Yin Jun, Hashimoto Ayako, Izawa Mineko, Miyazaki Keiko, Chen Guo-Yun, Takematsu Hiromu, Kozutsumi Yasunori, Suzuki Akemi, Furuhata Kimio, Cheng Feng-Leng, Lin Chun-Hung, Sato Chihiro, Kitajima Ken, Kannagi Reiji
Department of Molecular Pathology, Aichi Cancer Center, Nagoya, Japan.
Cancer Res. 2006 Mar 15;66(6):2937-45. doi: 10.1158/0008-5472.CAN-05-2615.
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.
肿瘤缺氧通过改变细胞内葡萄糖代谢和诱导血管生成因子产生，在恶性进展中起着重要作用，从而选择并扩增更具侵袭性的癌细胞克隆。然而，关于缺氧诱导癌症中的抗原变化却知之甚少。我们研究了N-羟乙酰神经氨酸（NeuGc）-神经节苷脂GM2（一种含有非人类唾液酸NeuGc的癌症相关神经节苷脂）在人类癌症中的表达。结肠癌患者制备的癌组织经常表达NeuGc-GM2，而在非恶性结肠上皮中几乎不存在。对培养癌细胞的研究表明，非人类唾液酸是从培养基中摄取的。缺氧培养显著诱导唾液酸转运体sialin的mRNA表达，这伴随着NeuGc以及N-乙酰唾液酸摄取的增加。用sialin基因转染细胞可加速唾液酸转运，并诱导NeuGc-GM2在细胞表面表达。我们提出，NeuGc-GM2在癌症中的优先表达与肿瘤缺氧密切相关。肿瘤细胞的缺氧培养诱导唾液酸转运体的表达，并增强从外部环境摄取非人类唾液酸。其结果是获得了癌症相关的细胞表面神经节苷脂，通常是含有非人类唾液酸（NeuGc）的GM2，由于人类缺乏合成酶基因，它不是通过CMP-N-乙酰唾液酸羟化酶内源性合成的。由于缺氧与放疗和化疗反应减弱有关，NeuGc-GM2是缺氧癌细胞的潜在治疗靶点。
