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factual status of EMT’s vital role in tumour biology, but is not declared to be the only mechanism for drug
resistance. In this review, we start with a brief introduction of EMT, the signalling pathways involved in
EMT, and the role of EMT in drug resistance, concluding with the need for developing new screening
methodologies to overcome the limitations of the existing modalities.

OVERVIEW OF EMT
Epithelial cells are a differentiated type of cells that constitute the outer lining of human body organs,
skin, urinary tract, and blood vessels. Mesenchymal cells originate from a type of connective tissue
(called mesenchyme) found during embryonic development and therefore are understood to be stem
cells. During embryogenesis, the process of EMT and mesenchymal to epithelial transition (MET) is a
[7,8]
[5,6]
common observation . EMT is not expected once the epithelial cells reach terminal differentiation ,
[7,9]
but the process is induced during tissue repair and unusual pathological stress . Mostcancers arise from
epithelial cells and grow indefinitely at that location. Epithelial cells interact laterally with other cells
through junctional complexes and with the basal membrane via integrin receptors. These contribute to
their apicobasal polarity and it is impossible to make them grow in isolation . Some of those epithelial
[10]
cells undergo EMT, lose cell-cell junctions, and acquire mesenchymal phenotype, which makes them
independent of these constraints [11,12] . Having done this, these cells can migrate to other tissues, undergo
[6]
MET, and establish successful metastases . Benign tumoursof epithelial origin are not very harmful to the
organism, but these metastases, especially when they are present in crucial tissues, are known to cause 90%
[13]
of the mortality associated with these cancers . The role of EMT in metastasis is not clearly established. In
fact, Fischer et al. showed that EMT is not required for successful breast to lung metastasis, as inhibition
[14]
of EMT by inhibiting microRNA miR-200 did not inhibit the development of lung metastasis. EMT’s role
[14]
in developing chemoresistance, however, is indisputable .

CELL SIGNALLING INVOLVED IN EMT
EMT has been an untargeted pathway of cancer progression resulting in significant mortality and
morbidity in multiple cancers. This has led researchers internationally to focus investigations on EMT
targeting pathways in the cell. EMT is a multistep process whereby epithelial marker genes are suppressed,
and mesenchymal markers are upregulated. The most important epithelial marker is E-cadherin. The
transcription factors which can suppress its transcription are Snail1, Snail2 (also called Slug), zinc finger
E-box-binding homeobox 1 (ZEB1), and ZEB2 [15-17] . Twist, which is a master regulator of embryonic
morphogenesis, is found to be essential for metastasis. High levels of Twist are observed in aggressive
[18]
cancers and are associated with decreased E-cadherin . The lymphoid-enhancing factor is needed for
[19]
EMT induced by transforming growth factor-β3 (TGF-β3) . Owing to their defined role in the process,
all these transcription factors are termed EMT transcription factors (EMT-TFs). Recently, it was realised
that EMT-TFs play key roles in almost all stages of cancer, i.e., initiation, primary tumour formation,
[4]
invasion, dissemination, metastasis, and colonization at the secondary site . Above all, the expression of
the combination of EMT-TFs is different in different cancers and even within a single tumour. Thus, the
markers determining the stages of EMT change, leading to the possibility of false-positive or false-negative
results in disease prognosis testing [20,21] . Most of the transcription factors are regulated by receptor tyrosine
[24]
[25]
[26]
[23]
[22]
kinases , TGF-β family , Wnt , Notch , and Hedgehog pathways. The activators of these pathways
include ligands such as EGF, TGF-β, cytokines, tumour hypoxia, and components of the extracellular
[27]
matrix . Of all these inducers, the TGF-β family has been most studied in the context of EMT. It consists
of the TGF-β superfamily of ligands which include isoforms of TGF-β (TGF-β1, β2, and β3) and bone
[27]
morphogenetic proteins . The addition of exogenous TGF-β induces EMT in many cancer cell lines and
is cell type-specific. Conversely, specific inhibition of TGF-β receptor-1 (TGF-βR1) abrogates this EMT
[28]
induction . As EMT is activated by these growth factors and transcription factors, most of the drugs
[29]
targeting EMT affect these signalling pathways .