Precancerous Stem Cells Can Serve As Tumor Vasculogenic Progenitors

Tumor neo-vascularization is critical for tumor growth, invasion and metastasis, which has been considered to be mediated by a mechanism of angiogenesis. However, histopathological studies have suggested that tumor cells might be the progenitor for tumor vasculature. Recently, we have reported that the precancerous stem cells (pCSCs) representing the early stage of developing cancer stem cells (CSCs), have the potential for both benign and malignant differentiation. Therefore, we investigated whether pCSCs serve as progenitors for tumor vasculogenesis. Herein, we report that in the pCSC-derived tumors, most blood vessels were derived from pCSCs. Some pCSCs constitutively expressed vasculogenic receptor VEGFR-2, which can be up-regulated by hypoxia and angiogenesis-promoting cytokines, such as GM-CSF, Flt3 ligand, and IL-13. The pCSCs are much more potent in tumor vasculogenesis than the differentiated tumor monocytic cells (TMCs) from the same tumor, which had comparable or even higher capacity to produce some vascular growth factors, suggesting that the potent tumor vasculogenesis of pCSCs is associated with their intrinsic stem-like property. Consistently tumor vasculogenesis was also observed in human cancers such as cervical cancer and breast cancer and xenograft lymphoma. Our studies indicate that pCSCs can serve as tumor vasculogenic stem/progenitor cells (TVPCs), and may explain why anti-angiogenic cancer therapy trials are facing challenge.

肿瘤新生血管生成（Tumor neo-vascularization）对肿瘤的生长、侵袭与转移至关重要，该过程曾被认为由血管生成（angiogenesis）机制介导。然而，组织病理学研究提示肿瘤细胞可能是肿瘤脉管系统的祖细胞来源。本团队此前报道，癌前干细胞（precancerous stem cells, pCSCs）作为癌症干细胞（cancer stem cells, CSCs）发育的早期阶段，兼具良性与恶性分化潜能。因此本研究旨在探究pCSCs是否可作为肿瘤血管发生（vasculogenesis）的祖细胞。本文报道，在pCSCs诱导生成的肿瘤中，绝大多数血管均源自pCSCs。部分pCSCs可组成性表达血管发生受体VEGFR-2，该受体的表达可因缺氧及促血管生成细胞因子（如GM-CSF、Flt3配体、IL-13）而上调。相较于同一肿瘤来源的分化型肿瘤单核细胞（tumor monocytic cells, TMCs）——后者产生部分血管生长因子的能力相当甚至更强——pCSCs在肿瘤血管发生中的活性显著更强，这提示pCSCs的强效肿瘤血管发生能力与其固有的干细胞样特性相关。与此一致的是，在宫颈癌、乳腺癌及异种移植淋巴瘤等人类癌症中也观察到了肿瘤血管发生现象。本研究表明，pCSCs可作为肿瘤血管发生干/祖细胞（tumor vasculogenic stem/progenitor cells, TVPCs），这或可解释抗血管生成癌症治疗临床试验面临困境的原因。