The conventional view of tumour vascularization is that tumours acquire their blood supply from neighbouring normal stroma. Additional methods of tumour vascularization such as intussusceptive angiogenesis, vasculogenic mimicry, vessel co-option and vasculogenesis have been demonstrated to occur. However, the origin of the endothelial cells and pericytes in the tumour vasculature is not fully understood. Their origin from malignant cells has been shown indirectly in lymphoma and neuroblastoma by immuno-FISH experiments. It is now evident that tumours arise from a small population of cells called cancer stem cells (CSCs) or tumour initiating cells. Recent data suggest that a proportion of tumour endothelial cells arise from cancer stem cells in glioblastoma. This was demonstrated both in vitro and in vivo. The analysis of chromosomal abnormalities in endothelial cells showed identical genetic changes to those identified in tumour cells. However, another report contradicted these results from the earlier studies in glioblastoma and had shown that CSCs give rise to pericytes and not endothelial cells. The main thrust of this review is the critical analysis of the conflicting data from different studies and the remaining questions in this field of research. The mechanism by which this phenomenon occurs is also discussed in detail. The transdifferentiation of CSCs to endothelial cells/pericytes has many implications in the progression and metastasis of the tumours and hence it would be a novel target for antiangiogenic therapy.

Angiogenesis is required for tumor growth and metastasis. The conventional view of tumour angiogenesis is that tumours get their blood supply from the neighbouring normal stroma. However, recently the origin of tumour endothelial cells or pericytes in part has been shown to be derived from cancer stem cells (CSC) in glioma. The spread of ovarian cancer (SOC) is different and the origin of endothelial cells in the tumor is not known. Using spheroids as an in vitro model (which is enriched for CSC), we have evaluated the role of CSC in primary malignant cells (PMCs) from patients with serous adenocarcinoma of ovary (n = 30) cultured under endothelial conditions. The expression of endothelial markers (CD31, CD105, and CLEC14a) was evaluated by flow cytometry. Further, the ability of CSC to express endothelial markers under appropriate growth conditions was also evaluated with Bevacizumab (Avastin) or Cediranib which antagonize VEGF or its receptor (VEGFR2) respectively. In addition, functional assays such as uptake of Dil labelled acetylated low density lipoprotein (Dil-ac-LDL) and expression of endothelial nitric oxide synthase (e-NOS) was performed to assess the endothelial phenotype. The localization of tumour blood vessels and CSC in primary ovarian tumors was examined by double immunohistochemistry of CD31/CD105/CLEC14a and ALDH1a1. Primary malignant cells (n = 30) grown in endothelial growth medium (EGM) showed significantly higher expression of CD105 (mean 20.8%, p = 0.001) and CLEC14a (mean 5.3%, p = 0.012) and a co-expression of CD105/CLEC14a (mean 1.6%, p = 0.012) than that of control (mean, 12.5%, 2.5% and 0.95% respectively). The co-expression of ALDH1a1 with endothelial markers, CD31, (mean, 1.58%), CD105, (mean 0.7%), CLEC14a (mean 0.44%) in primary malignant cells (n = 5), denovo, suggest that there is a small proportion of cells which are in transit to form endothelial cells. When the primary malignant cells were grown as spheroids in endothelial conditions in the presence or absence of Avastin (1 μg/μl), there was reduction in the expression of CD105 (mean, 12.5% (EGM) and 7.9% (Avastin), P = 0.056) and CLEC14a (mean. 5.5% (EGM) and 1.5% (Avastin), P = 0.04). However, when the spheroids were cultured in presence of cediranib (10 nM), the expression of CD105 was not reduced (Mean, 2.53% (EGM) and 4% (cediranib). The cells grown in endothelial conditions showed uptake of Dil-ac-LDL (n = 3) and expressed e-NOS (n = 3), confirming their endothelial phenotype. The double immunostaining with ALDH1a1 and CD31/CD105 demonstrated that the blood vessels were in proximity to ALDH1A1+ cells in primary serous adenocarcinoma of the ovary (n = 5). These results suggest that a proportion of endothelial cells (probably 20%) could be derived from CSC in serous ovarian carcinoma and the VEGF pathway has an important role. This property of CSC to contribute to tumour angiogenesis can be inhibited. Citation Format: Syama Krishna Priya, Rohit P. Nagare, V S. Sneha, C Sidhanth, S Bindhya, P Manasa, Trivadi S. Ganesan. Tumor angiogenesis and cancer stem cells in serous adenocarcinoma of the ovary. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3330.