Epithelium integrity is maintained by the apical-basal polarity of epithelial cells generated by adhesions at cell-cell junctions and with the basal lamina. However, under specific physiological conditions, epithelial cells lose the contacts with neighbouring cells and the subjacent matrix, adopting a highly motile mesenchymal phenotype. This cell behaviour is called epithelial-mesenchymal transition (EMT) and it is critical for tissue morphogenesis during embryonic development and in adulthood for wound healing.
1. Introduction
At the molecular level, EMT is characterised by the downregulation of the cell adhesion protein E-cadherin, leading to the disassembly of intercellular junctions and the initial dissociation of epithelia. In parallel, cells undergo major cytoskeletal rearrangements involving the downregulation of keratins and the upregulation of vimentin, which facilitates the highly migratory behaviour in the dissociated cells [2]. Several well characterised transcription factors (TFs) are upregulated during EMT such as SNAIL/SNAI1, SLUG/SNAI2, TWIST and the ZEB family of TFs, which orchestrate the downregulation of E-cadherin [3] and the upregulation and activation of N-cadherin and the intermediate filament vimentin [4]. Reciprocally, upregulated vimentin can promote the expression or the activity of EMT TFs and other signalling pathways favouring an invasive phenotype [5,6].
The induction and maintenance of EMT is highly regulated by extracellular signals during embryonic development, tissue repair and tumour progression. These include chemical cues such as cytokines, chemokines, the presence of reactive oxygen species (ROS) [22] and hypoxia [23,24], as well as mechanochemical signals provided by changes in the rigidity of the surrounding extracellular matrix [25,26]. Specifically in tumours, autocrine and paracrine stimulation of cancer cells by cytokines such as TGFβ1 induce EMT while promoting an immunosuppressive microenvironment [27,28]. Additionally, macrophages and cancer associated fibroblasts present in the tumour microenvironment can secrete classical EMT-inducing cytokines/chemokines including HGF, SDF1α, EGF, PDGF as well as TGFβ1 [24,28]. Cytokines also secreted by the tumour stroma and firstly identified as pro-survival, immunosuppressive or as chemotactic signals to recruit immune cells to the tumour microenvironment are now known to also induce EMT in cancer cells. Some examples are IL-6, IL-8, IL-10 and TNFα [27,29]. The hypoxic microenvironment generated in growing tumours prior to vascularisation is another extensively studied factor that promotes EMT in cancer cells [23,30,31]. Hypoxia drives EMT by triggering various signalling pathways [32], the most commonly known being the stabilisation of Hypoxia Inducible Factor-1 α (HIF-1α) [33], that results in increased activity of the EMT TFs SLUG [33], SNAIL [32] and TWIST [34].
A substantial body of evidence supports the central role of EMT in the invasive behaviour and the metastatic disease of carcinomas such as lung, prostate, colon, liver, pancreatic and breast cancers [24]. However, in the last decade it has become evident that an EMT behaviour is also present in non-epithelial solid tumours of mesenchymal origin and in haematological malignancies [9,10,23,43]. This EMT-like behaviour in mesenchymal tumours may echo the loss of polarity and increased migratory capacity of endothelial cells during tissue repair and angiogenesis in an EMT-related process named endothelial-mesenchymal transition [1,44].
2. EMT in Haematological Malignancies
Haematopoietic cells derive from the mesoderm and, therefore, have a mesenchymal developmental origin, however, the expression of EMT-like signatures with upregulation of canonical mesenchymal markers has been described in all types of haematological malignancies (lymphomas, multiple myeloma and lymphoid and myeloid leukaemia) [
10]. There is a clear correlation between the expression of these EMT signatures, or genetic abnormalities in EMT TFs, and poor prognosis of patients [
9,
45,
46,
47,
48,
49,
50,
51]. One of the most common characteristics is the expression of high levels of vimentin in various forms of aggressive haematological tumours [
9,
52,
53]. However, the exact biological role of the EMT markers in haematopoietic cancers remains largely unstudied.
