Epithelial Plasticity, Autophagy and Metastasis: Potential Modifiers of the Crosstalk to Overcome Therapeutic Resistance

Epithelial-to-mesenchymal transition (EMT) initiates malignant transformation of cancer cells and is responsible for the generation of heterogenic subsets of cancer stem cells (CSCs). Signals in the form of environmental cues and paracrine factors within tumor microenvironment (TME) niche, support the possibility of generation of pool of CSCs with two distinct functional transition states. Cyclic CSCs with predominant epithelial phenotype, self-renew and differentiate into mature cancer cells. Subsets of autophagic/ non-cyclic CSCs with predominant mesenchymal phenotype have capacity to invade, metastasize, resist to apoptosis, escape immunosurveillance, survive chemotherapies and are majorly responsible for cancer mortality. Differences in phenotypic plasticity may form the basis of differential impact of therapeutic outcomes on heterogeneous subpopulations of CSCs. Activation of autophagy is responsible for the recycling of damaged organelles and protein aggregates, regulates EMT, confers the survival advantage to neoplastic cells to anti-cancer therapies, significantly affects the invasive potential of cancer cells and supports their metastatic dissemination in a tissue and tumor stage dependent manner. Therapy resistance is the primary obstacle in the complete ablation of tumor cells. Combinational treatments based on targeting autophagic CSCs and inhibiting EMT regulators may represent potential anticancer strategies for the prevention of cancer invasion, metastatic spread and disease relapse.