Existence of tumor‐derived endothelial cells suggests an additional role for endothelial‐to‐mesenchymal transition in tumor progression

Dear Editor, The idea that cancer cells can acquire a new phenotype and participate in the formation of blood vessels has been proposed at least half a century ago by Willis. In recent years, this view received some support from findings demonstrating presence of cancer cells in blood vessels. Now, two recent reports published in the International Journal of Cancer provide evidence that cancer cells can acquire some endothelial features when incorporated in tumor blood vessels. This capability of cancer cells to acquire an endothelial-like phenotype and to form mosaic vessel walls is of tremendous interest with regard to tumor cell progression as endothelial cells are capable to acquire mesenchymal traits through a process named endothelial-to-mesenchymal transition (EndMT). EndMT is a special kind of epithelial mesenchymal transition that occurs physiologically in the developing heart and occurs pathologically in some fibrotic diseases and cancer. In cancer, EndMT of nontransformed endothelial cells is a nonexclusive source of cancer-associated fibroblasts (CAFs). The possibility that cancer endothelial-like cells that have been incorporated into vessels also undergo EndMT and participate to tumor progression can now be considered. The mesenchymal drift of cancer cells is critical for tumor progression. Currently, this transition is reported to occur through a process named epithelial-to-mesenchymal transition (EMT), a key developmental program activated during tumorigenesis. The importance of cancer cell mesenchymal transition in tumor progression motivates the model proposed herein in which EndMT acts as an additional driver of tumor progression. In this model, interactions of endotheliallike cancer cells (EndCC) with endothelial cells, blood components and inflammatory signals induce the transition of EndCC toward a mesenchymal phenotype. This process is comparable to the EndMT that occurs during embryonic vascular development and cardiac fibrosis or to the EndMT observed in tumors when endothelial cells generate CAFs. This EndMT generates mesenchymal cancer cells (MCC) with migratory and invasive properties that protrude at the outer surface of tumor vessels and invade tumor microenvironment or alternatively form perivascular satellitosis, a hallmark of tumors such as glioma (Fig. 1). The release and dissemination of these EndCC and MCC in the tumor environment is further enhanced following vessel disruption either during tumor vascular remodeling or antiangiogenic therapies. Release of MCC in the lumen vessel could also occur and be an additional mechanism participating to metastasis. In this latter case, it is notable that cancer cells do not necessarily need to penetrate vessels for entering blood circulation as the EndCC is already integrated in the tumor neovasculature. The interest of this model is that it gives clues for some unresolved points or paradoxes. For example, (i) EndMT is one possible mechanism for the mesenchymal drift observed during progression of nonepithelial tumors such as glioma; (ii) EndMT generates a population of cancer stem cells expected to express cell markers different from those found in the primitive cancer stem cell population. This provides an issue to some conflicting results reporting the emergence of heterogenous populations of CSCs in solid tumor such as glioma; (iii) CD133, a brain cancer stem cell marker regulated by hypoxia, is also paradoxically expressed by cancer stem cells in the normoxic perivascular space. This paradox can be solved if we consider that endothelial precursor cells are known to express CD133. Endothelial microenvironment cues is a possible explanation for the presence of CD133 positive cancer stem cells both in normoxic perivascular areas and hypoxic regions and (iv) it has been demonstrated that EMT can generate cells with properties of stem cells such as self-renewal. Hence, cancer cells integrated into blood vessels and undergoing EndMT could reacquire a stem cell phenotype. Regeneration of the stem cell features by EndMT provides an explanation for data reporting that cancer stem cell phenotype can fluctuate. In addition, the model provides new insights into the correlation between tumor aggressiveness and neoangiogenesis. In this model, tumor neoangiogenesis is not only a mandatory step for the delivery of O2 and nutrients but also provides the microenvironment (cell–cell interactions between endothelial and cancer cells and blood components) involved in the mesenchymal transdifferentiation process. This model also has therapeutic consequences. In vascular endothelium, the EndMT is triggered by TGF-b and inhibited by BMP-7. This identifies these pathways as potential therapeutic targets in the control of the tumoral EndMT. On the other hand, antiangiogenic therapies, by disrupting tumor vasculature, are expected to release the blood vessels-interacting CSC and suppress blood vessels migratory tracks observed in glioma. This provides one explanation for the increased cancer cells dissemination in Le tt er to th e E di to r