Hypoxia induces adhesion molecules on cancer cells: A missing link between Warburg effect and induction of selectin-ligand carbohydrates

Abstract

Cancer cells undergo distinct metabolic changes to cope with their hypoxic environment. These changes are achieved at least partly by the action of transcriptional factors called hypoxia-inducible factors (HIFs). We investigated gene expression in cultured human colon cancer cells induced by hypoxic conditions with special reference to cell-adhesion molecules and carbohydrate determinants having cell-adhesive activity by using DNA-microarray and RT-PCR techniques. Hypoxic culture of colon cancer cells induced a marked increase in expression of selectin ligands, the sialyl Lewis x and sialyl Lewis a determinants at the cell surface, which led to a definite increase in cancer cell adhesion to endothelial E-selectin. The transcription of genes for fucosyltransferase VII (FUT7), sialyltransferase ST3Gal-I (ST3O), and UDP-galactose transporter-1 (UGT1), which are all known to be involved in the synthesis of the carbohydrate ligands for E-selectin, was significantly induced in cancer cells by hypoxic culture. In addition, a remarkable induction was detected in the genes for syndecan-4 (SDC4) and α5-integrin (ITGA5), the cell-adhesion molecules involved in the enhanced adhesion of cancer cells to fibronectin. The transcriptional induction by hypoxia was reproduced in the luciferase-reporter assays for these genes, which were significantly suppressed by the co-transfection of a dominant-negative form of HIF. These results indicate that the metabolic shifts of cancer cells partly mediated by HIFs significantly enhance their adhesion to vascular endothelial cells, through both selectin- and integrin-mediated pathways, and suggest that this enhancement further facilitates hematogenous metastasis of cancers and tumor angiogenesis

E-/P-selectins and colon carcinoma metastasis: first in vivo evidence for their crucial role in a clinically relevant model of spontaneous metastasis formation in the lung

“…A similar phenomenon was found by labelling with HPA and anti-sLe a and no difference in the binding pattern or intensity was detected between both strains of mice. This observation leads to the idea that the expression of selectin ligands of the tumour cells can vary and that their selectin-binding pattern is probably influenced by the different environment of the tumour cells, as already shown by Koike et al (2004), who showed that oxygenation influences selectin-binding site expression. This difference in expression pattern is explained by the observation that transformational effects, such as growth to high cell densities, 2D vs 3D growth or hypoxia, lead to an alteration of carbohydrate patterns between tumour cells grown in vivo and in vitro (Warren et al, 1978).…”

Carbohydrate‐mediated cell adhesion in cancer metastasis and angiogenesis

“…The increment in the expression of these genes occurs in the advanced stage of cancers and partially explains the enhancement of sialyl Lewis a/x in advanced cancers. 39) The enhanced expression of sialyl Lewis a/x , however, is already obvious in the early stages of cancers.…”

Introducing α(1,2)‐linked fucose into hepatocarcinoma cells inhibits vasculogenesis and tumor growth

“…[6][7][8][9] To assess vascularization, frozen sections of the tumors were stained for the mouse CD31, an endothelial cell determinant and examined by fluorescence microscopy. As shown in Figure 5a, there is a striking difference between the tumors with respect to the vascular architecture and microvessel density.…”

“…3 Besides, several lines of evidence from selectin-deficient mice studies pointed out the contribution of selectins in facilitating tumor growth and progression. 4,5 In particular, E-selectin and its sLex-containing glycoconjugate ligands have been shown to be involved in the essential events of tumor angiogenesis, [6][7][8][9] including the fact that coinjection of tumor cells expressing high level of sLe x together with endothelial cells constitutively expressing E-selectin, has been found to promote tumor angiogenesis and growth. 10 We have recently succeeded in strongly blocking the expression of sLex on digestive cancer cells by a virally-delivered a(1,2)-fucosyltransferase-I (FUT1).…”