Inhibitor of DNA binding-1 is a key regulator of cancer cell vasculogenic mimicry.

Abstract

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.