Hypoxic Culture Induces Expression of Sialin, a Sialic Acid Transporter, and Cancer-Associated Gangliosides Containing Non–Human Sialic Acid on Human Cancer Cells

Abstract

Tumor hypoxia figures heavily in malignant progression by altering the intracellular glucose metabolism and inducing angiogenic factor production, thus, selecting and expanding more aggressive cancer cell clones. Little is known, however, regarding hypoxia-induced antigenic changes in cancers. We investigated the expression of N-glycolyl sialic acid (NeuGc)-G M2 , a cancer-associated ganglioside containing non-human sialic acid, NeuGc, in human cancers. Cancer tissues prepared from patients with colon cancers frequently expressed NeuGc-G M2 , whereas it was virtually absent in nonmalignant colonic epithelia. Studies on cultured cancer cells indicated that the non-human sialic acid was incorporated from culture medium. Hypoxic culture markedly induced mRNA for a sialic acid transporter, sialin, and this accompanied enhanced incorporation of NeuGc as well as N-acetyl sialic acid. Transfection of cells with sialin gene conferred accelerated sialic acid transport and induced cell surface expression of NeuGc-G M2 . We propose that the preferential expression of NeuGc-G M2 in cancers is closely associated with tumor hypoxia. Hypoxic culture of tumor cells induces expression of the sialic acid transporter, and enhances the incorporation of non-human sialic acid from the external milieu. A consequence of this is the acquisition of cancer-associated cell surface gangliosides, typically G M2 , containing nonhuman sialic acid (NeuGc), which is not endogenously synthesized through CMP-N-acetyl sialic acid hydroxylase because humans lack the gene for the synthetic enzyme. As hypoxia is associated with diminished response to radiotherapy and chemotherapy, NeuGc-G M2 is a potential therapeutic target for hypoxic cancer cells. (Cancer Res 2006; 66(6): 2937-45)

Characterization of the Antibody Response against NeuGcGM3 Ganglioside Elicited in Non-Small Cell Lung Cancer Patients Immunized with an Anti-Idiotype Antibody

“…The very small amounts of NeuGc conjugates detected in some human normal tissues appear to originate from exogenous sources (44,45). One explanation for the higher expression of NeuGccontaining gangliosides in some tumors is the recent demonstration that tumor hypoxia induces the transcription in the cells of a sialic acid transporter that facilitates the incorporation of NeuGc molecule into tumor gangliosides, as NeuGcGM2 (46). It is noteworthy that our previous preclinical studies proved that 1E10 mAb can behave as an immunogenic mimic, depending on the presence or absence of NeuGcGM3 ganglioside in the normal tissues of the immunized species (32).…”

Metabolism of Vertebrate Amino Sugars with N-Glycolyl Groups

“…As growing tumors are highly vascularized and characterized by high metabolism involving significantly increased macropinocytosis (83)(84)(85), these malignant cells are likely taking up more circulating Neu5Gc as compared with surrounding normal human cells at a time. Also, hypoxia up-regulates gene expression of the lysosomal sialin transporter, which releases free sialic acids into the cytosol (86). Together such mechanisms likely explain why Neu5Gc was suggested to be a tumorspecific antigen in the past when less sensitive detection methods did not yet reveal its lower abundance on normal human cells (24,26,64).…”

The role of the sialic acid in monitoring the evolution of malignant melanoma. From murine models to human research

“…Sialic acids are overexpressed as part of gangliosides in several malignancies and their involvement in the malignant cell behavior has been previously reported (44,45). The lack of expression of NeuGc in mouse tumor cells suggests that the silencing of the CMAH gene is an important step in the cell transformation process in this species (42).…”