PNAS：科学家发现新型的癌症开关—凝集素

2014年9月17日 讯    癌症发展过程中，肿瘤细胞可以“装饰”其表面的聚糖类化合物，肿瘤细胞表面的聚糖类化合物和健康细胞表面的并不一样。

近日，发表在国际杂志PNAS上的一篇研究报告中，来自加利福尼亚大学的研究人员表示，癌细胞聚糖分子上的唾液酸能够与免疫细胞发生作用来改变肿瘤细胞的迟发反应，即抑制或者促进肿瘤发展。

研究者Ajit Varki说道，癌细胞表面的聚糖分子可以促进或者抑制肿瘤的发展，我们的研究揭开了癌症发生的复杂性，也为开发新型策略战胜癌症提供了研究数据。中性白细胞和巨噬细胞小亚群中名为凝集素的受体可以结合肿瘤细胞表面的唾液酸，依据癌症处于的阶段和肿瘤的模式，研究人员表示，凝集素和肿瘤凝集素受体的相互作用或许会产生相反的结果。

在初期发展阶段，癌细胞会通过唾液酸帽状聚糖分子来保护自身不被消灭，但是一旦肿瘤建立了稳固的地位，其后期的生长就会通过巨噬细胞产生的凝集素来抑制。研究者表示，低浓度的抗体会促进癌细胞生长，而高浓度则会抑制其生长。事实上免疫系统就扮演着促进或者抑制癌症发展的角色，这依赖于癌症的情况及其处于的阶段，这对于临床上开发相应的药物非常重要。

最后研究者Ann Schwartz表示，凝集素或许可以有效抑制癌症的早期发展，文章中我们对332名肺癌患者进行研究，评估是否其机体中存在天然的凝集素缺失，从而减少了同肿瘤细胞表面唾液酸的结合，后期研究人员还需要进行更多深入的研究来揭示凝集素介导的促肿瘤或抑制肿瘤的开关，这对于开发治疗癌症的靶向疗法将非常关键。（生物谷Bioon.com）

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doi:10.1073/pnas.1409580111
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Engagement of myelomonocytic Siglecs by tumor-associated ligands modulates the innate immune response to cancer

Heinz L甀戀氀椀愀,1, Oliver M. T. Pearcea,1, Flavio Schwarza, Shoib S. Siddiquia, Lingquan Denga, Michal A. Stanczaka, Liwen Denga, Andrea Verhagena, Patrick Secresta, Chrissy Luskb, Ann G. Schwartzb, Nissi M. Varkia, Jack D. Buic, and Ajit Varkia,2

Certain pathogenic bacteria are known to modulate the innate immune response by decorating themselves with sialic acids, which can engage the myelomonocytic lineage inhibitory receptor Siglec-9, thereby evading immunosurveillance. We hypothesized that the well-known up-regulation of sialoglycoconjugates by tumors might similarly modulate interactions with innate immune cells. Supporting this hypothesis, Siglec-9–expressing myelomonocytic cells found in human tumor samples were accompanied by a strong up-regulation of Siglec-9 ligands. Blockade of Siglec-9 enhanced neutrophil activity against tumor cells in vitro. To investigate the function of inhibitory myelomonocytic Siglecs in vivo we studied mouse Siglec-E, the murine functional equivalent of Siglec-9. Siglec-E–deficient mice showed increased in vivo killing of tumor cells, and this effect was reversed by transgenic Siglec-9 expression in myelomonocytic cells. Siglec-E–deficient mice also showed enhanced immunosurveillance of autologous tumors. However, once tumors were established, they grew faster in Siglec-E–deficient mice. In keeping with this, Siglec-E–deficient macrophages showed a propensity toward a tumor-promoting M2 polarization, indicating a secondary role of CD33-related Siglecs in limiting cancer-promoting inflammation and tumor growth. Thus, we define a previously unidentified impact of inhibitory myelomonocytic Siglecs in cancer biology, with distinct roles that reflect the dual function of myelomonocytic cells in cancer progression. In keeping with this, a human polymorphism that reduced Siglec-9 binding to carcinomas was associated with improved early survival in non–small-cell lung cancer patients, which suggests that Siglec-9 might be therapeutically targeted within the right time frame and stage of disease.

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有待深入研究，希望尽快打开抑制开关。