EMT in breast cancer metastasis: an interplay of microRNAs, signaling pathways and circulating tumor cells.

Epithelial to Mesenchymal Transition (EMT) is a biological process characterized by the transition from immotile epithelial cells to motile mesenchymal cells. Though shown to be implicated in many biological processes, it has also been identified to enhance migration and invasion of cancer cells leading to metastasis. A class of microRNAs called "oncomiRs" plays a significant role in the regulation of malignant transformation and metastasis. In this review, the ability of different signaling pathways in controlling EMT through well-defined regulatory networks, and the role exerted by oncomiRs in regulating the specific signaling pathways like TGF-ß, Wnt, Notch and Hedgehog in modulating breast cancer metastasis have been discussed with updated information. Further, this review focuses on the significance of up and down regulated microRNAs in the pathogenesis and progression of breast cancer and how such microRNAs could be treated as potential therapeutic targets to circumvent cancer. As a prospective strategy, we highlight the importance of circulating tumor cells (CTCs) and their derived microRNAs as prognostic indicators and cancer therapy monitoring tools.

Vimentin activation in early apoptotic cancer cells errands survival pathways during DNA damage inducer CPT treatment in colon carcinoma model.

Epithelial to mesenchymal transitions (EMT) is a preparatory process for cancer cells to attain motility and further metastasis to distant sites. Majority of DNA damaging drugs have shown to develop EMT as one of the major mechanisms to attain drug resistance. Here we sought to understand the resistance/survival instincts of cancer cells during initial phase of drug treatment. We provide a tangible evidence of stimulation of EMT factors in Apc knockout colorectal carcinoma model. Our results implied that CPT-treated Apc knockout cohorts depicted increased pro-invasive and pro-survival factors (Vimentin/pser38Vimentin & NFκB). Moreover, by cell sorting experiment, we have observed the expression of Vimentin in early apoptotic cells (AnnexinV positive) from 36 to 48 h of CPT treatment. We also observed the expression of chimeric Sec-AnnexinV-mvenus protein in migrated cells on transwell membrane recapitulating signatures of early apoptosis. Notably, induction of Vimentin-mediated signaling (by CPT) delayed apoptosis progression in cells conferring survival responses by modulating the promoter activity of NFκB. Furthermore, our results unveiled a novel link between Vimentin and ATM signaling, orchestrated via binding interaction between Vimentin and ATM kinase. Finally, we observed a significant alteration of crypt-villus morphology upon combination of DIM (EMT inhibitor) with CPT nullified the background EMT signals thus improving the efficacy of the DNA damaging agent. Thus, our findings revealed a resistance strategy of cancer cells within a very initial period of drug treatment by activating EMT program, which hinders the cancer cells to achieve later phases of apoptosis thus increasing the chances of early migration.