Authors' Affiliations: The Visual Systems Group, Divisions of Pediatric Ophthalmology and Developmental Biology; Division of Immunobiology, Cincinnati Children's Hospital Medical Center; Department of Ophthalmology, University of Cincinnati, Cincinnati, Ohio; Departments of Developmental and Molecular Biology, Surgery, Pathology, and MRC Centre for Reproductive Health, University of Edinburgh, UKAuthors' Affiliations: The Visual Systems Group, Divisions of Pediatric Ophthalmology and Developmental Biology; Division of Immunobiology, Cincinnati Children's Hospital Medical Center; Department of Ophthalmology, University of Cincinnati, Cincinnati, Ohio; Departments of Developmental and Molecular Biology, Surgery, Pathology, and MRC Centre for Reproductive Health, University of Edinburgh, UK.
Authors' Affiliations: The Visual Systems Group, Divisions of Pediatric Ophthalmology and Developmental Biology; Division of Immunobiology, Cincinnati Children's Hospital Medical Center; Department of Ophthalmology, University of Cincinnati, Cincinnati, Ohio; Departments of Developmental and Molecular Biology, Surgery, Pathology, and MRC Centre for Reproductive Health, University of Edinburgh, UK.
Cancer Res. 2014 Jun 1;74(11):2962-73. doi: 10.1158/0008-5472.CAN-13-2421. Epub 2014 Mar 17.
Oncogenic targets acting in both tumor cells and tumor stromal cells may offer special therapeutic appeal. Interrogation of the Oncomine database revealed that 52 of 53 human breast carcinomas showed substantial upregulation of WNT family ligand WNT7B. Immunolabeling of human mammary carcinoma showed that WNT7B immunoreactivity was associated with both tumor cells and with tumor-associated macrophages. In the MMTV-PymT mouse model of mammary carcinoma, we found tumor progression relied upon WNT7B produced by myeloid cells in the microenvironment. Wnt7b deletion in myeloid cells reduced the mass and volume of tumors due to a failure in the angiogenic switch. In the tumor overall, there was no change in expression of Wnt/β-catenin pathway target genes, but in vascular endothelial cells (VEC), expression of these genes was reduced, suggesting that VECs respond to Wnt/β-catenin signaling. Mechanistic investigations revealed that failure of the angiogenic switch could be attributed to reduced Vegfa mRNA and protein expression in VECs, a source of VEGFA mRNA in the tumor that was limiting in the absence of myeloid WNT7B. We also noted a dramatic reduction in lung metastasis associated with decreased macrophage-mediated tumor cell invasion. Together, these results illustrated the critical role of myeloid WNT7B in tumor progression, acting at the levels of angiogenesis, invasion, and metastasis. We suggest that therapeutic suppression of WNT7B signaling might be advantageous due to targeting multiple aspects of tumor progression.
在肿瘤细胞和肿瘤基质细胞中起作用的致癌靶点可能具有特殊的治疗吸引力。对 Oncomine 数据库的查询显示，53 个人类乳腺癌中有 52 个显示出 WNT 家族配体 WNT7B 的大量上调。对人乳腺肿瘤的免疫标记显示，WNT7B 免疫反应性与肿瘤细胞和肿瘤相关的巨噬细胞都有关。在 MMTV-PymT 乳腺癌小鼠模型中，我们发现肿瘤进展依赖于微环境中髓细胞产生的 WNT7B。髓细胞中 Wnt7b 的缺失由于血管生成开关的失败而减少了肿瘤的质量和体积。在肿瘤整体中，Wnt/β-连环蛋白通路靶基因的表达没有变化，但在血管内皮细胞（VEC）中，这些基因的表达减少，表明 VEC 对 Wnt/β-连环蛋白信号有反应。机制研究表明，血管生成开关的失败可能归因于 VEC 中 Vegfa mRNA 和蛋白表达的减少，Vegfa mRNA 是肿瘤中的一个来源，在缺乏髓系 WNT7B 的情况下是有限的。我们还注意到与巨噬细胞介导的肿瘤细胞侵袭减少相关的肺转移明显减少。总之，这些结果说明了髓系 WNT7B 在肿瘤进展中的关键作用，作用于血管生成、侵袭和转移的水平。我们建议，由于靶向肿瘤进展的多个方面，抑制 WNT7B 信号可能具有优势。
