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

  • Andrew D. Redfern
  • Lisa J. Spalding
  • Erik W. Thompson
Research Paper
  • 15 Downloads

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.

Keywords

Epithelial mesenchymal transition Resistance Metastasis Treatment Proliferation Apoptosis 

Abbreviations

ALDH1

Aldehyde dehydrogenase 1

ALK

Anaplastic lymphoma kinase

ATRA

All-trans retinoic acid

CCL2

Chemokine ligand 2

CRISPR

Clustered regulatory interspaced short palindromic repeats

CSCs

Cancer stem cells

CTCs

Circulating tumour cells

CTLA-4

Cytotoxic T-lymphocyte–associated antigen 4

EGF

Epidermal growth factor

EIS

EMT-inhibiting sextet

EM-axis

Epithelial-mesenchymal axis

EMP

Epithelial-mesenchymal plasticity

EMT

Epithelial mesenchymal transition

EMT-TFs

EMT-transcriptional factors

ERα

Estrogen receptor alpha

ERK

Extracellular signal-regulated kinase

HCC

Hepatocellular carcinoma

HDAC

Histone deacetylase

HER2

Human epidermal growth factor receptor 2

HIF1α

Hypoxia inducible factor-1α

IAP

Inhibitor of apoptosis

MAPK

Mitogen activated protein kinase

MEK

Mitogen-activated protein/extracellular signal-regulated kinase kinase

MET

Mesenchymal epithelial transition

miRNA

MicroRNA

MMP

Matrix metalloproteinase

NF-kB

Nuclear factor kB

NSCLC

Non-small cell lung cancer

OS

Overall survival

PD1

Programmed death 1

PD-L1

Programmed death ligand 1

PFS

Progression-free survival

TGF-β

Transforming growth factor beta

VEGF

Vascular endothelial growth factor

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© Springer Science+Business Media B.V., part of Springer Nature 2018

Authors and Affiliations

  1. 1.School of MedicineUniversity of Western Australia (UWA)MurdochAustralia
  2. 2.Institute of Health and Biomedical Innovation and School of Biomedical SciencesQueensland University of Technology (QUT)BrisbaneAustralia
  3. 3.Translational Research InstituteWoolloongabbaAustralia
  4. 4.Department of SurgeryUniversity of MelbourneMelbourneAustralia

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