Loss of Cell-Cell Contact Is Induced by Integrin-Mediated Cell-Substratum Adhesion in Highly-Motile and Highly-Metastatic Hepatocellular Carcinoma Cells

Genda, Takuya; Sakamoto, Michiie; Ichida, Takafumi; Asakura, Hitoshi; Hirohashi, Setsuo

doi:10.1038/labinvest.3780043

Cited by 55 publications

(47 citation statements)

References 37 publications

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“…In response to cell-ECM adhesion, Genda et al (2000) observed an activation of Src with concomitant reduction in cell-cell adhesion in hepatocellular carcinoma cells. These effects were found to be inhibited by b1-and b5-specific neutralizing antibodies (Genda et al, 2000). In a later study, elevated Src activity in colon cancer cells was shown to induce disorganization of normal cell-cell contact formation .…”

Section: Integrins and Cadherinsmentioning

confidence: 97%

“…The role of SFKs in the regulation of cell-cell adhesion has been described in another paper in this issue. Two studies have implicated a role for Src in the regulation of cell-cell contacts via integrin signaling (Genda et al, 2000;Avizienyte et al, 2002). In response to cell-ECM adhesion, Genda et al (2000) observed an activation of Src with concomitant reduction in cell-cell adhesion in hepatocellular carcinoma cells.…”

Section: Integrins and Cadherinsmentioning

confidence: 99%

“…Two studies have implicated a role for Src in the regulation of cell-cell contacts via integrin signaling (Genda et al, 2000;Avizienyte et al, 2002). In response to cell-ECM adhesion, Genda et al (2000) observed an activation of Src with concomitant reduction in cell-cell adhesion in hepatocellular carcinoma cells. These effects were found to be inhibited by b1-and b5-specific neutralizing antibodies (Genda et al, 2000).…”

Section: Integrins and Cadherinsmentioning

confidence: 99%

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The interplay between Src and integrins in normal and tumor biology

2004

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Src family nonreceptor protein tyrosine kinases transduce signals that control normal cellular processes such as cell proliferation, adhesion and motility. Normally, cellular Src is held in an inactive state, but in several cancer types, abnormal events lead to elevated kinase activity of the protein and cause pleiotropic cellular responses inducing transformation and metastasis. A prerequisite of the ability of a cancer cell to undergo metastasis into distant tissues is to penetrate surrounding extracellular matrices. These processes are facilitated by the integrin family of cell adhesion molecules. As is the case with Src, altered integrin activity or substrate affinity can contribute to the neoplastic phenotype. Therefore, understanding the interplay between Src and integrin function has been of intense interest over the past few years. This review focuses on the role of Src and integrin signaling in normal cells and how this is deregulated in human cancer. We will identify the key players in the integrin-mediated signaling pathways involved in cell motility and apoptosis, such as FAK, paxillin and p130 CAS , and discuss how Src signaling affects the formation of focal adhesions and the extracellular matrix.

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Section: Integrins and Cadherinsmentioning

confidence: 97%

Section: Integrins and Cadherinsmentioning

confidence: 99%

Section: Integrins and Cadherinsmentioning

confidence: 99%

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The interplay between Src and integrins in normal and tumor biology

2004

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“…Hepatocellular carcinoma (HCC) is a very common malignancy and a major cause of cancer deaths in Asian countries. Although several molecules have also been involved in the metastatic process of HCC, [7][8][9][10] none of them has shown to be of great impact on the prognosis of this disease. It is, therefore, a matter of urgency to identify novel and effective prognostic indicators for this disease.…”

mentioning

confidence: 99%

RECK gene expression in hepatocellular carcinoma: Correlation with invasion-related clinicopathological factors and its clinical significance

Furumoto¹

2001

Hepatology

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The RECK (reversion-inducing-cysteine-rich protein with Kazal motifs) gene was initially isolated as a transformation suppressor gene. It encodes a membrane-anchored glycoprotein with multiple serine protease inhibitor-like domains. The RECK gene is expressed widely in normal organs but is undetectable in many tumor-derived cell lines. When artificially expressed in such cell lines, RECK suppresses their invasive and metastatic activities. Clinical implications of these findings, however, remained undefined because of the lack of studies using fresh human tumor samples. In the present study, we have addressed this issue by analyzing the levels of RECK gene expression in hepatocellular carcinoma (HCC). RECK mRNA was detectable by RNA blot hybridization in all the tumorous and contiguous nontumorous tissues obtained from 64 patients with HCC. In 26 cases, the RECK expression in tumorous tissues was higher than that in nontumorous tissues. The expression of RECK protein in these tissues could also be demonstrated by immunohistochemistry. Patients with high RECK mRNA expression in tumorous tissues tended to show better survival (P ‫؍‬ .02), and such tumors had a tendency to be less invasive. Univariate and multivariate analysis revealed that the RECK mRNA expression is a novel and independent variable affecting overall survival (P ‫؍‬ .01). These findings support the hypothesis that RECK has negative effects on the invasiveness of HCC cells and suggest the feasibility of RECK mRNA as a promising prognostic molecular marker for HCC. (HEPATOLOGY 2001;33:189-195.)The RECK (reversion-inducing-cysteine-rich protein with Kazal motifs) gene was isolated by cDNA expression cloning as a gene that induces flat morphology when expressed in a v-Ki-ras-transformed NIH 3T3 cell line. 1 The RECK gene encodes a membrane-anchored glycoprotein of about 110 kDa with multiple epidermal growth factor-like repeats and serine protease inhibitor-like domains. The RECK gene was ubiquitously expressed in various normal tissues and non-neoplastic cell lines, whereas in several tumor-derived cell lines and oncogene-transformed fibroblasts, its expression was strongly suppressed. Restored expression of the RECK gene inhibited the invasive or metastatic activities of some of these tumorderived cell lines with concomitant suppression of the secretion of matrix metalloproteinase (MMP)-9 from these cells.Many efforts have been devoted to understand the molecular mechanisms of invasion and metastasis in human cancers. 2 A number of molecules, including adhesion molecules, 3,4 metalloproteinases, 5 and angiogenic factors, 6 have been implicated as key players in invasion and metastasis. Hepatocellular carcinoma (HCC) is a very common malignancy and a major cause of cancer deaths in Asian countries. Although several molecules have also been involved in the metastatic process of HCC, 7-10 none of them has shown to be of great impact on the prognosis of this disease. It is, therefore, a matter of urgency to identify novel and effective prognostic indica...

