Metcalf Kevin James, Hayward Mary-Kate, Berens Eric, Ironside Alastair J, Stashko Connor, Hwang E Shelley, Weaver Valerie M
Department of Surgery, University of California, San Francisco, CA, United States.
Knight Cancer Institute, Oregon Health and Science University, Portland, OR, United States.
Matrix Biol Plus. 2022 Mar 9;14:100105. doi: 10.1016/j.mbplus.2022.100105. eCollection 2022 Jun.
Tumors feature elevated sialoglycoprotein content. Sialoglycoproteins promote tumor progression and are linked to immune suppression via the sialic acid-Siglec axis. Understanding factors that increase sialoglycoprotein biosynthesis in tumors could identify approaches to improve patient response to immunotherapy. We quantified higher levels of sialoglycoproteins in the fibrotic regions within human breast tumor tissues. Human breast tumor subtypes, which are more fibrotic, similarly featured increased sialoglycoprotein content. Further analysis revealed the breast cancer cells as the primary cell type synthesizing and secreting the tumor tissue sialoglycoproteins and confirmed that the more aggressive, fibrotic breast cancer subtypes expressed the highest levels of sialoglycoprotein biosynthetic genes. The more aggressive breast cancer subtypes also featured greater infiltration of immunosuppressive , , and -pos myeloid cells, indicating that triple-negative breast tumors had higher expression of both immunosuppressive Siglec receptors and their cognate ligands. The findings link sialoglycoprotein biosynthesis and secretion to tumor fibrosis and aggression in human breast tumors. The data suggest targeting of the sialic acid-Siglec axis may comprise an attractive therapeutic target particularly for the more aggressive HER2+ and triple-negative breast cancer subtypes.
肿瘤的特征是唾液酸糖蛋白含量升高。唾液酸糖蛋白促进肿瘤进展，并通过唾液酸-Siglec轴与免疫抑制相关。了解增加肿瘤中唾液酸糖蛋白生物合成的因素可以确定改善患者对免疫疗法反应的方法。我们定量分析了人类乳腺肿瘤组织纤维化区域中更高水平的唾液酸糖蛋白。纤维化程度更高的人类乳腺肿瘤亚型同样具有增加的唾液酸糖蛋白含量。进一步分析表明，乳腺癌细胞是合成和分泌肿瘤组织唾液酸糖蛋白的主要细胞类型，并证实侵袭性更强、纤维化程度更高的乳腺癌亚型表达唾液酸糖蛋白生物合成基因的水平最高。侵袭性更强的乳腺癌亚型还表现出免疫抑制性、和阳性髓样细胞的浸润增加，表明三阴性乳腺癌肿瘤中免疫抑制性Siglec受体及其同源配体的表达更高。这些发现将唾液酸糖蛋白的生物合成和分泌与人类乳腺肿瘤的纤维化和侵袭性联系起来。数据表明，靶向唾液酸-Siglec轴可能是一个有吸引力的治疗靶点，特别是对于侵袭性更强的HER2+和三阴性乳腺癌亚型。
