Modulation of Squamous Carcinoma Cell Growth, Morphology, Adhesiveness and Extracellular Matrix Production by Interferon-γ and Tumor Necrosis Factor-α

Abstract

Interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) were examined for effects on human squamous carcinoma cells. IFN-γ inhibited proliferation at concentrations between 100 and 1,500 units/ml and the inhibitory effects were potentiated by TNF-α. Inhibition of cell growth was not accompanied by cytotoxicity. Combined treatment with the two cytokines also inhibited cell-substrate adhesion and altered the morphology of the cells. The treated cells were large and flattened. These morphological features are similar to those that have been previously described for normal keratinocytes induced to differentiate by a variety of means. The changes in biological properties were accompanied by alterations in production of extracellular matrix components – e.g., fibronectin and thrombospondin. Synthesis of both components was decreased following treatment. The cytokine-induced alterations in squamous carcinoma cell properties were fully reversible. These findings indicate that malignant squamous epithelial cells may be similar to their normal counterparts in their responses to IFN-γ and TNF-α. In the malignant cells, however, these cytokines do not appear to induce permanent phenotypic changes.

Inhibition of collagenase-3 (MMP-13) expression in transformed human keratinocytes by interferon-γ is associated with activation of extracellular signal-regulated kinase-1,2 and STAT1

“…Previous observations show, that IFN-g inhibits proliferation of normal and transformed keratinocytes in culture (Schuger et al, 1990;MaÈ kelaÈ et al, 1998). In addition, inhibition of proliferation and induction of apoptosis in colon adenocarcinoma cells involves activation of STAT1 and induction of Fas and FasL expression (Xu et al, 1998).…”

“…IFN-g is a Th1 cell-derived cytokine, which plays an important role in host defense and is expressed by tumor in®ltrating lymphocytes in SCCs (Kim et al, 1995;Arany et al, 1998). Although long-term exposure of SCC cells to IFN-g has been shown to inhibit proliferation of SCC cells (Schuger et al, 1990), its role in tumor invasion is not known. IFN-g has been shown to enhance expression of MMP-1 and MMP-3 and inhibit expression of MMP-9 by normal human keratinocytes (Tamai et al, 1995;MaÈ kelaÈ et al, 1998).…”

“…In addition, IFN-g also potently inhibits invasion of transformed keratinocytes through type I collagen and reconstituted basement membrane (Matrigel). Although invasion of tumor cells also requires enhanced cell motility, which is inhibited by IFN-g (Schuger et al, 1990), it is evident that cells can not migrate through native type I collagen without degrading it ®rst by collagenolytic MMPs, i.e. MMP-13 or MMP-1.…”

“…TNF-a and TGF-b (Johansson et al, 1997b(Johansson et al, , 1999. Tumor in®ltrating lymphocytes in SCCs express IFN-g (Kim et al, 1995;Arany et al, 1998), which can inhibit proliferation of SCC cells (Schuger et al, 1990) and stimulate production of MMP-1 and MMP-3 by normal epidermal keratinocytes (Tamai et al, 1995). To elucidate the possible role of IFN-g in SCC invasion, we ®rst treated transformed keratinocytes with di erent concentrations of IFN-g and determined their MMP-13 and MMP-1 expression.…”

A Direct Comparison of Pharmacologic Effects of Retinoids on Skin Cells in vitro and in vivo

“…A human squamous epithelial cell line derived from a tumor in the floor of the mouth was used to assess the effects of the various retinoids on epithelial cells. We have recently demonstrated that this cell line, designated as UM-SCC-1, is capa ble of undergoing differentiation [18] in response to agents that induce differentiation in kératinocytes [19]. We have also recently shown that UM-SCC-1 cells are virtually identical to human epidermal kéra tinocytes in their response to retinoic acid [20].…”