Shreena Patidar

Introduction Cancer metastasis signifies an aggressive cell migration of a primary tumor to secondary tissues of the body. The process is correlated with poor prognosis and remains incompletely understood, despite the high mortality rates associated with this process^1,2. Both tumor progression and later metastatic stages are associated with hijacking of an innate cell developmental program called epithelial-to-mesenchymal transition (EMT). It has been suggested that the induction of this program serves as a prerequisite of metastatic properties and allows the tumor to develop stem-cell like properties, mesenchymal migratory properties and even drug-resistance^1,2,3. New studies indicate that EMT dysfunction is correlated with aberrant expression of the yes-associated protein (YAP), a transcriptional regulator^1,4. Methods To determine the role of YAP in EMT, gastric orthotopic implantation cancer models utilized severe combined immunodeficiency (SCID) mice with lentiviral vectors integrating small-hairpin RNA (shRNA) knockdowns of the YAP gene. The experimental groups included the YAP shRNA vector-transfected cells (YAP-shRNA group), negative control vector-transfected cells (NC group) and untransfected cells (CON group). The negative control vector carries a sequence unrelated to the human genome. Experimenters stained gastric tumor cells with anti-Ki67 antibodies and quantitated the percentage of cells containing this proliferation marker. Apoptotic cells were stained with a TUNEL assay and quantitated. The same experimental groups were assayed with the endothelial marker CD31 to quantitate micro-vessel densities in the gastric tumor after YAP knockdown⁵. Results The aforementioned study demonstrated that there were fewer proliferation positive cells in the YAP-shRNA group compared with the other two groups. These findings demonstrate that YAP silenced through RNA interference reduced cancer cell proliferation in the mouse gastric cancer model⁵. This suggests YAP plays a considerable role in conferring proliferative properties that may allow malignant cells the ability to metastasize. Numerous other studies suggest this occurs via YAP-mediated activation of TEAD. Through this recognized signaling pathway, TEAD stimulates the gene transcription of mesenchymal markers like vimentin, N-cadherin and fibronectin⁶. Conclusion The successful epithelial-to-mesenchymal transition of a single cell in a benign tumor may induce the metastasis of gastric cancer, as apparent by recent data^1-3. At the crux of this malicious EMT is a dysfunctional YAP pathway, and inhibition of proteins along the signaling pathway could have anti-metastatic therapeutic value⁵. The continued discovery of the nuances of this pathway hold immense clinical value in the form of increased survival for gastric cancer patients.

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