Fibrolamellar Carcinoma of the Liver: Composition of the Extracellular Matrix and Expression of Cell–Matrix and Cell–Cell Adhesion Molecules

Abstract

sinophilic, neoplastic, epithelial cells resembling hepatoWe have analyzed the composition of the tumor stroma cytes. 1,2,[4][5][6][7][8] The prognosis of FLC is usually favorable. [1][2][3][8][9][10] In and the expression of cell-matrix and cell-cell adhesion most cases, tumors are resectable at diagnosis, and prolonged molecules in 11 cases of fibrolamellar carcinoma of the survivals are obtained after surgical resection or liver transliver (FLC), in comparison with 34 cases of hepatocelluplantation. lar carcinoma and 8 cases of focal nodular hyperplasia.It has long been noted that, despite its slow local growth, Fibrolamellar carcinoma was characterized by the pres-FLC presents a high occurrence of initial or late metastatic ence of large amounts of tenascin in tumor stroma and disease. [1][2][3]8,9 Recent studies have pointed out the pivotal role by the scarce expression of basement membrane compoplayed by the tumor stroma and by cell adhesion molecules nents at the contact of neoplastic clusters. Like normal in the acquisition of invasive and metastatic properties by hepatocytes, neoplastic cells constantly expressed the neoplastic epithelial cells. It has been shown that the local a1 integrin chain, lacked the b4 integrin chain, and coexspreading of tumor cells and their metastatic dissemination pressed E-cadherin and the hepatocyte N-related cadare favored by the presence of tenascin 11 and the absence of herin. Abnormalities in the expression of cell adhesion basement membrane components in the tumor stroma, 12,13 molecules, including altered cadherin expression, aV inthe induction of certain integrins, such as the fibronectin tegrin chain induction, and CD44 expression, were dereceptor aVb5, 14 and of members of the CD44 protein family 15 tected in the majority of cases. The composition of the and the altered expression of the cell-cell adhesion molecules tumor stroma and the pattern of expression of cell adheof the cadherin superfamily. 16 We therefore studied 11 cases sion molecules in fibrolamellar carcinoma were reminisof FLC by combining immunohistochemical and Western cent of those observed in grade III and grade IV hepatoblotting techniques to analyze: (1) the composition of the tucellular carcinomas. Our results therefore show that, mor stroma, which has so far deserved little attention dedespite its slow local growth and good prognosis, fibrolaspite its characteristic appearance, and (2) the pattern of mellar carcinoma expresses many characteristics usuexpression of cell-matrix and cell-cell adhesion molecules by ally associated with clinically aggressive malignancies. neoplastic epithelial cells. For purposes of comparison, we Further studies are needed to identify the factors reanalyzed the same parameters in 38 cases of typical hepatosponsible for the apparent dissociation between clinical cellular carcinomas of various grades and in 8 cases of focal behavior and biological characteristics in this tumor. nodular hyperplasia, of which FLC has sometimes been con-(HEPATOLOGY 1996;24:1128-1...

Transforming Growth Factor β Controls the Directional Migration of Hepatocyte Cohorts by Modulating Their Adhesion to Fibronectin

“…To investigate the loss of substrate anchorage, we analyzed the profile of expression of integrins, which are the major receptors mediating the ECM attachment. We concentrated on the integrin subunits known to be expressed by hepatocytes under physiological and pathological conditions (Stamatoglou and Hughes, 1994;Scoazec et al, 1996). In agreement with published data (Bhowmick et al, 2001) the RTqPCR analysis of the principal hepatic integrin ␤ mRNA, ␤1, showed a slight increase in response to TGF-␤ (Figure 4).…”

“…The pattern becomes somewhat more complex in hepatocellular carcinoma where, in addition to an increase in the ␣5 subunit, the ␣3 and ␣6 chains are also abundantly expressed (Scoazec et al, 1996). We found that TGF-␤ induced high level expression of ␣5 and ␣6 in the mhAT3F cells, whereas the ␣3 expression remained constantly low (data not shown).…”

Human Hepatocellular Carcinoma (HCC) Cells Require Both α3β1 Integrin and Matrix Metalloproteinases Activity for Migration and Invasion

“…However, noninvasive HCC cells express MT1-MMP but do not migrate on Ln-5, even in the presence of added exogenous MMP-2. These contradictory results might be explained by the fact that nonmigratory cells hardly express ␣3␤1 integrin, which is also absent in normal adult hepatocytes; whereas it is highly expressed in hepatocytes that are migrating from the endoderm germ layer to the mesenchyme of the septum transversum during embryogenesis (Lora et al, 1998;Nejjari et al, 1999;Scoazec et al, 1996). We found that ␣3␤1 was expressed in HCC tissue, suggesting a role for this integrin in migration on ECM components such as Ln-5 and in metastasis formations.…”

Tenascins: regulation and putative functions during pathological stress

“…In squamous carcinomas of the mouth and larynx a general increase of tenascin-C staining was found to correlate with invasiveness and malignancy [144][145][146][147]. Tumours of the lung [148][149][150], liver [151], kidney, and bladder [152,153] all showed increased tenascin-C staining, most prominent in the stroma at the invasion borders. The number of reports is not yet large enough to make any general statements, although some reports raise the hope that tenascin-C staining could have diagnostic value.…”