Angiogenesis is the development of new blood vessels through the remodeling of a pre-existing vasculature, supported by the sprouting, proliferation and fusion of endothelial cells. Upon exposure to angiogenic stimuli, normally quiescent endothelial cells are activated, which is the foundation for vascular network formation during embryonic development and also aids wound healing following injury. Solid tumor cells have the ability to bring about angiogenesis and sustain it, this is termed neoangiogenesis in the cancer context and it is one of the distinguishing features of cancer. When rapidly growing tumors outgrow their blood supply, they display areas of localized lack of oxygen, a condition referred to as hypoxia. Hypoxia activates neoangiogenesis, thereby promoting tumor outgrowth and triggering the epithelial-mesenchymal transition (EMT), which confers cells with mesenchymal traits and the potential for differentiation into multiple lineage.
In a new original research article published in the Journal Oncotarget, Texas A&M University Scientists: Dr. Tapasree Roy Sarkar, Dr. Akhilesh Gaharwar, Cody King, Jonathan Hoar and, M.D. Anderson Cancer Center scientists: Dr. Nathalie Sphyris, Steven Werden and Geraldine Vijay, and led by Professor Tapasree Roy Sarkar investigated whether EMT can confer endothelial attributes upon carcinoma cell, amplifying the growth of tumors and vasculature. The research team showed that cells that had undergone EMT had the ability to promote tumor growth and neovasculature both directly and indirectly. The patterns of hypoxia and EMT were found to be related to the degree of vascularization in tumors of different sizes. Significant hypovascularization was seen in small sized tumors compared to larger tumors that had progressively developed vascular networks. In tumors sized 5–7 mm there was pronounced hypoxia-inducible factor 1 (HIF-1α) staining, distinguishing hypoxic regions, whereas a heterogeneous, more diffuse, and somewhat weaker HIF1α staining pattern was displayed by tumors sized 14–15 mm. The team discovered that larger tumors sized 5–7 mm or 14–15 mm, had blood vessels that were decorated by a human-specific anti-CD31 antibody. Professor Naoyuki Miura from the Hamamatsu University School of Medicine in Japan was also a co-author in the study.
The authors noticed an increase in the expression of the mesenchymal marker vimentin and the EMT-inducing transcription factor transcription factor Forkhead Box C2 (FOXC2) in HIF-1α-positive regions. This was associated with marked reduction in E-cadherin membrane staining at discrete foci, possibly indicating regional loss of cell-cell cohesion and local invasion. As the tumors outgrew their blood supply and developed hypoxic regions, it was noticed that the tumor cells displayed phenotypic changes that were consistent with the initiation of EMT and transdifferentiation to a CD31-positive endothelial-like lineage.
Based on their findings the authors proposed that EMT induction contributed to tumor neoangiogenesis in two different ways. Firstly, directly, through the generation of stem-like cells that can acquire endothelial-like phenotypic and functional attributes and directly integrate into the vasculature of a nascent tumor. Secondly, indirectly, via the modification of the tumor niche through paracrine signaling or alterations in extracellular matrix deposition, to aid the endothelial transdifferentiation of epithelial tumor cells. In addition, they also proposed that FOXC2 is essential in the acquisition of endothelial phenotypic and functional characteristics by the tumor cells in vitro and in vivo. Consequently, the inhibition of FOXC2 signaling could hinder tumor neoangiogenesis
In summary, the new findings of Texas A&M University are consistent with the concept that the phenotypic attributes of cells within growing tumors are notably flexible and that with increasing tumor size and oxygen deficit increase, cancer cells become progressively dedifferentiated towards a mesenchymal, stem-like phenotype.
Sphyris N, King C, Hoar J, Werden SJ, Vijay GV, Miura N, Gaharwar A, Sarkar TR. Carcinoma cells that have undergone an epithelial-mesenchymal transition differentiate into endothelial cells and contribute to tumor growth. Oncotarget. 2021 ;12(8):823-844.Go To Oncotarget