Metformin against TGFβ-induced epithelial-to-mesenchymal transition (EMT): From cancer stem cells to aging-associated fibrosis

Epithelial-to-mesenchymal transition (EMT) confers primary resistance to trastuzumab (Herceptin)

“…The targeting of the EMT phenomenon is, therefore, a promising therapeutic strategy to prevent and circumvent the de novo resistance to trastuzumab-based therapeutic regimens. 36,[79][80][81][82][83][84][85][86][87] the trastuzumab-sensitive SLUG/SNAIL2 KD-JIMT1 cells. Our findings favor a functional heterogeneity in the breast CS-like compartment and suggest that, in addition to the widely recognized CSCs with mesenchymal-like phenotypes, tumor-initiating cells with an epithelia-like morphology and functionality might be considered to understand better the breast cancer responses to molecularly targeted drugs.…”

Activation of AMP-activated protein kinase (AMPK) provides a metabolic barrier to reprogramming somatic cells into stem cells

“…Our findings validate the notion that the loss of AMPK activation sensitivity in response to metabolic stresses is a molecular strategy that might allow somatic cells to de-differentiate and acquire properties of tumor-propagating cells and add a new molecular dimension to metformin anticancer stem cell activity. 104,105,119,[131][132][133][134][135] Because it is reasonable to expect more AMPK activators with higher specificity and potency to appear in the market in the near future, the fact that AMPK activation reprograms cellular metabolism in a manner that successfully impedes somatic cells from de-differentiating and acquiring stemness properties may provide a roadmap to a new-generation poorly differentiated, biologically aggressive carcinomas appear to hijack self-renewal transcription factor machinery (e.g., Oct4) to support aberrant proliferation and tumor initiation. Previous studies have shown that Oct4 overexpression leads to the generation of dysplastic lesions in epithelial tissues due to aberrant expansion of early progenitor cells in mice.…”

Metformin lowers the threshold for stress-induced senescence: A role for the microRNA-200 family and miR-205

“…Recent studies have revealed that the onset of myofibroblasts senescence is a programmed wound-healing response that functions as a self-limiting mechanism for fibrosis, a process that is triggered through integrin-mediated induction of ROS. 115,116 Because a hallmark of several carcinomas is the presence of a pronounced collagen-rich fibrotic extracellular matrix, metformin's ability to impede EMT by promoting an epithelial status of differentiation 117,118 and to induce a SIS response in fibroblasts while enhancing the expression of anti-EMT miRNAs (i.e., miR-200s and miR-205) can strongly function to accelerate the resolution of fibrogenesis and, therefore, to impede the development of fibrosis-related preneoplastic lesions.…”