IL-6 Cytokines and EMP: Comparison
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Epithelial–mesenchymal plasticity (EMP) plays critical physiological roles during embryonic development, postnatal growth and epithelial homeostasis, but it is also involved in a number of pathological conditions, including wound repair, fibrosis, inflammation and cancer. EMP has been intimately linked with most, if not all, of the steps during cancer development and progression (e.g., migration, invasion, immune escape, drug resistance and metastatic dissemination). Cytokines from the interleukin 6 (IL-6) family play fundamental roles in mediating tumour-promoting inflammation within the tumour microenvironment. In general, IL-6 cytokines activate EMP processes, fostering the acquisition of mesenchymal features in cancer cells. Here, we will summarise all the relevant literature related to all members of the IL-6 family and EMP.

  • cancer
  • epithelial–mesenchymal transition
  • epithelial–mesenchymal plasticity
  • cytokines
  • IL-6
  • oncostatin M (OSM)
  • invasion
  • migration

1. Introduction

Epithelial–mesenchymal transition (EMT) is a dynamic process in which epithelial cells reorganize their cytoskeleton, lose apical–basal polarity, cell–cell adhesions and acquire mesenchymal phenotypes with increased migration and invasion capacities [1]. In the opposite process, mesenchymal–epithelial transition (MET), motile, spindle-shaped mesenchymal-like cells reorganize their cytoskeleton, resulting in an organized epithelium [1]. Both EMT and MET are key processes during physiological (embryonic development, regeneration) and pathological processes, such as cancer and fibrosis [1].

Epithelial–mesenchymal transition (EMT) has been a controversial concept in the last years. The criteria to define EMT have been based on context-specific or even research-community-specific observations, leading to discrepancies in data interpretation and persistent disagreements about whether the process studied in vivo could be considered EMT or not [2][3][4][5][6][7][8][9]. Besides, increasing evidence supports that the complexity, plasticity and diversity of EMT manifestations have been underestimated or oversimplified, and that cells can adopt various degrees of mixed epithelial and mesenchymal features, leading to a continuum of intermediate hybrid phenotypes known as “partial” EMT, which is a heterogeneous, dynamic and reversible process [10][11][12]. Those partial EMT states have been reported to be more relevant to cancer metastasis than the mesenchymal phenotype itself [13], and multiple partial EMT states have been proposed and verified to coexist in the same tumour. Moreover, it was recently suggested that the number of potential intermediate EMT states within a tumour can be an indicator of malignancy [14]. Therefore, the EMT International Association (TEMTIA) has recently published a consensus statement to avoid misinterpretations of the generated research data and encourage scientists to adhere to the term EMP instead of the traditional EMT [1].

Epithelial–mesenchymal plasticity (EMP) plays critical physiological roles during embryonic development, postnatal growth and epithelial homeostasis, but it is also involved in a number of pathological conditions, including wound repair, fibrosis, inflammation and cancer. EMP has been intimately linked with most, if not all, of the steps during cancer development and progression (e.g., migration, invasion, immune escape, drug resistance and metastatic dissemination), and these links have been extensively reviewed [15][16][17][18][19][20][21].

During cancer progression, tumour cells and the surrounding tumour microenvironment (TME) components (e.g., immune cells, fibroblasts, endothelial cells) secrete a variety of inflammatory mediators (including cytokines, chemokines, matrix metalloproteinases (MMPs)) that can foster the acquisition of mesenchymal features in cancer cells by fuelling the EMP-promoting inflammation [22][23][24]. Tumour microenvironment-associated inflammation, mainly regulated by cytokines, has been long described to contribute to every stage of cancer progression [25][26][27][28]. Pro-inflammatory cytokines alert the immune system to potential threats, playing a fundamental role in the body’s immune defence. However, dysregulated cytokine production can result in harmful responses to the body and consequent development of pathological conditions, including cancer [29].

The interleukin 6 (IL-6) cytokine family plays important physiological roles in inflammation, immune responses and haematopoiesis [30]. Deregulation of IL-6 signalling has been associated with chronic inflammation, autoimmunity, infectious diseases and cancer, where it often acts as a diagnostic or prognostic indicator of disease activity and response to therapy [31][32]. IL-6 has been considered a keystone cytokine in the link between inflammation and cancer, and has received a lot of attention as a potential therapeutic target [33].

