Macrophage migration inhibitory factor: Roles in regulating tumor cell migration and expression of angiogenic factors in hepatocellular carcinoma

Abstract

Macrophage migration inhibitory factor (MIF) may contribute to multiple aspects of tumor progression, including control of cell proliferation, differentiation, cell survival and angiogenesis. However, the potential roles of MIF in regulating hepatocellular carcinoma (HCC) tumor cell migration and the expression of angiogenic factors by HCC tumor cells have not been studied yet. In our study, we reported that intracellular MIF mRNA and protein were overexpressed in HCC tissues compared to nontumor tissues by using in situ hybridization and immunohistochemic staining. HCC tumor cell lines also secreted large amounts of MIF into the supernatants of tumor cell culture. To assess the role of MIF in HCC, we employed the transwell invasion chamber to study the effect of MIF on tumor cell migration. Our results showed that recombinant MIF and the supernatants of tumor cell line culture could enhance the invasion and migration of HCC cells. This effect can be inhibited by the addition of a neutralizing anti-MIF antibody. We observed that increased MIF serum levels correlated with higher levels of interleukin-8 (IL-8) in the sera of patients with HCC than in normal volunteers. We therefore hypothesized that MIF may regulate the production of angiogenic factors by HCC cells. To test this hypothesis, we examined the effect of MIF treatment on vascular endothelial growth factor (VEGF) and IL-8 expression by HCC cell lines. MIF induced a significant dose-dependent increase in IL-8 and VEGF production. Taken Key words: macrophage migration inhibitory factor; hepatocellular carcinoma; angiogenesis; metastasisHepatocellular carcinoma (HCC) is one of the most common human cancers in the world, and its incidence is particularly high among the Chinese. HCC has been the second largest cause of cancer death in China since the 1990s. 1 Although morbidity and mortality rates have decreased in patients with surgically treated HCC in recent years, the long-term prognosis remains unsatisfactory because of a high recurrence rate. 2 The high recurrence rate is related to a propensity of HCC for vascular invasion and metastasis. Although the risk factors of tumor recurrence in HCC are well known, the precise molecular mechanisms contributing to the invasiveness of HCC still remain unclear. Understanding of the molecular mechanisms of the complex multistep process of tumor invasion and metastasis could facilitate the development of better treatment modalities and preventive measures.Tumor growth and metastasis depend upon the ability of the tumor to induce its own blood supply. This process is dependent on the induction of angiogenesis mediated by angiogenic factors secreted by the tumor cells. Tumor cells secrete a wide variety of angiogenic factors that participate in the development of microvasculature in the tumor. 3,4 Among the identified angiogenic factors, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) are the most potent and representative angiogenic factors. [5][6][7][8] Other angiogenic factors such as basic fib...

Inhibition of tumor growth and metastasis in vitro and in vivo by targeting macrophage migration inhibitory factor in human neuroblastoma

“…Recent studies have also demonstrated that IL-8 regulates tumor cell growth and metastasis in many tumors such as melanoma, carcinoma of breast, stomach, pancreas and liver. Our previous results indicated that serum IL-8 from patients with hepatocellular carcinoma significantly correlated with tumor size, tumor stage and venous invasion (Ren et al, 2003b), suggesting that IL-8 may be directly or indirectly involved in tumor progression. We have also demonstrated that MIF is able to stimulate neuroblastoma cells to express IL-8 .…”

“…Overexpression of MIF has been identified in prostatic lymph node metastases (Meyer-Siegler and Hudson, 1996), human melanomas (Shimizu et al, 1999), breast carcinomas (Bini et al, 1997), adenocarcinomas of the lung (Kamimura et al, 2000), bladder cancer (Meyer-Siegler et al, 2004) and hepatocellular carcinomas (Akbar et al, 2001;Ren et al, 2003a). It has been shown that high levels of MIF significantly correlate with an unfavorable outcome in esophageal squamous cell carcinoma (Ren et al, 2005) and hepatocellular carcinoma (Ren et al, 2003a) and other tumors (del Vecchio et al, 2000;Meyer-Siegler, 2000;Tomiyasu et al, 2000). Our previous results revealed that MIF was highly expressed in neuroblastoma, and can stimulate oncogene N-myc expression and upregulate the expression of angiogenic factors .…”

Macrophage migration inhibitory factor (MIF) promotes fibroblast migration in scratch‐wounded monolayers in vitro

“…In a recent report, Hagemann et al conclude that tumor necrosis factor-a (TNF-a) induces tumour-associated macrophages to secrete MIF, which serves to enhance the invasive capacity of the tumour cells [8]. In line with these observations, MIF was found to promote the migration of hepatic carcinoma cells through the angiogenic factors interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF) [9] and to stimulate the migration of microvascular endothelial cells [10]. In elucidating the molecular mechanism underlying MIF-induced leukocyte recruitment into atherogenic vessels, Bernhagen et al demonstrated that MIF triggers monocyte/ neutrophil and T-cell arrest and chemotaxis through interaction with the chemokine receptors CXCR2 and CXCR4, respectively [11,12].…”

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…The secretion of CCL4 and MMP-9 by neutrophils was stimulated by macrophage migration inhibitory factor (MIF) produced by the HNSCC cells [376]. MIF was also shown to be produced by other cancer cell types, including breast cancer, esophageal squamous cell carcinoma and hepatocellular carcinoma, where it contributes to angiogenesis [377][378][379][380]. Breast cancer patients with positive MIF expression in tumor tissues showed a significantly worse disease-free survival compared with MIF negative patients [377].…”