Abstract
BackgroundConventional 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.MethodsWe 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.ResultsWe 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.ConclusionsThese 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.
Highlights
Conventional models of carcinogenesis suggest that tumors recruit blood vessel formation from normal host tissues
Conventional models of carcinogenesis posit that tumor vasculature develops in response to factors produced by neoplastic tissues that elicit the sprouting of new blood vessels from surrounding pre-existing “normal” vasculature while promoting the recruitment and differentiation of bone marrow-derived vascular progenitor cells [1]
We focused on generating xenografts within the murine liver in order to study tumor vasculature in the microenvironment most relevant for human Hepatocellular carcinoma (HCC) pathobiology
Summary
Conventional models of carcinogenesis suggest that tumors recruit blood vessel formation from normal host tissues. Conventional models of carcinogenesis posit that tumor vasculature develops in response to factors produced by neoplastic tissues (such as vascular endothelial growth factor) that elicit the sprouting of new blood vessels from surrounding pre-existing “normal” vasculature while promoting the recruitment and differentiation of bone marrow-derived vascular progenitor cells [1]. This concept has recently been challenged by the cancer stem cell (CSC) model, which suggests that tumors are sustained by a distinct population of Hepatocellular carcinoma (HCC) is one of the five most common cancers worldwide, and the third most common cause of cancer death [5]. Pathways and mediators regulating angiogenesis and neovascularization are recognized to play an important role in the development and progression of HCC and have emerged as attractive targets in the development of new therapies against this lethal disease [9]
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