Interleukin 6 (IL-6) cytokine family plays important physiological roles in inflammation, immune responses, and haematopoiesis [30]. Deregulation of IL-6 signalling has been associated with chronic inflammation, autoimmunity, infectious diseases and cancer, where it often acts as a diagnostic or prognostic indicator of disease activity and response to therapy [31,32]. IL-6 has been considered a keystone cytokine in the link between inflammation and cancer; and has received a lot of attention as a potential therapeutic target [33].

The IL-6 cytokine family includes IL-6, IL-11, IL-27, IL-31, ciliary neurotrophic factor (CNTF), leukaemia inhibitory factor (LIF), cardiotrophin 1 (CT-1), cardiotrophin-like cytokine (CLC) and oncostatin M (OSM), all sharing the common glycoprotein 130 (gp130, IL6ST) receptor signalling subunit. Cytokine specificity is dependent on its unique cell-surface receptor, which shows a restricted expression pattern and dimerises with the ubiquitously expressed gp130 subunit. This restricted pattern is what makes some cells more responsive to certain cytokines than others [31]. All IL-6-related cytokine receptor complexes transduce intracellular signals via the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway, but they can also activate the mitogen-activated protein kinase (MAPK)–extracellular signal-regulated kinase (MAPK/ERK) and phosphoinositide 3-kinase (PI3K)–protein kinase B (PKB or Akt) pathways [34]. Activated STATs enter the nucleus and activate context dependent genes [35]. STAT3 signalling is considered a major pathway for cancer inflammation due to its frequent activation in malignant cells and key role in regulating many crucial genes associated with inflammation in the tumour microenvironment [36]. STATs also induce the suppressors of cytokine signalling (SOCS) [37][38], which bind to tyrosine-phosphorylated JAK and tyrosine-phosphorylated gp130 [39], respectively, to stop IL-6 family signalling by means of a negative feedback loop. Interestingly, the IL-6 family has been described to have a great deal of promiscuity, with some members presenting affinity to more than one specific receptor and being able to induce the same or different physiological outcomes [31].

The IL-6 cytokine family includes IL-6, IL-11, IL-27, IL-31, ciliary neurotrophic factor (CNTF), leukaemia inhibitory factor (LIF), cardiotrophin 1 (CT-1), cardiotrophin-like cytokine (CLC), and oncostatin M (OSM), all sharing the common glycoprotein 130 (gp130, IL6ST) receptor signalling subunit. Cytokine specificity is dependent on its unique cell-surface receptor, which shows a restricted expression pattern and dimerises with the ubiquitously expressed gp130 subunit. This restricted pattern is what makes some cells more responsive to certain cytokines than others [31]. All IL-6-related cytokine receptor complexes transduce intracellular signals via the Janus kinase (JAK) - signal transducer and activator of transcription (STAT) pathway, but they can also activate the mitogen-activated protein kinase (MAPK) – extracellular signal-regulated kinase (MAPK/ERK) and phosphoinositide 3-kinase (PI3K) – protein kinase B (PKB or Akt) pathways [34]. Activated STATs enter the nucleus and activate context dependent genes [35]. STAT3 signalling is considered a major pathway for cancer inflammation due to its frequent activation in malignant cells and key role in regulating many crucial genes associated with inflammation in the tumour microenvironment [36]. STATs also induce the suppressors of cytokine signalling (SOCS) [37,38], which bind to tyrosine-phosphorylated JAK and tyrosine-phosphorylated gp130 [39] respectively, to stop IL-6 family signalling by means of a negative feedback loop. Interestingly, the IL-6 family has been described to have a great deal of promiscuity, with some members presenting affinity to more than one specific receptor and being able to induce the same or different physiological outcomes [31].

2. Role of IL-6 and OSM in Epithelial–Mesenchymal Plasticity

The reciprocal causative link between EMP and IL-6 family has been supported by a large number of independent studies. The experimental evidence linking OSM and EMP is less, but it is still supported by a considerable number of scientific reports. The main effects of IL-6 and OSM in EMP and the signalling pathways involved are summarised in Figure 1. In general, IL-6 and OSM induce EMP in cancer cells by favouring the acquisition of mesenchymal traits and cancer stem cell (CSC) associated features. They also promote stemness, migration, invasion and metastasis in different in vitro and in vivo experimental settings of several cancer types including breast, head and neck, lung and gastric cancers.

