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Open Access Highly Accessed Research article

Endothelial cells do not arise from tumor-initiating cells in human hepatocellular carcinoma

Anand Ghanekar124*, Sharif Ahmed1, Kui Chen1 and Oyedele Adeyi3

Author Affiliations

1 Toronto General Research Institute, University Health Network, Toronto, ON, Canada

2 Department of Surgery, University Health Network, Toronto, ON, Canada

3 Department of Pathology, University Health Network, Toronto, ON, Canada

4 Toronto General Hospital, University Health Network, NCSB 11C-1227, 585 University Avenue, Toronto, ON M5G 2N2, Canada

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BMC Cancer 2013, 13:485  doi:10.1186/1471-2407-13-485

Published: 20 October 2013

Abstract

Background

Conventional models of carcinogenesis suggest that tumors recruit blood vessel formation from normal host tissues. This concept has recently been challenged by prominent studies of glioblastoma, which suggest that intratumoral endothelial cells (ECs) may arise from cancer stem cells/tumor-initiating cells (TICs). Hepatocellular carcinoma (HCC) is a common, highly vascularized tumor with few effective therapies, against which anti-angiogenic strategies are being actively explored. TICs are felt to play a role in HCC pathobiology, but their contributions to tumor vasculature have not been studied.

Methods

We examined human HCCs in settings that selected for tumor formation from functionally defined TICs, and in which the origin of intratumoral ECs from TICs as opposed to host tissues could be clearly distinguished. We generated HCC nodules in the livers of immunodeficient mice by intrasplenic injection of HCC cells from cell lines and patient specimens and studied the tumor ECs by immunohistochemistry for mouse and human markers. We then used immunohistochemistry for EC markers in combination with fluorescence in situ hybridization (FISH) for X and Y chromosomes to study the endothelium of recurrent HCC specimens resected from sex-mismatched liver allografts of patients who had undergone liver transplantation for HCC.

Results

We observed that all ECs in intrahepatic human HCC xenografts expressed mouse rather than human CD31. FISH analysis of recurrent HCCs resected from patients with sex-mismatched liver allografts revealed that all CD31+ and CD34+ intratumoral ECs originated from the donor allograft rather than the tumor.

Conclusions

These observations suggest that the vasculature of human HCC arises from normal host tissues rather than from TICs, supporting ongoing efforts to target angiogenesis in HCC as it is currently understood, and suggesting that the contribution of TICs to the vasculature of other cancers is disease-specific.

Keywords:
Hepatocellular carcinoma; Endothelial cell; Angiogenesis; Cancer stem cell; Tumor-initiating cell; CD31; CD34; Xenograft; Liver transplantation; Recurrence