Myofibroblasts are responsible for collagen synthesis in the stroma of human hepatocellular carcinoma: an in vivo and in vitro study

Faouzi, Saadia; Bail, Brigitte Le; Neaud, Véronique; Boussarie, Liliane; Saric, Jean; Bioulac‐Sage, Paulette; Balabaud, Charles; Rosenbaum, Jean

doi:10.1016/s0168-8278(99)80074-9

Cited by 105 publications

(75 citation statements)

References 28 publications

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“…Collagens are the most abundant protein in the ECM and provide a structural support for cells. As mentioned above, myofibroblasts/activated HSCs are the main source of collagen production in the HCC stroma (128,129). Collagens also promote cell migration and proliferation in HCC.…”

Section: Hepatic Stellate Cells (Hscs)mentioning

confidence: 94%

The tumor microenvironment in hepatocellular carcinoma (Review)

et al. 2012

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Abstract. The tumor microenvironment has been largely studied as a dynamic system orchestrated by inflammatory cells, including cancer cells, stroma as well as the extracellular matrix. It is useful to describe and predict the phenotypic characteristics of cancer. Furthermore, a better understanding of its interplay with the various aspects of the tumor cells may be utilized for the discovery of novel molecular targets. Liver cancer is considered a model of the relation occurring between the tumor microenvironment and tumor development. The chronic inflammatory status of the liver, sustained by the infection of hepatitis viruses, as well as the production of cytokines and growth factors within the parenchyma, lead to an intricate microenvironment. The identification of novel molecular therapeutic targets may improve the outcome of patients with liver cancer as it remains the third leading cause of cancer death worldwide. In the present study, the tumor microenvironment in hepatocellular carcinoma (HCC) was explored by a review of the literature. Studies on hepatitis virus infections and the consequent chronic inflammatory status were examined. In this context, immune-mediated and/or virusrelated molecular mechanisms have been hypothesized as being responsible for liver cancer development. The interlink among HCC microenvironment components, comprising cellular elements, cytokines, growth factors and several proteins is also described together with the role of matrix metalloproteinases in HCC development. Finally, the rationale for targeting tumorstromal interface is summarized in the context of new therapeutic opportunities.

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Section: Hepatic Stellate Cells (Hscs)mentioning

confidence: 94%

The tumor microenvironment in hepatocellular carcinoma (Review)

et al. 2012

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“…Here, we investigated effects mediated by activated HSCs because these cells form and infiltrate the HCC stroma and affect HCC development and progression (16,36,46,51,52). Furthermore, we recently identified activated HSCs as the cellular source of increased FAT1 expression in liver fibrosis and demonstrated that FAT1 is a profibrogenic factor in these cells (17).…”

Section: Fat1 In Hccmentioning

confidence: 99%

Regulation and Function of the atypical cadherin FAT1 in hepatocellular carcinoma

Valletta¹,

Czech²,

Wild³

et al. 2013

Z Gastroenterol

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“…HCC are characterized by a high rate of local, intra-hepatic invasion. HCC are infiltrated by myofibroblastlike cells, located around tumoral sinusoids and in fibrous septa and capsule, when present (2)(3)(4). We have previously shown that cultured human liver myofibroblasts strongly promoted in vitro invasion of human HCC cell lines through their secretion of hepatocyte growth factor (HGF) (5).…”

Section: Hepatocellular Carcinoma (Hcc)mentioning

confidence: 99%

Paradoxical Pro-invasive Effect of the Serine Proteinase Inhibitor Tissue Factor Pathway Inhibitor-2 on Human Hepatocellular Carcinoma Cells

Neaud¹,

Hisaka²,

Monvoisin³

et al. 2000

Journal of Biological Chemistry

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We have previously shown that human liver myofibroblasts promote in vitro invasion of human hepatocellular carcinoma (HCC) cells through a hepatocyte growth factor (HGF)/urokinase/plasmin-dependent mechanism. In this study, we demonstrate that myofibroblasts synthesize the serine proteinase inhibitor tissue factor pathway inhibitor-2 (TFPI-2). Despite the fact that recombinant TFPI-2 readily inhibits plasmin, we show that it potentiates HGF-induced invasion of HCC cells and is capable of inducing invasion on its own. Furthermore, HCC cells stably transfected with a TFPI-2 expression vector became spontaneously invasive. HCC cells express tissue factor and specifically factor VII. Addition of an antibody to factor VII abolished the pro-invasive effect of TFPI-2. We suggest that TFPI-2 induces invasion following binding to a tissue factor-factor VIIa complex preformed on HCC cells. Our data thus demonstrate an original mechanism of cell invasion that may be specific for liver tumor cells.Hepatocellular carcinoma (HCC) 1 is one of the most frequent primary tumors in the world (1). It is a major complication of liver cirrhosis, although more rarely it will develop on a noncirrhotic liver. HCC are characterized by a high rate of local, intra-hepatic invasion. HCC are infiltrated by myofibroblastlike cells, located around tumoral sinusoids and in fibrous septa and capsule, when present (2-4). We have previously shown that cultured human liver myofibroblasts strongly promoted in vitro invasion of human HCC cell lines through their secretion of hepatocyte growth factor (HGF) (5). In further studies, we showed that HGF induced invasion by increasing the expression of the urokinase-type plasminogen activator (uPA) by the cancer cells (6). Indeed, myofibroblast-or HGFinduced invasion was dose-dependently blocked by a selective uPA antagonist (6). One of the main functions of uPA is to convert the inactive zymogen plasminogen into plasmin, a broad-spectrum proteinase able to degrade several components of the extracellular matrix and thus a likely effector of cancer cell invasion.Tissue factor pathway inhibitor-2 (TFPI-2), also known as placental protein 5 is a serine proteinase inhibitor containing 3 tandemly arranged Kunitz-type proteinase inhibitor domains, homologous to tissue factor pathway inhibitor (7). TFPI-2 exists as 3 isoforms of 27, 31, and 33 kDa that are synthetic products of a single gene and arise from differential glycosylation. TFPI-2 is a strong inhibitor of plasmin as well as of trypsin, plasma kallikrein, and factor XIa. It does not inhibit uPA (8). TFPI-2 synthesis has been described in dermal fibroblasts and endothelial cells (9 -11). In these cell types, the major part of TFPI-2 is sequestered within the extracellular matrix (ECM), presumably bound to heparan sulfate. In the course of a systematic sequencing of a human liver myofibroblast cDNA library described elsewhere (12), we found that these cells expressed transcripts for TFPI-2. Given the ability of TFPI-2 to inhibit plasmin, we were interest...

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Myofibroblasts are responsible for collagen synthesis in the stroma of human hepatocellular carcinoma: an in vivo and in vitro study

Cited by 105 publications

References 28 publications

The tumor microenvironment in hepatocellular carcinoma (Review)

The tumor microenvironment in hepatocellular carcinoma (Review)

Regulation and Function of the atypical cadherin FAT1 in hepatocellular carcinoma

Paradoxical Pro-invasive Effect of the Serine Proteinase Inhibitor Tissue Factor Pathway Inhibitor-2 on Human Hepatocellular Carcinoma Cells

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