The STAT3 transcription factor is the leading EMP effector upon activation of IL-6 receptor (IL-6R) and OSM receptor (OSMR) [40][41][40,41], although the involvement of other downstream effectors cannot be disregarded. There is strong experimental evidence supporting the role of the transcription factor STAT3 as the main mediator of EMP induction by IL-6 and OSM in cancer [40][41][42][43][40,41,43,47]. STAT3 can cooperate with other signalling nodules (mainly Src, SMAD and c-Myc) to mediate IL-6 and OSM promotion of EMP in cancer cells [42][44][43][45][46][47][48][49][50][43,44,47,49,50,59,60,67,68]. Interestingly, a few reports have described anti-EMP and anti-metastatic effects of OSM mediated by STAT1 [51][52][53][69-71]. It is widely accepted that activation of STAT3 by IL-6 related cytokines leads to EMP while activation of STAT1 leads to anti-tumorigenic and anti-EMP effects.

Transcription factors involved in EMP (EMT-TFs) have been recently classified as core and non-core EMT-TFs [1]. IL-6 is able to induce the expression of EMT-TFs in a wide variety of cancer types. It is widely accepted that Snail is increased after OSM exposure in many cancer types, including prostate [30], pancreatic [31], cervical [32] and breast cancers [33][34][35][36]. In addition, OSM has been described to increase the Zeb1 protein levels in PDAC [31] and breast cancer [36] and Zeb2 in cervical cancer [32].

Apart from the transcriptional regulation, EMT-TFs levels can be altered by a variety of post-transcriptional, translational and post-translational regulatory networks including micro-RNAs (miRNAs). The list of miRNAs directly or indirectly associated with EMP is extensively increasing [54][91]. So far, miR200 [55][56][92,93] and miR34 [57][58][94,95] families are the best characterized, being both miRNA families strong protectors of the epithelial phenotype in different cellular systems and positively regulated by the tumour suppressor p53 [57][59][60][94,96,97]. Both miRNA families have been shown to be modulated by IL-6 and OSM in cancer cells.

Most of the scientific evidence point to similar molecular and functional consequences of IL-6 and OSM-induced EMP in cancer cells. Both IL-6 and OSM induce E-cadherin repression, increase the expression of mesenchymal markers, promote mesenchymal/ fibroblastic morphology, stemness and migration, as well as invasion in vitro and in vivo. In addition, IL-6 has been reported to induce resistance to cancer therapies and anoikis. Although most of the evidence is derived from studies performed in cancer cell lines, the pro-EMT and pro-invasive effects of IL-6 and OSM have been proved in vivo in animal models of breast, lung, gastric, cervical, and head and neck cancers, among others.

Despite some controversy regarding the direct effect of EMP on cancer metastasis, EMP related features have been associated with aggressiveness and worse prognosis [2][3][4][5][6][7][8][9][2–9]. Similarly, IL-6 and OSM are linked to decreased overall and disease-free survival in various cancer types, in part due to their role in EMP and metastasis [61][132]. The association between IL-6, OSM and EMP observed in cancer cell lines and animal models is relevant in the clinical setting. 

3. Role of LIF on Epithelial-Mesenchymal Plasticity

The relevance of the leukaemia inhibitory factor (LIF) in stem cell maintenance and development is well described [37]. However, its role in cancer-related epithelial–mesenchymal plasticity is less clear, as both pro- and anti-EMP functions have been reported.

In nasopharyngeal carcinoma, LIF reprograms the cancer cell invasive mode from collective to mesenchymal migration via acquisition of EMP, as shown by increased expression of N-cadherin, vimentin and IQ motif-containing GTPase-activating protein 1 (IQGAP1) concomitant with a decreased expression of E-cadherin [38]. In those cancer cells, LIF promoted invadopodia-associated characteristics and markers, such as tyrosine kinase substrate with five SH3 domains (TKS5), cortactin (CTTN), matrix metallopeptidase 2 (MMP2) and SRC proto-oncogene (SRC). Furthermore, LIF induced fibroblastic morphology with enhanced vascular dissemination and local invasion through modulation of the YAP1-FAK/PXN signalling in 3D gels and xenografts [38]. These results are relevant in the clinical setting, as higher levels of LIF and LIF receptor (LIFR) correlated with poorer metastasis/recurrence-free survival [38].

