Tumor-Associated Endothelial Cells with Cytogenetic Abnormalities

Abstract

Tumor angiogenesis is necessary for solid tumor progression and metastasis. Tumor blood vessels have been shown to differ from normal counterparts, for example, by changes in morphology. An important concept in tumor angiogenesis is that tumor endothelial cells are assumed to be genetically normal, although these endothelial cells are structurally and functionally abnormal. However, we hypothesized that given the phenotypic differences between tumor and normal blood vessels, there may be genotypic alterations as well. Mouse endothelial cells were isolated from two different human tumor xenografts, melanoma and liposarcoma, and from two normal endothelial cell counterparts, skin and adipose. Tumor-associated endothelial cells expressed typical endothelial cell markers, such as CD31. They had relatively large, heterogeneous nuclei. Unexpectedly, tumor endothelial cells were cytogenetically abnormal. Fluorescence in situ hybridization (FISH) analysis showed that freshly isolated uncultured tumor endothelial cells were aneuploid and had abnormal multiple centrosomes. The degree of aneuploidy was exacerbated by passage in culture. Multicolor FISH indicated that the structural chromosomal aberrations in tumor endothelial cells were heterogeneous, indicating that the cytogenetic alterations were not clonal. There was no evidence of human tumor-derived chromosomal material in the mouse tumor endothelial cells. In marked contrast, freshly isolated normal skin and adipose endothelial cells were diploid, had normal centrosomes, and remained cytogenetically stable in culture even up to 20 passages. FISH analysis of tumor sections also showed endothelial cell aneuploidy. We conclude that tumor endothelial cells can acquire cytogenetic abnormalities while in the tumor microenvironment.

Angiogenesis in a human neuroblastoma xenograft model: mechanisms and inhibition by tumour-derived interferon-γ

“…However, evaluation of efficacy of potential angiogenic inhibitors requires a better understanding of the in vivo angiogenic potential of NB cells and of their contribution to vasculogenic mimicry (Folberg and Mantiotis, 2004). Endothelial cells showing the same genetic alteration as tumour cells have recently been found in human tumours (Gunsilius, 2003;Hida et al, 2004;Streubel et al, 2004), supporting the hypothesis that this could be a general phenomenon.…”

“…As microvascular endothelial cells may exhibit the same genetic aberrations as tumour cells (Gunsilius, 2003;Hida et al, 2004;Streubel et al, 2004), we first analysed whether the tumour vasculature in ACN/neo and ACN/IFN-g xenografts contained tumour-derived endothelial cells. As shown in Figure 2A, microvessels of both human and murine origin were found in both xenografts.…”

A liposomal delivery system that targets liver endothelial cells based on a new peptide motif present in the ApoB-100 sequence

“…Liver endothelial cells (Liver ECs) were isolated as previously described (Hida et al, 2004, Akino et al, 2009. Briefly, the liver of a female KSN mouse was excised.…”

Deciphering the Key Features of Malignant Tumor Microenvironment for Anti-cancer Therapy

“…The CSC-differentiated tumor endothelial cells are important in tumor neovascularization and the genesis of TME [72][73][74][75]. Third, CSCs release various stem cell factors that induce normal stromal cells to become cancer-associated stromal cells, such as cancer-associated fibroblasts (CAFs) [1] and tumor endothelial cells (TEMs) [76], and to recruit immune cells from bone marrow and blood to the tumor tissue. Normal macrophages are converted into tumor-associated macrophages (TAMs) in the TME [77].…”

“…The CAFs can release growth factors, cytokines, and chemokines, and are important tumorassociated stromal cells in the genesis of the TME [1]. The TAMs contribute to the generation of the TME [77], and TECs also are important in tumor neovascularization and the formation of the vascular stem cell niche [76].…”