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.

New pathway links from cancer‐progression determinants to gene expression of matrix metalloproteinases in breast cancer cells

“…Cancer cell MMP-1, MMP-2, MMP-9, MMP-11, MMP-13, MMP-14, MMP-16, and MMP-19 stimulate MDA-MB-231 cancer cell invasiveness (Ramos-DeSimone et al, 1999;Jiang et al, 2005Jiang et al, , 2006Wyatt et al, 2005;Merrell et al, 2006;Muñoz-Nájar et al, 2006;Hegedüs et al, 2008). AP-2a, E-cadherin, fibulin 1D, IL-4, KAI1, p16 INK4a , PTEN and RKIP inhibit, and S100A4 promotes, cancer cell invasiveness and other cancer progression traits, in MDA-MB-231 breast cancer cells, and other types of cancers (Frixen et al, 1991;Dong et al, 1995;Uchiyama et al, 1996;Chintala et al, 1997;Qing et al, 1997;Hayashido et al, 1998;Tamura et al, 1999;Uozumi et al, 2000;Koul et al, 2001;Twal et al, 2001;Yang et al, 2001;Adachi et al, 2002;Fu et al, 2003;Lee et al, 2003;Wong and Gumbiner, 2003;Xu and Yu, 2003;Zheng et al, 2003;Gildea et al, 2004;Lu et al, 2004;Schuierer et al, 2004;Sumigama et al, 2004;Wu et al, 2004;Zhou et al, 2004;Cai et al, 2005;Hjelmeland et al, 2005;Jee et al, 2006;Saleem et al, 2006;Sridhar and Miranti, 2006;Chen et al, 2007;Schwartz et al, 2007). These UCPDs have been connected to various cell signaling pathways (Fig.…”

“…Several cancer cell matrix metalloproteinases (MMPs), such as MMP-1, MMP-2, MMP-9, , enhance MDA-MB-231 cancer cell invasiveness (Ramos-DeSimone et al, 1999;Jiang et al, 2005Jiang et al, , 2006Wyatt et al, 2005;Merrell et al, 2006;Muñoz-Nájar et al, 2006;Hegedüs et al, 2008). Activator protein-2a (AP-2a), E-cadherin, fibulin 1D, interleukin 4 (IL-4), KAI1, p16 INK4a , phosphatase and tensin homolog (PTEN), and raf kinase inhibitor protein (RKIP) suppress, and S100A4 enhances, cancer cell invasiveness and other cancer progression traits, in MDA-MB-231 breast cancer cells and cells from other types of cancers (Uchiyama et al, 1996;Chintala et al, 1997;Qing et al, 1997;Hayashido et al, 1998;Twal et al, 2001;Adachi et al, 2002;Fu et al, 2003;Wong and Gumbiner, 2003;Zheng et al, 2003;Schuierer et al, 2004;Sumigama et al, 2004;Hjelmeland et al, 2005;Saleem et al, 2006;Chen et al, 2007;). They are located upstream of MMPs in cell signaling pathways.…”

“…A very large number of proteins determine invasiveness and other cancer progression traits (Uchiyama et al, 1996;Twal et al, 2001;Wong and Gumbiner, 2003;Zheng et al, 2003;Schuierer et al, 2004;Sumigama et al, 2004;Saleem et al, 2006). The progression of different types of cancers depends on different profiles of cell signaling pathways (Walsh and King, 2007;Cybulski et al, 2008).…”

Functional variants of IL4 and IL6 genes and risk of tobacco‐related oral carcinoma in high‐risk Asian Indians

“…IL4 is an anti-inflammatory cytokine and various in vitro studies have documented its anti-tumor activity on breast and colon cancers (Toi et al, 1992). In colon carcinoma, it inhibited matrix metalloproteinases (MMP-1, MMP-2, and MMP-9), hepatocyte growth factor induced invasion and migration of tumor cells (Uchiyama et al, 1996). It also directly modulates proliferation of various cancer cell types including gastric and renal cancers by increasing expression of p21 WAFI and interferon regulating factor (IRF-1) and decreasing cyclin-dependent kinase (CDK)-2 activities besides facilitating the infiltration of inflammatory cells such as macrophages, eosinophils, and neutrophils (Yu et al, 2004).…”

Microarray Analysis of Metastasis-Associated Gene Expression Profiling in a Murine Model of Thyroid Carcinoma Pulmonary Metastasis: Identification of S100A4 (Mts1) Gene Overexpression as a Poor Prognostic Marker for Thyroid Carcinoma

“…It also overexpressed in highly metastatic thyroid carcinoma as shown in our study. Considering Met product is a tyrosine-kinase receptor for hepatocyte growth factor and activation of this receptor by hepatocyte growth factor can induce proliferation, motility, adhesion, and invasion in tumor cells, it is likely that Met is not only involved in the thyroid carcinogenesis but thyroid cancer metastasis as well (45)(46)(47)(48)(49).…”