Structural, cellular and molecular mechanisms involved in the Epithelial-to-Mesenchymal Transition in Cancer

Intoduction: 

Cancer as one of the most common genetic diseases is the leading cause of death worldwide. Cancer cells undergo various genetic and phenotypic changes to spread and survive. In the early stages, these changes lead to the development of tumor, while at the advanced stages they can provide a suitable pre-metastatic microenvironment in which various uncontrolled events occur including cell proliferation, traversing through the extracellular matrix, and crossing barriers to enter the bloodstream. Extracellular changes in this microenvironment can induce intracellular changes in primary cancer cells that assist in the sustainability and propagation of these cells. Complicated interactions between the external and internal factors result in the establishment of various regulatory networks between different types of carcinogenesis promoting factors. Identification of these modifications plays a critical role in understanding the mechanisms of disease progression, prognosis and management. Text: Various mutations and differential gene expression trigger metastasis of cancer cells by epithelial to mesenchymal transition (EMT) mechanism, among which the role of chromatin structural changes, intracellular signal transduction pathways, regulation of cell cycle and microRNAs, and genomic instability has been reported. The alterations in gene expression patterns of mentioned pathways lead to potential regulatory complications that faced the management of disease progression and response to therapies with problems. Cancer cells provide their requirements by neutralizing biological barriers, modifying the regulation of inhibiting processes of cancer progression, establishing de novo endogenous mechanisms and providing specialized molecular and structural markers, and various combinations of these methods have been demonstrated in different types of cancer. Furthermore, EMT and cancer stem cells (CSCs) have a mutual relationship in which the presence of one assists the occurrence of the other. Altogether,  cancer cells take the advantage of  multiple approaches including  upregulation of main transcription factors such as snail, slug, Foxc2, Twist and ZEB1/2, benefiting the mechanisms of telomere length protection, production of CD133,CD44 and BMI1 biomarkers, mutation in P53 coding gene, Failure in acquiring aging phenotype, mutation in amino acid residue S115 of SIM2S gene and increased genomic instability, enhanced activity of signaling pathways such as NF-κB, TGF-β, Wnt, Notch and Hh, mitotic rounding process, facilitated cell division, epigenetic changes such as acetylation and methylation of histones and dysregulation of miRNAs.

EMT plays a crucial role in cancer progression, crossing the cells through the biological and body barriers, and metastasis that are usually associated with poor prognosis of cancer patients. Molecular and cellular changes in the main pathways of cells, development are considered as the promoting factors of EMT and resulted from the differential expression of genes in EMT compared to the normal phenotype of cells. Advancement in the exploration of these changes and their role in the progression of cancer can remarkably affect the early diagnosis, treatment and management of disease.

In this review, various molecular and cellular mechanisms involved in EMT progression and cancer have been investigated, including signal transduction pathways, structural changes of chromatin and telomeres, up/down-regulation of small non-coding RNAs such as miRNAs, cell cycle regulation and genomic instability.