In particular, the actual correlation between the higher levels of EMT markers with a more motile phenotype, which is a key EMT feature, has not yet been studied in great depth in haematological malignancies in comparison to solid tumours. The majority of the studies have concentrated on various other tumour traits that may explain the correlation between expression of EMT signatures and the poor prognosis of patients. For example, the expression of EMT TFs has been associated with the repression of differentiation markers, correlating with more aggressive forms of haematological malignancies. Increased expression of ZEB1 promotes the methylation and downregulation of B-Cell Lymphoma protein 6 (BCL6), a key transcription factor that promotes differentiation of B cells and whose expression is associated with a benign profile [
45]. A correlation has also been established between EMT and resistance to therapies. ZEB1 has been shown to promote drug resistance in mantle cell lymphoma by activating proliferation-associated genes while repressing pro-apoptotic ones and regulating the expression levels of membrane transporters involved in drug influx and efflux [
46]. The upregulation of TWIST1 levels in chronic myeloid leukaemia (CML) promotes resistance to the therapeutic drug imatinib [
50]. However, the cellular and molecular TWIST1-dependent mechanisms that may explain the lack of response to this drug have not yet been elucidated. Similarly, expression of EMT TFs in multiple myeloma cells in response to cues from the tumour microenvironment correlates with resistance to the clinical drugs dexamethasone and Velcade (bortezomib) [
54].
Only a few of these studies have addressed the connection between the expression of EMT markers and increased cell migration. In paediatric anaplastic large cell lymphoma cells, expression of the oncogenic protein anaplastic lymphoma kinase (ALK) correlated with expression of higher levels of TWIST1. Downregulation of TWIST1 in these cells inhibited invasive migration and reinstated the efficacy of therapeutic drugs [
49]. In MLL-AF9 driven acute myeloid leukaemia (AML), poor prognosis in patients correlated with expression of EMT markers and experimental downregulation of ZEB1 in AML cells inhibited the invasive capacity of this aggressive cancer [
9].
Multiple myeloma is the haematological tumour where the EMT phenotype has been studied in more depth, and there is substantial evidence of the acquisition of a migratory phenotype orchestrated by the EMT program [
23,
43,
51,
54]. Multiple myeloma results from the accumulation of malignant plasma cells in disseminated tumour foci within the bone marrow. In 2012, the Ghobrial lab demonstrated that during tumour progression, hypoxia induced an EMT program in multiple myeloma cells that resulted in increased mobilisation and formation of further bone marrow foci [
23]. This program was the result of the upregulation of HIF-1α leading to expression of SNAIL and downregulation of E-cadherin [
23]. It was then proposed that multiple myeloma may be envisaged as a metastatic disease where progression results from continuing trafficking of myeloma cells from initial proliferating tumours in the bone marrow that acquire a hypoxic-driven EMT phenotype as they expand, leading to mobilisation of myeloma cells undergoing EMT [
43]. Mobilised myeloma cells into the circulation express cell adhesion molecules such as β7 integrins [
55] that would facilitate the interaction of circulating cells with the bone marrow endothelium and the extravasation into a new site. The re-entry into the bone marrow in this vascularised normoxic environment would repress the expression of HIF-1 α, silencing the EMT program and promoting a transition similar to MET in epithelial tumours, leading to the proliferation of myeloma cells and development of a new tumour [
23]. Additional factors that may lead to the mobilisation of myeloma cells through the acquisition of an EMT-phenotype include the increased concentration of cytokines such as IL-6, TNFα, VEGF, HGF and IGF-1 in the tumour microenvironment during the symptomatic phase of the disease [
43]. More recently, further evidence shows that cytogenetic abnormalities associated with a poor prognosis in multiple myeloma [
51] as well as the composition of the extracellular matrix of the myeloma bone marrow microenvironment [
54] promote an EMT invasive phenotype in these cancer cells.
Taken together, the studies in haematological malignancies indicate a compelling connection between expression of EMT markers and poor prognosis (Table 1). In addition, the acquisition of an invasive migratory phenotype has been corroborated in the limited number of in depth studies so far available (Table 1).
Table 1. Upregulation of canonical EMT markers in haematological malignancies correlates with poor prognosis and/or the enhanced migration of cancer cells.
Mechanism
Regulated |
EMT TF |
Haematological
Malignancy Type |
References |
| Resistance to therapy and poor prognosis |
ZEB1 |
B-Cell Lymphoma |
[45] |
| |
Mantle cell lymphoma |
[46] |
| TWIST1 |
CML |
[50] |
| SNAIL, SLUG |
Multiple myeloma |
[54] |
| ZEB1, HGF |
MLL-AF9 AML |
[9] |
| Enhanced capacity for cell migration |
TWIST1 |
Paediatric anaplastic |
[49] |
| |
large cell lymphoma |
/ |
| ZEB1 |
MLL-AF9 AML |
[9] |
| TWIST1, SNAIL, SLUG |
Multiple myeloma |
[23,51,54] |
This entry is adapted from the peer-reviewed paper 10.3390/cells11040649
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