The Kraken Wakes: induced EMT as a driver of tumour aggression and poor outcome

Abstract

Epithelial mesenchymal transition (EMT) describes the shift of cells from an epithelial form to a contact independent, migratory, mesenchymal form. In cancer the change is linked to invasion and metastasis. Tumour conditions, including hypoxia, acidosis and a range of treatments can trigger EMT, which is implicated in the subsequent development of resistance to those same treatments. Consequently, the degree to which EMT occurs may underpin the entire course of tumour progression and treatment response in a patient. In this review we look past the protective effect of EMT against the initial treatment, to the role of the mesenchymal state, once triggered, in promoting disease growth, spread and future treatment insensitivity. In patients a correlation was found between the propensity of a treatment to induce EMT and failure of that treatment to provide a survival benefit, implicating EMT induction in accelerated tumour progression after treatment cessation. Looking to the mechanisms driving this detrimental effect; increased proliferation, suppressed apoptosis, stem cell induction, augmented angiogenesis, enhanced metastatic dissemination, and immune tolerance, can all result from treatment-induced EMT and could worsen outcome. Evidence also suggests EMT induction with earlier therapies attenuates benefits of later treatments. Looking beyond epithelial tumours, de-differentiation also has therapy-attenuating effects and reversal thereof may yield similar rewards. A range of potential therapies are in development that may address the diverse mechanisms and molecular control systems involved in EMT-induced accelerated progression. Considering the broad reaching effects of mesenchymal shift identified, successful deployment of such treatments could substantially improve patient outcomes.

Differential engagement of ORAI1 and TRPC1 in the induction of vimentin expression by different stimuli

“…The ability of some cancer cells to adopt a more metastatic phenotype and/or acquire resistance to therapies through enhanced expression of multidrug resistance proteins is a significant contributor to cancer mortality [1,2], and has been associated with EMT [37,38]. Increased expression of vimentin, along with the remodeling of cellular adhesion proteins can occur in response to the milieu of signals (growth factors, acidification, hypoxia and physical stresses) in the tumor microenvironment [4].…”

Editorial: Therapy-induced metastasis

“…The challenge of cancer treatment-induced EMT and drug resistance has been further developed in this special issue. Redfern et al [13] review EMT changes in cancer by analogy with "The Kraken Wakes". Taking the name from an Alfred Lord Tennyson sonnet, the John Wyndham novel with this name describes the invasion of Earth by unseen aliens.…”

“…Conversely, they list the benefit of chemotherapies that trigger a reversal of EMT, resulting in mesenchymal to epithelial transition (MET) and an increased overall survival of patients. Redfern et al also review therapeutic approaches to manipulate EMT to the benefit of the patient [13]. The review by Nikolaou et al [14] addresses the mechanisms of resistance to cancer drugs, leading to repopulation within a treated tumour, or systemic dissemination of resistant tumour cells.…”

Licochalcone A Inhibits BDNF and TrkB Gene Expression and Hypoxic Growth of Human Tumor Cell Lines

“…To adapt to a hypoxic microenvironment, cells change the expression of the genes responsible for extracellular neo-vascularization and the intracellular metabolic shift to aerobic glycolysis [1,2]. The metabolic shift in hypoxia causes acidosis and induces cell invasion and metastasis via epithelial-to-mesenchymal transition (EMT) [3,4]. A key regulator of these processes is the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway [1,5,6].…”