Interleukin 4 inhibits hepatocyte growth factor-induced invasion and migration of colon carcinomas

Abstract

Hepatocyte growth factor (HGF) is known to have a number of biological properties including promoting tumor progression of human carcinomas. Metastasis involves a number of events that are attributed to induction by paracrine factors such as HGF. Identification of natural inhibitors of these events would allow better control of tumor progression. Recently we demonstrated that interleukin 4 (IL-4) can regulate proliferation of various human carcinoma cell lines. In the present study, we used established human colon carcinoma cell lines and primary colon carcinoma cell cultures to determine if IL-4 could regulate HGF-induced cell proliferation and other events of tumor progression such as MMP (matrix metalloproteinases)-1, -2, and -9 production, cell migration and cell-matrix invasive activity. All colon carcinoma cell lines expressed HGF and IL-4 receptors. IL-4 significantly inhibited HGF-induced proliferation of one cell line. Cell-matrix invasion was significantly enhanced by HGF (0.1-10 ng/ml); IL-4 (1-10 U/ml) significantly inhibited HGF-induced invasion in a dose-dependent manner. IL-4 also inhibited HGF-induced cell-matrix invasion of metastatic colon carcinoma cells and HGF-induced cell migration. HGF enhanced MMP-1, -2, and -9 production by cell lines. This effect could be inhibited by IL-4. These findings indicate that IL-4 is a potent inhibitor of HGF-induced invasion and metastasis-related functions of human colon carcinoma cells.

Mitogenic synergy through multilevel convergence of hepatocyte growth factor and interleukin-4 signaling pathways

“…Activation of PKC can lead to the phosphorylation of c-Met on serine 985, and in turn, inhibition of the receptor's intrinsic tyrosine kinase activity (Gandino et al, 1994). IL-4 blocked the HGF-stimulated migration of colon carcinoma cells in a cell-matrix invasion assay (Uchiyama et al, 1996). In that study, IL-4 also inhibited HGF-stimulated expression of matrix metalloproteinases (MMP)-1, -2, and -9.…”

“…The biological eects of IL-4 are also in¯uenced by other cytokines and growth factors. IL-4 complements IL-2 in T-cell tumor lines for ex vivo autocrine growth and for in vivo tumorigenicity (Hassuneh et al, 1997), acts synergistically with platelet-derived growth factor (PDGF) in mitogenesis (Patel et al, 1996), and inhibits HGFstimulated migration of colon carcinoma cells (Uchiyama et al, 1996).…”

Inhibition by Evodiamine of Hepatocyte Growth Factor-Induced Invasion and Migration of Tumor Cells

“…26) IL-12 and g-linolenic acid inhibit HGF-induced tumor migration via up-regulation of cell-surface Ecadherin. 27,28) IL-4 is also shown to inhibit HGF-induced tumor migration but its mechanism is unknown. 29) In contrast, evodiamine suppressed HGF-induced tumor migration by acting to repress the cell spreading.…”

Serum DNA Microsatellites as Surrogate Genetic Markers of Breast Cancer Progression

“…The association of these findings with tumors manifesting known pathologic features consistent with increased prohferation suggests a possible etiology for their presence. Recently it has been shown that free tumor-associated DNA can be identified in the serum and plasma from patients with melanoma, breast, lung, renal, gastrointestinal and head and neck tumors (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). Furthermore a high-quality concordance has been shown to exist between the genetic alterations (i.e.…”

“…The c-Met oncogene encodes for hepatocyte growth factor receptor, which is a tyrosine kinase ti-ansmembrane protein receptor (24). Hepatocyte growth factor binding to the receptor transduces a signal for cell dissociation, motihty, and mitogenesis (25,26). Its expression in breast cancer has been shown recently to independently predict survival (27).…”