Other studies have also associated LIF signalling with EMP features such as increased cell migration, invasion, CSC properties and metastasis, reporting both promoting and inhibitory roles, despite not always showing a direct link between LIF and EMP. In gastric cancer, LIF promoted proliferation, colony formation, invasion, migration and tumour growth by inhibiting the Hippo pathway, resulting in increased YAP nuclear translocation and transcriptional activity, giving rise to cancer cells with decreased E-cadherin and increased MMP7 protein levels [39]. Interestingly, LIF promoted mesenchymal epithelial transition in lung cancer cells through the LIF/LIFR/p-ERK/pS727-STAT3 signalling pathway leading to increased metastasis [40].

Intriguingly, in breast cancer, anti-metastatic potential has been attributed to LIFR [41][6242], as LIFR downregulation was responsible for the pro-metastatic effect of the E-cadherin suppressor miR-9 [41]. Additionally, in the TNBC cell line MDA-MB-231, LIFR overexpression did not alter vimentin protein levels in vitro but reduced vimentin positive metastatic foci in vivo [41]. The anti-tumorigenic roles of LIF in gastric CSCs also have been described, where it decreased the CSC properties and population in both cell lines and a patient-derived xenograft (PDX) [4243]. Both in breast and in gastric cancer cells, the anti-metastatic role of LIF-LIFR was mediated through the activation of Hippo tumour suppressor kinases (MST1/2 and LATS1/2), with the consequent inhibition of the YAP/TAZ/TEAD oncogenic effector activity. It would be interesting to know if STAT1 is involved in the anti-metastatic effect of LIF, as has been described for other cytokines of the family [44].

4. Role of IL-11 on Epithelial–Mesenchymal Plasticity

Interleukin-11 (IL-11) is known to participate in osteoclast-mediated bone remodelling together with TGFβ, and both have been associated with increased bone metastasis [6345][6446]. However, reports linking IL-11 and EMP are limited, as far as we know, with few exceptions supporting a positive contribution of IL-11 to EMP features. 

IL-11 is increased by HIF1α in hypoxia and induces EMP via the PI3K/Akt/GSKβ3/Snai1 pathway in anaplastic thyroid carcinoma cells, as demonstrated by reduced ZO-1 and E-cadherin and increased vimentin and Snail protein levels, ultimately improving their migratory and invasive potential [4347]. IL-11 treatment also promoted EMP in different in vivo NSCLC models, via AKT and STAT3, leading to increased levels of mesenchymal markers, such as Snail, Slug, Twist1, vimentin and N-cadherin, and downregulation of E-cadherin, claudin-1 and ZO-1 expression [6548][4549]. One of these studies reported that IL-11 treatment promoted lung adenocarcinoma cell growth and EMT through activation of the STAT3/HIF-1α/EMT signalling pathway [6548]. In TNBC cells, IL-11 cooperated with its upstream regulator twinfilin 1 in promoting EMT and chemoresistance. In addition, knockdown of IL-11 favoured a mesenchymal-to-epithelial transition phenotype as demonstrated by rearranged actin filaments and increased vinculin-stained focal adhesions [4650]. The relevance in the clinical setting was demonstrated as low IL-11 correlated with relapse-free survival in breast cancer patients [4650]. Additionally, the IL-11/STAT3 pathway, activated by the oncogene HMGA2, has been shown to facilitate the migratory and invasive capacities of colorectal cells in vitro together with increased vimentin and decreased E-cadherin levels, and to promote tumorigenesis and distant metastasis in vivo [6651]. Of interest, the oncogene HMGA2 is also a master regulator of OSM-induced epithelial plasticity in breast cancer and can be induced by OSM [36], as we described in previous sections.

A recent study has shown that, in PDAC cells, IL-6 and IL-11 stimulated the expression of most S100 proteins regulating epithelial/mesenchymal features [6752]. Even if IL-11 treatment alone did not induce EMP by itself in this study, it synergised with IL-6 to activate STAT3, which cooperated with ZEB1 to upregulate the mesenchymal S100A4/A6 proteins, nullify the effect of epithelial S100A14 expression and promote an invasive phenotype [6752].

