Glycosaminoglycans and their synthetic mimetics inhibit RANTES-induced migration and invasion of human hepatoma cells

Abstract

The CC-chemokine regulated on activation, normal T-cell expressed, and presumably secreted (RANTES)/CCL5 mediates its biological activities through activation of G protein -coupled receptors, CCR1, CCR3, or CCR5, and binds to glycosaminoglycans. This study was undertaken to investigate whether this chemokine is involved in hepatoma cell migration or invasion and to modulate these effects in vitro by the use of glycosaminoglycan mimetics. We show that the human hepatoma Huh7 and Hep3B cells express RANTES/CCL5 G protein -coupled receptor CCR1 but not CCR3 nor CCR5. RANTES/CCL5 binding to these cells depends on CCR1 and glycosaminoglycans. Moreover, RANTES/CCL5 strongly stimulates the migration and the invasion of Huh7 cells and to a lesser extent that of Hep3B cells. RANTES/CCL5 also stimulates the tyrosine phosphorylation of focal adhesion kinase and activates matrix metalloproteinase-9 in Huh7 hepatoma cells, resulting in increased invasion of these cells. The fact that RANTES/CCL5-induced migration and invasion of Huh7 cells are both strongly inhibited by anti-CCR1 antibodies and heparin, as well as by B-D-xyloside treatment of the cells, suggests that CCR1 and glycosaminoglycans are involved in these events. We then show by surface plasmon resonance that synthetic glycosaminoglycan mimetics, OTR4120 or OTR4131, directly bind to RANTES/CCL5. The preincubation of the chemokine with each of these mimetics strongly inhibited RANTES-induced migration and invasion of Huh7 cells. Therefore, targeting the RANTES-glycosaminoglycan interaction could be a new therapeutic approach for human hepatocellular carcinoma. [Mol Cancer Ther 2007;6(11):2948 -58]

Overexpressed focal adhesion kinase predicts a higher incidence of extrahepatic metastasis and worse survival in hepatocellular carcinoma

“…Therefore, it is important to identify biological markers for extrahepatic metastasis in HCC so that preventive strategies such as adjuvant chemotherapy or targeted therapy can be initiated shortly after primary treatment. Several similar studies have shown that FAK plays as an important role in HCC progression, cancer invasion, and an independent prognostic factor for disease-free and overall survival [16][17][18]23] that was further confirmed in our study. However, our current study is the first to provide solid evidence that FAK overexpression in primary HCC predicts extrahepatic metastases in human subjects.…”

“…In HCC cell lines, FAK expression has long been correlated with invasiveness and aggressiveness [17][18][19]. Furthermore, FAK-mediated signals have not only been found to be involved in antiapoptotic effects [20] but are also correlated with several critical survival pathways such as cSrc [21] and PTEN [22].…”

C‑C motif chemokine receptors in gastric cancer (Review)

“…The third group of inhibitors comprises GAG mimetics, which serve as 'decoys' of chemokines and bind to their receptors. Of these compounds, OTR4120 and OTR4131 inhibited CCL5-dependent migration and invasion of hepatoma cells in vitro (81). Consistent with this, in gastric cancer, Mencarelli et al (61) reported that inhibition of CCR5 signaling reduced gastric cancer cell migration and adhesion to explanted murine peritoneum in vitro.…”

Role of RANTES and its receptor in gastric cancer metastasis

“…Our results were consistent with those of other researches. Sutton et al found that the migration of hepatoma cells was inhibited when glycosaminoglycans and their synthetic mimetics, which could inhibit the combination of RANTES and CCR3/CCR5, were used [23] . Some scholars used siRNA to down-regulate the expression of CCR5 and the combination of RANTES and CCR5, and they found the metastatic ability of MDA-MB-231 breast cancer cells was also significantly suppressed [19] .…”