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“…21 Src has been shown to increase migration and invasion of human colon cancer cells in vitro. [22][23][24][25] The increase in invasion may be a result of a variety of events including altered activity of adhesion proteins, integrins and cadherins 26,27 and altered secretion of proteinases into the extracellular matrix. 28 However, while Src levels are increased during the progression of colorectal cancer as early as adenomatous polyps, there is little proof that Src initiates tumor development.…”

mentioning

confidence: 99%

Src kinase induces tumor formation in the c‐SRC C57BL/6 mouse

Kline

Jackson

Engelman

et al. 2008

Intl Journal of Cancer

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Src kinase has been linked as a causative agent in the progression of a number of cancers including colon, breast, lung and melanoma. Src protein and activity levels are increased in colorectal cancer and liver metastases arising secondary to colon cancer. However, although Src protein is increased in colon cancer as early as the adenomatous polyp stage, a role for Src in carcinogenesis has not been established. We developed the c-SRC transgenic mouse in the C57BL/6 strain to address the issue of carcinogenesis in cells with high levels of Src expression. The transgene was constructed with the human c-SRC gene downstream of the mouse metallothionein promoter to create zinc inducible gene expression. In these C57BL/6 mice, Src protein was increased in a number of tissues both with and without zinc induction. No additional carcinogenic agent was administered. After 20 months, mice were assessed for tumor development in the liver and GI tract, as well as other organs. Of the mice with the transgene, 15% developed tumors in the liver while no tumors were detected in wild type C57BL/6 mice. A further study was conducted by crossing c-SRC C57BL/6 mice with p21 nullizygous mice to determine the effect of oncogene expression combined with inactivation of the tumor suppressor gene, p21. Addition of the c-SRC transgene to the p212/2 background increased tumor formation almost 3-fold, while it increased metastasis 6-fold. The data from our study show, for the first time, that Src kinase may play a role in carcinogenesis. ' 2008 Wiley-Liss, Inc.Key words: Src; transgenic mice; p21; carcinogenesis; metastasis Src is a nonreceptor tyrosine kinase that induces signal transduction in multiple pathways regulating cellular behavior. 1-3 Previous studies have shown that Src kinase activity is elevated in a variety of human cancers, 4-8 and has been linked with the progression and metastasis of cancer in humans. However, the exact role of Src in these processes remains elusive. 9-11 Src has been the focus of a number of studies using cultured cells, human tissues, and nude mouse experiments. [11][12][13][14][15][16] Src activity was shown to be important for tumor formation and metastasis in mouse models of prostate, ovarian and colon tumors, often through VEGF, Akt and Erk pathways. [17][18][19][20] Fibroblasts transfected with activated Src show a transformed phenotype when used in soft agar assays and in nude mouse models of metastasis. 21 Src has been shown to increase migration and invasion of human colon cancer cells in vitro. [22][23][24][25] The increase in invasion may be a result of a variety of events including altered activity of adhesion proteins, integrins and cadherins 26,27 and altered secretion of proteinases into the extracellular matrix. 28 However, while Src levels are increased during the progression of colorectal cancer as early as adenomatous polyps, there is little proof that Src initiates tumor development. To study the tumorigenicity of the Src protein, we developed a c-SRC C57BL/6 mouse model.Mouse model...

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Loss of Cell-Cell Contact Is Induced by Integrin-Mediated Cell-Substratum Adhesion in Highly-Motile and Highly-Metastatic Hepatocellular Carcinoma Cells

Cited by 55 publications

References 37 publications

The interplay between Src and integrins in normal and tumor biology

The interplay between Src and integrins in normal and tumor biology

RECK gene expression in hepatocellular carcinoma: Correlation with invasion-related clinicopathological factors and its clinical significance

Src kinase induces tumor formation in the c‐SRC C57BL/6 mouse

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