Ulcerative Proctitis, Rectal Prolapse, and Intestinal Pseudo-Obstruction in Transgenic Mice Overexpressing Hepatocyte Growth Factor/Scatter Factor

Abstract

SUMMARY:Hepatocyte growth factor/scatter factor (HGF/SF) can stimulate growth of gastrointestinal epithelial cells in vitro;however, the physiological role of HGF/SF in the digestive tract is poorly understood. To elucidate this in vivo function, mice were analyzed in which an HGF/SF transgene was overexpressed throughout the digestive tract. Nearly a third of all HGF/SF transgenic mice in this study (28 of 87) died by 6 months of age as a result of sporadic intestinal obstruction of unknown etiology. Enteric ganglia were not overtly affected, indicating that the pathogenesis of this intestinal lesion was different from that operating in Hirschsprung's disease. Transgenic mice also exhibited a rectal inflammatory bowel disease (IBD) with a high incidence of anorectal prolapse. Expression of interleukin-2 was decreased in the transgenic colon, indicating that HGF/SF may influence regulation of the local intestinal immune system within the colon. These results suggest that HGF/SF plays an important role in the development of gastrointestinal paresis and chronic intestinal inflammation. HGF/SF transgenic mice may represent a useful model for the study of molecular mechanisms associated with a subset of IBD and intestinal pseudo-obstruction. Moreover, our data identify previously unappreciated side effects that may be encountered when using HGF/SF as a therapeutic agent. (Lab Invest 2001, 81:297-305).H epatocyte growth factor/scatter factor (HGF/ SF) was first identified as a highly potent hepatocyte mitogen (Gohda et al, 1988;Nakamura et al, 1989) but is now known as a multifunctional cytokine based on its ability to stimulate proliferation, movement, and/or morphogenesis of a broad spectrum of cultured epithelial cells expressing the tyrosine kinase receptor encoded by the c-met proto-oncogene (Gherardi and Stoker, 1991;Montesano et al, 1991;Rosen et al, 1994;Rubin et al, 1991;Vande Woude, 1992;Zarnegar and Michalopoulos, 1995). HGF/SF is produced in cells of mesenchymal origin, whereas c-met is expressed in adult and embryonic epithelium, implicating HGF/SF-Met signal transduction pathways as important in the epithelial-mesenchymal interaction that occurs during embryogenesis, tissue organization, and organogenesis. Gene targeting studies have shown that HGF/SF-Met signaling is required for the normal development of liver, skeletal muscle, and placenta Schmidt et al, 1995;Uehara et al, 1995).In the fetal digestive tract, c-met transcripts were found in the epithelia of the intestinal anlagen and the villi, whereas the distribution of HGF/SF RNA showed dynamic changes during mouse development by in situ hybridization (Sonnenberg et al, 1993). Immunohistochemical analysis of temporal expression revealed that both HGF/SF and c-Met could be detected between 7 and 8 weeks of gestation in human fetal digestive tissues (Kermorgant et al, 1997). These results suggest that HGF/SF-Met signaling participates in digestive system morphogenesis. Moreover, previous studies demonstrated that HGF/SF can stimulate both esophageal ...

HGF ameliorates a high-fat diet-induced fatty liver

“…Transgenic mice (Tg), in which the expression of a murine HGF cDNA was driven by the metallothionein promoter and locus control regions, were generated on the inbred albino FVB/NCr genetic background (hereafter referred to as FVB) as described previously (30). Furthermore, Takayama et al demonstrated that HGF transgene expressed in all organs and there were a number of phenotypes, such as hepatomegaly, cystic disease accompanied by focal segmental glomerulosclerosis, ulceration associated with chronic active inflammation of the rectum, and so on (25,(31)(32)(33).…”

Hepatocyte growth factor promotes hepatocarcinogenesis through c-Met autocrine activation and enhanced angiogenesis in transgenic mice treated with diethylnitrosamine

“…However, we have previously shown that aberrant HGF expression induces developmental anomalies , renal dysfunction (Takayama et al, 1997a) and intestinal disease (Takayama et al, 2001) in mice, as well as spontaneous neoplastic transformation in older animals (Takayama et al, 1997b;Otsuka et al, 1998). Here we present data demonstrating that environmental carcinogens can cooperate with, and dramatically accelerate, HGFmediated tumorigenesis in the liver, further supporting the oncogenic risk associated with persistent in vivo exposure to robust levels of HGF.…”

“…Unfortunately, it was dicult to monitor HGF transgenic females over long periods because more than half of females died as a result of renal failure or intestinal disease, as described previously (Takayama et al, 1997a(Takayama et al, , 2001. Nonetheless, 39% (12/31) of HGF transgenic females developed liver tumors by 40 weeks.…”

Age and cellular context influence rectal prolapse formation in mice with caecal wall colorectal cancer xenografts

“…Treating serotonin-lacking mice with 5-HTP, the direct precursor of serotonin, increased the severity of colitis demonstrating a pivotal mediating role of serotonin in intestinal inflammation [29, 30]. Rectal prolapse frequently occurred in mice with rectal inflammatory bowel disease [31]. Consequently, serotonin may play a role in the development of rectal prolapse.…”