Chemical induction of liver tumors in HGF transgenic multiple tumors was about threefold greater than age- mice matched wild-type. A signi®cant dierence in the development of liver tumors was observed at 48 weeks of age between HGF Histopathological and immunohistochemical analyses transgenic mice and wild-type mice treated with DEN (Table 1). In males, 59% (16/27) of HGF transgenic Histopathological analysis of livers of treated and mice developed grossly visible liver tumors, although untreated HGF transgenic mice showed striking only 20% (6/30) of wild-type mice had such tumors heterogeneity in hepatocytes and numerous small (P50.005). hepatocytes surrounding portal veins (Sakata et al., Interestingly, this promoting eect of HGF on liver 1996). Livers from DEN-treated transgenic mice tumorigenesis was also detected in females, although contained more preneoplastic foci per unit area than females are known to be resistant to HCC in wild-type at 16 weeks, although foci could not be experimental mouse models, including those employing evaluated at later time points because of coalescing chemical carcinogenesis (Farber and Sarma, 1987; tumors (Table 4). This preneoplastic change was also Pressumann, 1988; Takagi et al., 1993). Unfortunately, noted in transgenic females, similar to transgenic it was dicult to monitor HGF transgenic females over males. Notably, neither in¯ammation nor ®brosis long periods because more than half of females died as was found in livers of transgenic and wild-type mice a result of renal failure or intestinal disease, as in this study, in sharp contrast to human. HCCs Table 1 Incidence of liver tumors in HGF transgenic mice and wild-type mice treated with diethylnitrosamine (DEN) Mouse Incidence of liver tumor (weeks) Sex genotypea 16b 24 32 40 48 Total Male WT 0/4 (0%) 1/6 (17%) 0/8 (0%) 2/7 (29%) 3/5 (60%) 6/30 (20%) TG 0/4 (0%) 3/6 (50%) 3/6 (50%) 6/7 (86%) 4/4 (100%) 16/27 (59%)f Female WT 0/5 (0%) 1/9 (11%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 1/42 (2%) TG 0/4 (0%) 2/14 (14%)c 7/10 (70%)d 3/3 (100%) N.A.e 12/31 (39%)g Number of mice per group possessing at least one adenoma or HCC, relative to the total number of mice in that group. Numbers in parentheses represent the occurrence rate of liver tumors. DEN was administered as a single i.p. injection of 5 mg/g body weight at 15 days of age. More than half of the HGF female mice died of renal failure or intestinal disease by 24 weeks. aWT, wilt-type mice; TG, HGF transgenic mice.
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