Transitions in epithelial cells trigger the formation of endothelial cells, which contribute to tumor growth, as reported in Oncotarget.

In a groundbreaking study published in the peer-reviewed, open-access biomedical journal Oncotarget, researchers have uncovered a significant link between FOXC2 and tumor angiogenesis. The study, titled "Carcinoma cells that have undergone an epithelial-mesenchymal transition differentiate into endothelial cells and contribute to tumor growth," was authored by Liling Wan and led by the Sarkar Research Team, with Tapasree Roy Sarkar serving as the corresponding author (contactable at [email protected]).

The study sheds light on the process of angiogenesis, which involves the development of new blood vessels through remodeling of a pre-existing vasculature. This process is essential for tumor growth, as it allows for the necessary nutrients and oxygen to reach the growing cells.

The researchers discovered that carcinoma cells, which have undergone an epithelial-mesenchymal transition (EMT), can contribute to tumor growth by differentiating into endothelial cells. This transformation can occur either indirectly, by promoting endothelial transdifferentiation of carcinoma cells, or directly, by acquiring an endothelial phenotype.

The study further links the stemness conferred through EMT to the acquisition of endothelial cell traits and the augmentation of tumor angiogenesis in a FOXC2-dependent manner. FOXC2, a common factor in multiple EMT pathways, is crucial for the acquisition of endothelial phenotypic and functional characteristics, both in vitro and in vivo.

The findings suggest a role for FOXC2 in the process of tumor neoangiogenesis. Inhibition of FOXC2 signaling may potentially compromise tumor neoangiogenesis, offering a promising avenue for future cancer treatments.

The Sarkar Research Team concluded that their findings are consistent with the notion that the phenotypic attributes of cells within growing tumors are eminently pliable, and that, as tumor size and the oxygen deficit increase, carcinoma cells become progressively dedifferentiated towards a mesenchymal, stem-like phenotype.

The study also proposes that the induction of EMT contributes to tumor neoangiogenesis in two ways: indirectly, by modifying the tumor niche, and directly, by generating stem-like cells that can assume endothelial-like phenotypic and functional attributes and directly integrate into the nascent tumor vasculature.

One mechanism, termed vasculogenic mimicry, entails the de novo generation of microvessels lined with highly invasive tumor cells embedded in a rich extracellular matrix, lacking in the endothelial cell markers CD31 and CD34.

Intra-tumoral vessels contain CD31-positive cells derived from either donor cell type, indicating the potential for tumor cells to differentiate into endothelial-like cells.

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The study also found that subcutaneous injection of B16 melanoma cells into Foxc2 haploinsufficient mice leads to impaired formation of tumor blood vessels and compromised tumor growth, further underscoring the importance of FOXC2 in tumor angiogenesis.

In addition, the implantation of MCF-7 cells co-mixed with human mammary epithelial cells overexpressing the EMT-inducer Snail results in potentiated tumor growth and vascularization compared to MCF-7 cells injected alone or co-mixed with HMLE-vector cells.

Hypoxic regions in tumors show focal areas of E-cadherin loss and elevated levels of vimentin and the EMT-mediator FOXC2. These findings suggest that the induction of EMT contributes to tumor neoangiogenesis, in part, through the role of FOXC2.

In conclusion, this study provides valuable insights into the complex process of tumor angiogenesis and offers promising directions for future cancer research and treatment strategies.

Transitions in epithelial cells trigger the formation of endothelial cells, which contribute to tumor growth, as reported in Oncotarget.