In conclusion, the available literature supports the role of IL-11 as a pro-EMP and pro-tumorigenic factor in anaplastic thyroid, lung, breast, colorectal and pancreatic cancer, mainly through activation of the STAT3 and PI3K/Akt pathways [6752][4347][6548][4549][4650][6651].

5. Conclusions

IL-6 family cytokines share many similarities as they have the potential to activate the same signalling pathways (e.g., JAK/STATs, MAPK/ERK and PI3K/AKT), but play different roles and are involved in different physiological and pathological processes as it is evidenced in the case of EMP. IL-6 and OSM are clear EMP promoters and their role in tumour progression and metastasis is widely accepted. IL-11 and LIF seem to promote EMP in some cancer types, even if the mechanisms are not as thoroughly described. However, the implication of LIF is less clear as it can exert both pro and anti-metastatic functions and their link with EMP is less studied. IL-27 is the unique strong EMP inhibitor of the family by a dominant STAT1 activation, while, interestingly, its subunit p28 (IL-30) has been suggested to favour an invasive phenotype in breast cancer cells.

Although it is widely accepted that IL-6 and OSM promote EMP in many cancer types, the data gathered in this review further suggest that both promote different EMP programmes depending on the cancer type and the experimental setting, giving rise to cells with intermediate phenotypes within the epithelium-mesenchymal spectrum rather than generating complete mesenchymal cells with no epithelial features. Repression of E-cadherin and increased Snail levels seem to be common features of the EMP programmes activated by IL-6 and OSM, while there is more discrepancy in the mesenchymal markers and other core EMT-TFs induced by those cytokines. The tumorigenic properties of IL-6 and OSM are principally mediated by STAT3, while few anti-EMP functions of OSM have been described by a dominant STAT1 activation in specific contexts.   

Even if the EMP process induced by IL-6 and OSM has been shown to be reversible, there are several autocrine and paracrine positive feedback loops leading to long term pro-EMP signalling. In addition, both cytokines are required for the initiation and maintenance of transdifferentiated/ mesenchymal and CSC-like populations, supporting a role in the acquisition of therapy resistance [44][68][69][70][61][71][72][44,55,111,116,132,162,163]. In conclusion, the data presented here, obtained from in vitro and in vivo experiments and from clinical samples, strongly supports the role of IL-6 and OSM on EMP promotion and suggests that both cytokines could be potential therapeutic targets to halt tumour progression by blocking EMP.

