Human Hepatocellular Carcinoma Tumor–derived Endothelial Cells Manifest Increased Angiogenesis Capability and Drug Resistance Compared with Normal Endothelial Cells

Abstract

Purpose: Increasing evidence indicates that tumor-derived endothelial cells (TEC) possess a distinct and unique phenotype compared with endothelial cells (NEC) from adjacent normal tissue and may be able to acquire resistance to drugs. The aim of this study was to investigate the angiogenesis activity and response to drug treatment of TECs and NECs derived from human hepatocellular carcinoma (HCC). Experimental Design: TECs or NECs were isolated from HCC or adjacent normal liver tissue using anti-CD105 antibody coupled to magnetic beads. The phenotypic and functional properties of endothelial cells were characterized by testing the expression of CD105, CD31, CD144, vascular endothelial growth factor receptor-1, vascular endothelial growth factor receptor-2, and von Willebrand factor, and the ability of DiIAc-LDL-uptake and tube formations. + TECs acquired more resistance to Adriamycin, 5-fluorouracil, and sorafenib than CD105 + NECs and HUVECs. Conclusions: TECs possessed enhanced angiogenic activity and resistance to chemotherapeutic drugs and an angiogenesis inhibitor, and may provide a better tool for studying tumor angiogenesis and antiangiogenesis drugs in HCC.

Molecular Imaging of Changes in the Prevalence of Vascular Endothelial Growth Factor Receptor in Sunitinib-Treated Murine Mammary Tumors

“…Thus, it appears that tumor endothelium that arises from the host vasculature after prolonged treatment with different VEGF-and VEGFR-targeting drugs can expand despite continuous treatment with VEGFR-targeting drugs. Although such resistance might depend on multiple mechanisms (37,38), it is tempting to speculate that tumor endothelium that reemerges from the drug-resistant host vasculature that is resistant to VEGF-and VEGFR-targeting drugs is cured from the addiction to VEGF and VEGFR signaling and can engage alternative survival mechanisms.…”

Suicidal gene therapy in the effective control of primary human hepatocellular carcinoma as monitored by noninvasive bioimaging

“…28 However, a recent report suggests that tumor-derived endothelial cells are biologically different from normal endothelial cells in that they have acquired greater resistance to 5-FU. 39 Thus, it is anticipated that the transduction of tumor-derived endothelial cells may enhance the bystander effect by delivering more 5-FU to the tumor cells. This could explain the observation by Ram et al 40 whereby researchers reported that b-galpositive endothelial cells were detected in the intracerebral 9 l glioma mouse model, which was indicated to enhance the therapeutic efficacy.…”

Infantile Hemangiomas: A Disease Model in the Study of Vascular Development, Aberrant Vasculogenesis and Angiogenesis

“…These cells were also relatively resistant to chemotherapeutic drugs including adriamycin and 5-fluorouracil, and the antiangiogenic drug sorafenib. Tumor endothelial cells share many of the same characteristics of HemECs, and further research comparing the similarities and differences between the two cell types may give insight both into the origin of IHs and the unique properties of tumor endothelial cells (Xiong et al, 2009). Interestingly, Dudley and colleagues have recently reported that tumor endothelial cells isolated from a transgenic mouse model in which the mice develop prostate adenocarcinoma at puberty demonstrate some of the features of mesenchymal stem cells.…”