Membrane Type 1-Matrix Metalloproteinase Is Involved in the Formation of Hepatocyte Growth Factor/Scatter Factor-Induced Branching Tubules in Madin-Darby Canine Kidney Epithelial Cells

Kadono, Yoshifumi; Shibahara, Kazushige; Namiki, Mikio; Watanabe, Yoh; Seiki, Motoharu; Sato, Hiroshi

doi:10.1006/bbrc.1998.9531

Cited by 78 publications

(67 citation statements)

References 29 publications

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“…Addition of the hydroxamate MMP inhibitor BB94 to collagen gel cultures abrogated both the formation of ectatic cysts (Figure 2c) and the increase in cell number (Table 1). In agreement with previous studies using MDCK cells constitutively transfected with MT1-MMP (Kadono et al, 1998b;Hotary et al, 2003), these findings show that conditional expression of MT1-MMP enhances the ability of MDCK cells to degrade, and to proliferate within, collagen matrices. They also indicate that these effects are dependent on the catalytic activity of MT1-MMP.…”

Section: Conditional Expression Of Mt1-mmp Alters the Morphogenetic Asupporting

confidence: 92%

Membrane-type-1 matrix metalloproteinase confers tumorigenicity on nonmalignant epithelial cells

et al. 2004

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Overexpression of membrane-type-1 matrix metalloproteinase (MT1-MMP) in tumor cells has previously been shown to enhance tumor growth and metastasis. To establish if MT1-MMP is also able to confer tumorigenicity on nonmalignant epithelial cells, we transfected human MT1-MMP cDNA into Madin-Darby canine kidney (MDCK) cells expressing a tetracycline-repressible transactivator. Induction of MT1-MMP in the absence of doxycycline (Dox) was associated with activation of exogenous MMP-2 as well as with formation of large cysts and increased invasiveness in collagen matrices. Transfected cells were inoculated subcutaneously into two groups of nude mice, one of which received Dox to inhibit expression of MT1-MMP. Formation of tumor xenografts was observed in 11 of 17 mice maintained without Dox, but only in two of nine mice that received Dox (Po0.05). The xenografts were composed of tubular structures interspersed within a highly cellular stroma. The epithelial cells delimiting the lumen were polarized, as indicated by the basolateral distribution of Na,K-ATPase. Despite their differentiated appearance, the tumors lacked a well-defined boundary, and epithelial tubules invaded adjacent muscular layers. These results demonstrate that conditional expression of MT1-MMP in nonmalignant MDCK epithelial cells is by itself sufficient to drive formation of invasive tumors.

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Section: Conditional Expression Of Mt1-mmp Alters the Morphogenetic Asupporting

confidence: 92%

Membrane-type-1 matrix metalloproteinase confers tumorigenicity on nonmalignant epithelial cells

et al. 2004

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“…However, in contrast to VEGF and bFGF, HGF is a potent morphogen for multiple cell types. 11 For example, in addition to promoting endothelial organization into tubule-like structures on Matrigel and on the surface of collagen gels, HGF will also induce Madin-Darby canine kidney epithelial cells to organize into a branching network of tubules with the proper apical-basolateral polarity, 35 and mammary epithelial cells to form duct-like structures. 28 HGF synergistically interacts with VEGF to induce endothelial cell proliferation and migration (in monolayer cultures).…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte Growth Factor Enhances Vascular Endothelial Growth Factor-Induced Angiogenesis in Vitro and in Vivo

Xin¹,

Yang²,

Ingle³

et al. 2001

The American Journal of Pathology

355

224

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Vascular endothelial growth factor (VEGF) is an important mediator of angiogenesis in both physiological and pathological processes. Hepatocyte growth factor (HGF) is a mesenchyme-derived mitogen that also stimulates cell migration, and branching and/or tubular morphogenesis of epithelial and endothelial cells. In the present study, we tested the hypothesis that simultaneous administration of HGF and VEGF would synergistically promote new blood vessel formation. HGF acted in concert with VEGF to promote human endothelial cell survival and tubulogenesis in 3-D type I collagen gels, a response that did not occur with either growth factor alone. The synergistic effects of VEGF and HGF on endothelial survival correlated with greatly augmented mRNA levels for the anti-apoptotic genes Bcl-2 and A1. Co-culture experiments with human neonatal dermal fibroblasts and human umbilical vein endothelial cells demonstrated that neonatal dermal fibroblasts, in combination with VEGF, stimulated human umbilical vein endothelial cells tubulogenesis through the paracrine secretion of HGF. Finally, in vivo experiments demonstrated that the combination of HGF and VEGF increased neovascularization in the rat corneal assay greater than either growth factor alone. We suggest that combination therapy using HGF and VEGF co-administration may provide a more effective strategy to achieve therapeutic angiogenesis.

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“…HGF decreases cadherin-mediated adhesiveness (Watabe et al, 1993;Shibamoto et al, 1994;Tannapfel et al, 1994;Nabeshima et al, 1998), enhances cell-matrix interaction through the recruitment of integrins, p125 FAK , and paxillin into focal adhesion complexes and concomitant protein phosphorylation of p125 and paxillin (Matsumoto et al, 1994;Jiang et al, 1996). HGF stimulates proteolytic breakdown of the extracellular matrix, through enhancing matrix methaloproteinases (MMPs) and urokinase-type plasminogen activator (uPA)-dependent proteolytic network (Pepper et al, 1992;Jeffers et al, 1996;Date et al, 1998;Kadono et al, 1998;Rosenthal et al, 1998). On the other hand, we found that NK4 inhibits scattering, migration and invasion of SUIT-2 cells, induced by HGF, cocultured fibroblasts and ascitic fluid obtained from patients who underwent pancreatic cancer surgery.…”

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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Membrane Type 1-Matrix Metalloproteinase Is Involved in the Formation of Hepatocyte Growth Factor/Scatter Factor-Induced Branching Tubules in Madin-Darby Canine Kidney Epithelial Cells

Cited by 78 publications

References 29 publications

Membrane-type-1 matrix metalloproteinase confers tumorigenicity on nonmalignant epithelial cells

Membrane-type-1 matrix metalloproteinase confers tumorigenicity on nonmalignant epithelial cells

Hepatocyte Growth Factor Enhances Vascular Endothelial Growth Factor-Induced Angiogenesis in Vitro and in Vivo

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

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