Transforming Growth Factor‐β and Hepatocyte Growth Factor Produced by Gastric Fibroblasts Stimulate the Invasiveness of Scirrhous Gastric Cancer Cells

Inoue, Tohru; Chung, Yong‐Suk; Yashiro, Masakazu; Nishimura, Shigehiko; Hasuma, Tadayoshi; Otani, Shuzo; Sowa, Michio

doi:10.1111/j.1349-7006.1997.tb00360.x

Cited by 74 publications

(63 citation statements)

References 30 publications

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“…TGFβ produced from fibroblasts increases the invasiveness of scirrhous gastric cancer cells [24]. TGFβ is detected in a latent form in the conditioned medium from fibroblasts and in an active form in the conditioned medium from gastric cancer cells [18,24]. The latent TGFβ is activated by proteases such as plasmin and cathepsin [25].…”

Section: Migration-stimulating Activity Of Gastric Cancer Cells By Fimentioning

confidence: 99%

Cancer–Stromal Interactions in Scirrhous Gastric Carcinoma

Yashiro

Hirakawa

2010

Cancer Microenvironment

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Fibroblasts play an important role in the progression, growth and spread of gastric cancers. Cancer-stroma interactions have been especially evident in the scirrhous type of gastric carcinoma. Fibroblasts are associated with the cancer progression at the primary and metastatic site. The proliferative and invasive ability of scirrhous gastric cancer cells are closely associated with the growth factors produced by organ-specific fibroblasts. Fibroblasts are therefore a key determinant in the malignant progression of gastric cancer and represent an important target for cancer therapies.

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Section: Migration-stimulating Activity Of Gastric Cancer Cells By Fimentioning

confidence: 99%

Cancer–Stromal Interactions in Scirrhous Gastric Carcinoma

Yashiro

Hirakawa

2010

Cancer Microenvironment

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“…19,20 In vitro studies have demonstrated that HGF stimulates invasion or proliferation of gastric cancer cells. 20,21 Furthermore, HGF affects the morphology of mesothelial cells, such that they become prone to peritoneal dissemination of cancer cells. 22 Recently, a small molecular c-Met inhibitor, SU11274, has been developed and shown to inhibit c-Met phosphorylation and c-Met-dependent cell motility, invasion and proliferation in vitro.…”

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Co‐expression of hepatocyte growth factor and c‐Met predicts peritoneal dissemination established by autocrine hepatocyte growth factor/c‐Met signaling in gastric cancer

Toiyama¹,

Yasuda²,

Saigusa³

et al. 2011

Intl Journal of Cancer

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Epithelial–mesenchymal transition (EMT) promotes and facilitates migration and invasion of epithelial tumor cells. EMT is induced by factors such as hepatocyte growth factor (HGF). This study aimed to establish whether the HGF/c‐Met pathway is associated with gastric cancer metastasis; especially peritoneal dissemination. HGF and c‐Met expression and EMT‐related molecules were evaluated using real‐time PCR and immunohistochemistry. The role of the HGF/c‐Met pathway in EMT and anoikis was determined, and kinase inhibitor SU11274 was tested for its ability to block HGF‐induced biological effects. In HGF−/c‐Met+ gastric cancer cells, recombinant HGF promoted an EMT phenotype that was characterized by morphology, impaired E‐cadherin and induction of vimentin. HGF promoted cell growth, invasiveness and migration and inhibition of anoikis. SU11274 blocked HGF‐induced EMT and biological effects in vitro. In HGF+/c‐Met+ gastric cancer cells, HGF did not affect the biological outcome of EMT and anoikis, but SU11274 exerted the same inhibitory effects as in HGF−/c‐Met+ cells. In vivo, HGF+/c‐Met+ gastric cancer cells only established peritoneal dissemination and SU11274 inhibited tumor growth. Clinically, HGF expression was significantly correlated with c‐Met expression in gastric cancer. Increased HGF and c‐Met had a significant association with poor prognosis and predicted peritoneal dissemination. We demonstrated that the HGF/c‐Met pathway induces EMT and inhibition of anoikis in gastric cancer cells. Co‐expression of HGF and c‐Met has the potential to promote peritoneal dissemination in gastric cancer. Blockade of the autocrine HGF/c‐Met pathway could be clinically useful for the treatment of peritoneal dissemination in gastric cancer.

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“…Accumulating evidence has shown that HGF plays a distinct role in tumour-stromal interactions (Seslar et al, 1993;Rosen et al, 1994;Matsumoto et al, 1996;Inoue et al, 1997;Nakamura et al, 1997;Jiang et al, 1999). HGF has potent motogenic activity on various types of carcinoma cells, leading to the dissociation, scattering and migration of cells (Weidner et al, 1990;Jiang et al, 1993Jiang et al, , 1999Matsumoto et al, 1994Matsumoto et al, , 1996Jeffers et al, 1996;Rosen et al, 1996;Inoue et al, 1997;Nakamura et al, 1997).…”

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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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Transforming Growth Factor‐β and Hepatocyte Growth Factor Produced by Gastric Fibroblasts Stimulate the Invasiveness of Scirrhous Gastric Cancer Cells

Cited by 74 publications

References 30 publications

Cancer–Stromal Interactions in Scirrhous Gastric Carcinoma

Cancer–Stromal Interactions in Scirrhous Gastric Carcinoma

Co‐expression of hepatocyte growth factor and c‐Met predicts peritoneal dissemination established by autocrine hepatocyte growth factor/c‐Met signaling in gastric cancer

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

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