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 non-human
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.