References

  1. Tanaka, T.; Narazaki, M.; Kishimoto, T. Il-6 in Inflammation, Immunity, and Disease. Cold Spring Harb. Perspect. Biol. 2014, 6, 16295–16296.Yang, J.; Antin, P.; Berx, G.; Blanpain, C.; Brabletz, T.; Bronner, M.; Campbell, K.; Cano, A.; Casanova, J.; Christofori, G.; et al. Guidelines and Definitions for Research on Epithelial–Mesenchymal Transition. Nat. Rev. Mol. Cell Biol. 2020, 21, 341–352.
  2. Rose-John, S. Interleukin-6 Family Cytokines. Cold Spring Harb. Perspect. Biol. 2018, 10, 1–18.Tarin, D. The Fallacy of Epithelial Mesenchymal Transition in Neoplasia. Cancer Res. 2005, 65, 5996–6000.
  3. Jones, S.A.; Jenkins, B.J. Recent Insights into Targeting the IL-6 Cytokine Family in Inflammatory Diseases and Cancer. Nat. Rev. Immunol. 2018, 18, 773–789.Thompson, E.W.; Newgreen, D.F. Carcinoma Invasion and Metastasis: A Role for Epithelial-Mesenchymal Transition? Cancer Res. 2005, 65, 5991–5995.
  4. Hunter, C.A.; Jones, S.A. IL-6 as a Keystone Cytokine in Health and Disease. Nat. Immunol. 2015, 16, 448–457.Fischer, K.R.; Durrans, A.; Lee, S.; Sheng, J.; Li, F.; Wong, S.T.C.; Choi, H.; El Rayes, T.; Ryu, S.; Troeger, J.; et al. Epithelial-to-Mesenchymal Transition Is Not Required for Lung Metastasis but Contributes to Chemoresistance. Nature 2015, 527, 472–476.
  5. Heinrich, P.C.; Behrmann, I.; Haan, S.; Hermanns, H.M.; Müller-Newen, G.; Schaper, F. Principles of Interleukin (IL)-6-Type Cytokine Signalling and Its Regulation. Biochem. J. 2003, 374, 1–20.Zheng, X.; Carstens, J.L.; Kim, J.; Scheible, M.; Kaye, J.; Sugimoto, H.; Wu, C.C.; Lebleu, V.S.; Kalluri, R. Epithelial-to-Mesenchymal Transition Is Dispensable for Metastasis but Induces Chemoresistance in Pancreatic Cancer. Nature 2015, 527, 525–530.
  6. Harrison, D.A. The JAK/STAT Pathway. Cold Spring Harb. Perspect. Biol. 2012, 4, a011205.Ye, X.; Brabletz, T.; Kang, Y.; Longmore, G.D.; Nieto, M.A.; Stanger, B.Z.; Yang, J.; Weinberg, R.A. Upholding a Role for EMT in Breast Cancer Metastasis. Nature 2017, 547, E1–E6.
  7. Yu, H.; Pardoll, D.; Jove, R. STATs in Cancer Inflammation and Immunity: A Leading Role for STAT3. Nat. Rev. Cancer 2009, 9, 798–809.Aiello, N.M.; Kang, Y. Context-Dependent EMT Programs in Cancer Metastasis. J. Exp. Med. 2019, 216, 1016–1026.
  8. Liau, N.P.D.; Laktyushin, A.; Lucet, I.S.; Murphy, J.M.; Yao, S.; Whitlock, E.; Callaghan, K.; Nicola, N.A.; Kershaw, N.J.; Babon, J.J. The Molecular Basis of JAK/STAT Inhibition by SOCS1. Nat. Commun. 2018, 9, 1–14.Williams, E.D.; Gao, D.; Redfern, A.; Thompson, E.W. Controversies around Epithelial–Mesenchymal Plasticity in Cancer Metastasis. Nat. Rev. Cancer 2019, 19, 716–732.
  9. Carow, B.; Rottenberg, M.E. SOCS3, a Major Regulator of Infection and Inflammation. Front. Immunol. 2014, 5, 58.Mittal, V. Epithelial Mesenchymal Transition in Tumor Metastasis. Annu. Rev. Pathol. Mech. Dis. 2018, 13, 395–412.
  10. Schmitz, J.; Dahmen, H.; Grimm, C.; Gendo, C.; Müller-Newen, G.; Heinrich, P.C.; Schaper, F. The Cytoplasmic Tyrosine Motifs in Full-Length Glycoprotein 130 Have Different Roles in IL-6 Signal Transduction. J. Immunol. 2000, 164, 848–854.Nieto, M.A.; Huang, R.Y.Y.J.; Jackson, R.A.A.; Thiery, J.P.P. Emt: 2016. Cell 2016, 166, 21–45.
  11. Wendt, M.K.; Balanis, N.; Carlin, C.R.; Schiemann, W.P. STAT3 and Epithelial–Mesenchymal Transitions in Carcinomas. JAK-STAT 2014, 3, e28975.Cook, D.P.; Vanderhyden, B.C. Context Specificity of the EMT Transcriptional Response. Nat. Commun. 2020, 11, 2142.
  12. Jin, W. Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial–Mesenchymal Transition. Cells 2020, 9, 217.Bhatia, S.; Wang, P.; Toh, A.; Thompson, E.W. New Insights Into the Role of Phenotypic Plasticity and EMT in Driving Cancer Progression. Front. Mol. Biosci. 2020, 7, 71.
