K. Takabe1, E. Katsuta1, M. G. Dozmorov2, A. L. Olex5, S. N. Hochwald1, L. J. Fernandez4 1Roswell Park Cancer Institute,Department Of Surgical Oncology,Buffalo, NY, USA 2Virginia Commonwealth University,Department Of Biostatistics,Richmond, VA, USA 3Roswell Park Cancer Institute,Gastrointestinal Surgery, Department Of Surgical Oncology,Buffalo, NY, USA 4Virginia Commonwealth University,Division Of Surgical Oncology, Department Of Surgery,Richmond, VA, USA 5Virginia Commonwealth University,Wright Center For Clinical And Translational Research,Richmond, VA, USA
Introduction: Pancreatic ductal adenocarcinoma (PDAC) is known for its hypovascularity and hypoxic microenvironment compared to other types of cancers. Angiogenesis, generation of new blood vessels, is one of the hallmarks of cancer and is well established to contribute to tumorigenesis. However, some types of tumors with a rich vascular network have excellent survival. A phase 3 study showed no improvement in outcome with bevacizumab added to standard chemotherapy for PDAC. Therefore, we hypothesized that PDAC with relatively high vascularity may be associated with improved survival.
Methods: Using Level 3 gene expression data from The Cancer Genome Atlas (TCGA), we performed survival analysis of genes related to angiogenesis, vascular endothelial cells and hypoxia. Data for n=178 patients was log2-transformed and analyzed using Kaplan-Meyer log-rank test. For each gene of interest, the cutoff was determined by automated scanning 25%-75% gene expression interval and selecting the threshold yielding the lowest p-value.
Results: First, we verified our dataset by confirming whether high expression of angiogenic factor and vascular signals associate with survival in colon cancer, which is known to respond to bevacizumab. High expression of angiogenic gene (VEGF-A) as well as marker gene for vascular endothelial cells (CD31) was associated with poor overall survival (OS) in colon cancer. In the PDAC cohort, the mean observation period was 451 days. High expression of CD31, which indicate presence of vascular endothelial cells, was significantly associated with better OS (p=0.019). Further, genetic markers of mature vessels, TIE1 and TIE2, which are endothelium-specific receptor tyrosine-kinases, and S1PR1, which play a critical role for acquisition of vascular stability, were all associated with better OS (p=0.008, 0.041, and 0.013, respectively). No angiogenic factors, VEGFs or Angiopoietins were associated with survival. Multivariate analysis using Cox proportional hazard regression demonstrated that residual tumor (R1, 2; p=0.020) and CD31 high expression (p=0.009) were the only independent factors that negatively impacted on OS. Additionally, CD31 expression demonstrated strongly positive correlation with not only vascular endothelial cell markers such as TAL1 (R=0.67), but also vascular stability related genes, such as JAM2 and CD93 (R=0.77 and 0.70), and vascular morphogenesis genes, RHOJ and ERG (R=0.74, 0.79). CD31 also demonstrated strong positive correlation with BCL6B (R=0.79), an anti-fibrogenic factor, which implies that less fibrosis in PDAC correlates with higher vascularity and better OS. Interestingly, there was no survival difference by expression of HIF1-alpha, an ischemia marker.
Conclusion: PDAC with mature blood vessels, detected by high expression of CD31, TIE1, TIE2 or S1PR1 have better overall survival, independent of the presence of hypoxia.