Aberrant fucosylation enables breast cancer clusterin to interact with dendritic cell-specific ICAM-grabbing non-integrin (DC-SIGN)

Abstract

Clusterin is a glycoprotein able to mediate different physiological functions such as control of complement activation, promotion of unfolded protein clearance and modulation of cell survival. Clusterin is overexpressed in many types of cancers and a large body of evidence suggests that it promotes carcinogenesis and tumor progression. We have previously described a novel clusterin glycoform present in human semen, but not in serum, highly enriched in terminal fucose motifs. Here we show that human luminal breast cancer (LBC) clusterin also bears terminal fucosylated glycans, conferring clusterin the ability to interact with DC-SIGN, a C-type lectin receptor expressed by myeloid cells. This clusterin glycosylation pattern was absent or diminished in non-involved juxtatumoral tissue, suggesting that fucosylated clusterin might represent a cancer associated glycoform. We also found that DC-SIGN is expressed by luminal breast cancer intratumoral macrophages. Moreover, experiments performed in vitro using semen fucosylated clusterin and monocyte derived macrophages showed that the interaction of semen clusterin with DC-SIGN promoted a proangiogenic profile, characterized by a high production of VEGF, IL-8 and TNF-α. Our results reveal an unexpected complexity on the structure and function of secretory clusterin produced by tumors and suggest that fucosylated clusterin produced by luminal breast cancer cells might play a role in tumor progression by promoting the release of pro-angiogenic factors by intratumoral macrophages.

TSTA3 facilitates esophageal squamous cell carcinoma progression through regulating fucosylation of LAMP2 and ERBB2

“…The former one formed α-1,6-fucosylation, the main type of N-fucosylation which is under the charge of fucosyltransferases 8 (Fut8) transferring GDP-L-fucose to GlcNAc residue 35 . The latter one formed α-1,2-fucosylation or α-1,3/4-fucosylation which is under the charge of Fut1-2 or Fut3-7/9-11 transferring GDP-L-fucose to terminal galactose or acetyl glucosamine residue 36 . Moreover, core fucosylation and α-1,2-fucosylation can be specifically bound and recognized by LCA and UEA-I lectin respectively 37 .…”

Glycosylation of Cancer Extracellular Vesicles: Capture Strategies, Functional Roles and Potential Clinical Applications

“…An additional example of relevant lectins of the immune system is the dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), which is present in macrophages. The interaction between this lectin and fucosylated glycans promotes tumor evasion from the immune response in breast cancer [ 64 ].…”

Cracking the Breast Cancer Glyco-Code through Glycan-Lectin Interactions: Targeting Immunosuppressive Macrophages

“…Other abnormal glycans expressed by BC cells have been reported to modulate macrophages [ 37 , 46 ]. Merlotti et al reported an increase in fucosylated clusterins with terminal sialylation in BC tissues [ 77 ]. Clusterins are highly glycosylated glycoproteins, being one of the most prominent extracellular chaperones, involved in scavenging and clearance events [ 78 ].…”