Thompson Emma J, Dorward Emma L, Jurrius Kristyn, Nataren Nathalie, Tondl Markus, Myo Min Kay K, Cockshell Michaelia P, Fouladzadeh Anahita, Toubia John, DeNichilo Mark, Merino Delphine, Bonder Claudine S
Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia.
ACRF Cancer Genomics Facility, Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia.
Mol Oncol. 2025 Sep;19(9):2537-2556. doi: 10.1002/1878-0261.70027. Epub 2025 Mar 21.
Solid tumours routinely access the blood supply by promoting endothelium-dependent angiogenesis; but tumour vasculature can also be formed by cancer cells themselves via vasculogenic mimicry (VM). Investigation of the gene expression profile during the early stages of VM formation by MDA-MB-231-LM2 breast cancer cells identified the transcriptional regulator inhibitor of DNA binding 1 (ID1) to be elevated ~ 10-fold within the first 2 hours. This role for ID1 in promoting VM was supported by ID1 genetic knockdown or chemical inhibition interrupting VM formation by MDA-MB-231-LM2 (breast) and BxPC-3 (pancreatic) cancer cells. More specifically, reducing ID1 lowered cancer cell expression of endothelial cell genes (e.g. CDH5, TIE2) and production of pro-angiogenic proteins (e.g. VEGF, CD31, MMP9 and IL-8). In silico analysis of MDA-MB-231 cells engrafted into mice identified elevated ID1 expression in cancer cells that had metastasised to the lungs or liver, and an enrichment of pro-angiogenic genes. Additionally, Id1 knockdown in 4T1.13 murine breast cancer cells demonstrated reduced tumour growth and metastasis in vivo. Taken together, this study further implicates ID1 in a vascular program within cancer cells that supports disease progression.
实体瘤通常通过促进内皮细胞依赖性血管生成来获取血液供应；但肿瘤血管系统也可由癌细胞自身通过血管生成拟态（VM）形成。对MDA-MB-231-LM2乳腺癌细胞VM形成早期阶段的基因表达谱进行研究，发现转录调节因子DNA结合抑制因子1（ID1）在最初2小时内升高了约10倍。ID1基因敲低或化学抑制可中断MDA-MB-231-LM2（乳腺癌）和BxPC-3（胰腺癌）癌细胞的VM形成，这支持了ID1在促进VM中的作用。更具体地说，降低ID1可降低癌细胞中内皮细胞基因（如CDH5、TIE2）的表达以及促血管生成蛋白（如VEGF、CD31、MMP9和IL-8）的产生。对移植到小鼠体内的MDA-MB-231细胞进行的计算机分析发现，转移到肺或肝脏的癌细胞中ID1表达升高，且促血管生成基因富集。此外，4T1.13小鼠乳腺癌细胞中的Id1敲低表明体内肿瘤生长和转移减少。综上所述，本研究进一步表明ID1参与支持疾病进展的癌细胞血管生成程序。
