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

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“Far, far beneath in the abysmal sea, The Kraken sleepeth.

Until the latter fire shall heat the deep; In roaring he shall rise.” Alfred Lord Tennyson

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.

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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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Authors and Affiliations

  1. School of Medicine, University of Western Australia (UWA), Harry Perkins Building, Fiona Stanley Hospital Campus, Robin Warren Drive, Murdoch, WA, 6150, Australia

    Andrew D. Redfern & Lisa J. Spalding

  2. Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, Australia

    Erik W. Thompson

  3. Translational Research Institute, Woolloongabba, Australia

    Erik W. Thompson

  4. Department of Surgery, University of Melbourne, Melbourne, Australia

    Erik W. Thompson

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  1. Andrew D. Redfern
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  2. Lisa J. Spalding
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Correspondence to Andrew D. Redfern.

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Redfern, A.D., Spalding, L.J. & Thompson, E.W. The Kraken Wakes: induced EMT as a driver of tumour aggression and poor outcome. Clin Exp Metastasis 35, 285–308 (2018). https://doi.org/10.1007/s10585-018-9906-x

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