ID3, a transcription regulator, has been shown to contribute to the aggressive spread of certain cancers by facilitating the generation of tumor blood vessels. Tumor vascular cells characterized as CD133+ endothelial stem/progenitor cells are associated with poor prognosis in lung cancer. Previously, we have shown that ID3 overexpression reprograms adult endothelial cells to acquire vascular stem markers including CD133. However, little is known regarding the molecular contribution of ID3 to tumor vascular reprogramming and how this may impact the aggressive growth of lung cancer. In the current project, we evaluated ID3 mediated vascular reprogramming upon polychlorinated biphenyl (PCB) exposure. This idea is consistent with the literature, which shows that PCBs accumulate in the human lung; PCBs produce pathological vascular remodeling; high levels of PCBs are found in human lung tissue; and epidemiological studies associating lung toxicity with PCBs. Recent studies identify PCB153 as one of the largest contributors for total PCB body burden in humans. Using human lung endothelial and smooth muscle cells, we exposed ID3 overexpressing and vector control cells to PCB153. We observed a significant increase in cell proliferation as determined by the BrdU incorporation assay and FACS analysis. Similarly, a 3D HuBiogel model, which mimics in vivo conditions, showed a significant increase in size and number of vascular spheres upon PCB153 treatment. Pluripotent vascular stem cells showed the loss of VE-cadherin and gain of MMP9, N-cadherin, and vimentin, which are markers of endothelial-mesenchymal transition. RNA-seq analysis showed that PCB153 exposed vascular stem cells had a significant increase in lncRNAs MALAT1 (Metastasis Associated Lung Adenocarcinoma Transcript 1) and HIF1A-AS2. A combination of ChIP-seq and transcriptome analysis identified significantly up-regulated genes (HES1, WEE1, E2F2) and down-regulated genes (SMURF2, CDKN2C, SH2B3). Our findings suggest that ID3 mediates vascular reprogramming through transcriptional regulation of pluripotency factors and epigenetic regulating lncRNAs. ID3 may also serve as a novel diagnostic/prognostic indicator for evaluating chemical-induced vascular reprogramming. Its potential application may be useful in identifying individuals who are susceptible to aggressive lung cancer from exposure to vascular toxicants.
Citation Format: Mayur Doke, Jayanta Das, Quentin Felty. ID3 mediated vascular reprogramming of PCB exposed endothelial cells and its potential contribution to lung tumorigenicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5052.