Introduction Galectin-3 is a galactoside-binding protein whose concentration is increased up to 31-fold in the bloodstream of patients with cancer including colorectal cancer. We have recently shown that circulating galectin-3 promotes metastasis. This effect of galectin-3 is partly due to its interaction with the transmembrane mucin protein MUC1 expressed by the tumour cells, leading to clustering of MUC1 and exposure of adhesion molecules that increases cancer cell heterotypic adhesion to vascular endothelium and cancer cell homotypic aggregation to form micro-tumour emboli. We also showed that circulating galectin-3 has another, as yet unidentified, MUC1-independent action that contributes to its promotion of metastasis.
Methods Cytokine release was assessed using a protein array that includes the 36 commonest human cytokines. Galectin-3–induced adhesion of MUC1-negative human colon cancer HCT116 and melanoma ACA19- cells to microvascular lung endothelial cells (HMVECs) were assessed.
Results The presence of galectin-3 at concentrations seen in sera of cancer patients increased the secretion of IL-6, sICAM-1, G-CSF and GM-CSF from cultured HMVECs in a galectin-3 dose- and time-dependent manner. A 117.67±13.25% (p<0.01), 37.84±11.89% (p<0.05), 100.33±14.55% (p<0.01) and 31.47±11.36% (p<0.05) increased secretion of IL-6, sICAM-1, G-CSF and GM-CSF from HMVECs to the culture medium were seen with 1 μg/ml galectin-3 after 24 hr. The culture supernatant from galectin-3-treated HMVECs increased adhesion of HCT116 (74.01±14.33%, p<0.05) and ACA19- (43±6.67%, p<0.05) cells to fresh HMVECs monolayers when compared to the supernatant from non-galectin-3 treated HMVECs. This effect was largely inhibited by the presence of a combination of neutralising antibodies against IL-6, ICAM-1, G-CSF and GM-CSF or the presence of galectin-3 inhibitor lactose. Treatment of HMVECs with galectin-3 increased the expressions of HMVEC cell surface adhesion molecules integrinαvβ1, E-selectin and ICAM-1 which was largely prevented by the presence of the four neutralising anti-cytokine antibodies in combination. Serum galectin-3 concentrations were seen to be correlated (p=0.045) with serum G-CSF (but not that of the other three cytokines) in colon cancer patients (n=50).
Conclusion Galectin-3, at concentrations found in the bloodstream of cancer patients, induces secretion of cytokines from the vascular endothelium that enhances cancer cell- endothelial adhesion as a result of up-regulation of the endothelial cell surface adhesion molecules. As cancer cell adhesion to blood vascular endothelium is an important step in metastasis, the secretion of those cytokines likely makes important contribution to galectin-3-mediated metastasis promotion.
Competing interests None declared.
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