Strike a balance between advanced breast cancer eradication and E-cadherin restoration: EMT events in the spotlight

Cancer cells often express a massive amount of proteins that are needed to their own proliferation.  One of the molecular abnormalities related to tumour progression, invasion and fixation requires the impairment of E-cadh expression, a tumour invasion suppressor protein. Epithelial‑mesenchymal transitions (EMT), is associated with the silencing of E-cad expression and further expression of EMT related molecules, such as Akt2 and Twist, crucial for progression of non-invasive into a malignant metastatic carcinomas, due to a polarity and adhesion loss between adjacent cells. This mechanism, found in various human solid tumours, correlates with loss of differentiation characteristics and acquisition of a more invasive and metastatic phenotype. These phenotype changes enable the cells to detach from their original site, penetrate the bloodstream, and subsequently metastasis infiltration in pre-metastatic niche tissues.

Triggered by breakthroughs in molecular biology and further deep insight in RNAi technology, therapeutic RNAi-mediated strategy is grounded in oncologic field. Specific siRNAs that can interfere with AKT2 regulation have been identified, that if succeed as a therapeutic strategy, would represent an enormous step forward in oncology. However, the impact of this siRNA on AKT2 knockdown gene expression and further restore E-cadh expression is not fully explored making this signalling pathway a suitable target for impairment of tumor progression. Target therapy using selective siRNA oligonucleotides can contribute to overcome therapy limitations and therefore improved anticancer strategies.

Authors and Affiliations:

D Rafael, S Doktorovová, H. F Florindo, P Gener, I Abasolo, S Schwartz and M. A Videira 
Research Institute for Medicines and Pharmaceutical Sciences (iMED.UL), School of Pharmacy, University of Lisbon, Lisbon, Portugal

Molecular Biology and Biochemistry Research Centre for Nanomedicine (CIBBIM-Nanomedicine), Vall d'Hebron Research Institute, Barcelona, Spain

Abstract:

Epithelial Mesenchymal Transition (EMT) is an event where epithelial cells acquire mesenchymal-like phenotype. EMT can occur as a physiological phenomenon during tissue development and wound healing, but most importantly, EMT can confer highly invasive properties to epithelial carcinoma cells. The impairment of E-cadherin expression, an essential cell-cell adhesion protein, together with an increase in the expression of mesenchymal markers, such as N-cadherin, vimentin, and fibronectin, characterize the EMT process and are usually correlated with tumor migration, and metastization. A wide range of micro-environmental and intracellular factors regulates tumor development and progression. The dynamic cross-talk between the adhesion-related proteins such as E-cadherin and the EMT-related transcription factors, with special focus on TWIST, will be discussed here, with the aim of finding a suitable biological pathway to be used as potential target for cancer therapy. Emerging concepts such as the role of the PI3K/AKT/TWIST pathway in the regulation of the E-cadherin expression will be highlighted, since it seems to be consistently involved in cells EMT. The well-known efficacy of the RNA interference as a tool to silence the expression of specific proteins has come into focus as a strategy to control different tumor sub-populations. Despite the oligonucleotides enormous sensitivity and low in vivo stability, new (nano)technological solutions are expected to enable RNAi clinical application in cancer therapy.

Journal: Current Gene Therapy

Link: http://www.eurekaselect.com/128005/article