  13. Junk, D.J.; Bryson, B.L.; Smigiel, J.M.; Parameswaran, N.; Bartel, C.A.; Jackson, M.W. Oncostatin M Promotes Cancer Cell Plasticity through Cooperative STAT3-SMAD3 Signaling. Oncogene 2017, 36, 4001–4013.Jolly, M.K.; Boareto, M.; Huang, B.; Jia, D.; Lu, M.; Onuchic, J.N.; Levine, H.; Ben-Jacob, E. Implications of the Hybrid Epithelial/Mesenchymal Phenotype in Metastasis. Front. Oncol. 2015, 5, 155.
  14. Yu, Z.; Li, Z.; Wang, C.; Pan, T.; Chang, X.; Wang, X.; Zhou, Q.; Wu, X.; Li, J.; Zhang, J.; et al. Oncostatin M Receptor, Positively Regulated by SP1, Promotes Gastric Cancer Growth and Metastasis upon Treatment with Oncostatin M. Gastric Cancer 2019, 22, 955–966.Goetz, H.; Melendez-Alvarez, J.R.; Chen, L.; Tian, X.J. A Plausible Accelerating Function of Intermediate States in Cancer Metastasis. PLoS Comput. Biol. 2020, 16, e1007682.
  15. Kim, M.S.; Jeong, J.; Seo, J.; Kim, H.S.; Kim, S.J.; Jin, W. Dysregulated JAK2 Expression by TrkC Promotes Metastasis Potential, and EMT Program of Metastatic Breast Cancer. Sci. Rep. 2016, 6, 33899.Sistigu, A.; Di Modugno, F.; Manic, G.; Nisticò, P. Deciphering the Loop of Epithelial-Mesenchymal Transition, Inflammatory Cytokines and Cancer Immunoediting. Cytokine Growth Factor Rev. 2017, 36, 67–77.
  16. Bryson, B.L.; Junk, D.J.; Cipriano, R.; Jackson, M.W. STAT3-Mediated SMAD3 Activation Underlies Oncostatin M-Induced Senescence. Cell Cycle 2017, 16, 319–334.Gonzalez, D.M.; Medici, D. Signaling Mechanisms of the Epithelial-Mesenchymal Transition. Sci. Signal. 2014, 7, re8.
  17. Bryson, B.L.; Tamagno, I.; Taylor, S.E.; Parameswaran, N.; Chernosky, N.M.; Balasubramaniam, N.; Jackson, M.W. Aberrant Induction of a Mesenchymal/Stem-Cell Program Engages Senescence in Normal Mammary Epithelial Cells. Mol. Cancer Res. 2020, 19.Lamouille, S.; Xu, J.; Derynck, R. Molecular Mechanisms of Epithelial-Mesenchymal Transition. Nat. Rev. Mol. Cell Biol. 2014, 15, 178–196.
  18. Shintani, Y.; Fujiwara, A.; Kimura, T.; Kawamura, T.; Funaki, S.; Minami, M.; Okumura, M. IL-6 Secreted from Cancer-Associated Fibroblasts Mediates Chemoresistance in NSCLC by Increasing Epithelial-Mesenchymal Transition Signaling. J. Thorac. Oncol. 2016, 11, 1482–1492.Demirkan, B. The Roles of Epithelial-to-Mesenchymal Transition (EMT) and Mesenchymal-to-Epithelial Transition (MET) in Breast Cancer Bone Metastasis: Potential Targets for Prevention and Treatment. J. Clin. Med. 2013, 2, 264.
  19. Yamada, D.; Kobayashi, S.; Wada, H.; Kawamoto, K.; Marubashi, S.; Eguchi, H.; Ishii, H.; Nagano, H.; Doki, Y.; Mori, M. Role of Crosstalk between Interleukin-6 and Transforming Growth Factor-Beta 1 in Epithelial-Mesenchymal Transition and Chemoresistance in Biliary Tract Cancer. Eur. J. Cancer 2013, 49, 1725–1740.De Craene, B.; Berx, G. Regulatory Networks Defining EMT during Cancer Initiation and Progression. Nat. Rev. Cancer 2013, 13, 97–110.
  20. Gao, X.; Liu, X.; Lu, Y.; Wang, Y.; Cao, W.; Liu, X.; Hu, H.; Wang, H. PIM1 Is Responsible for IL-6-Induced Breast Cancer Cell EMT and Stemness via c-Myc Activation. Breast Cancer 2019, 26, 663–671.Quail, D.F.; Joyce, J.A. Microenvironmental Regulation of Tumor Progression and Metastasis. Nat. Med. 2013, 19, 1423–1437.
  21. Kan, C.E.; Cipriano, R.; Jackson, M.W. C-MYC Functions as a Molecular Switch to Alter the Response of Human Mammary Epithelial Cells to Oncostatin M. Cancer Res. 2011, 71, 6930–6939.Polyak, K.; Weinberg, R.A. Transitions between Epithelial and Mesenchymal States: Acquisition of Malignant and Stem Cell Traits. Nat. Rev. Cancer 2009, 9, 265–273.
  22. Pan, C.M.; Wang, M.L.; Chiou, S.H.; Chen, H.Y.; Wu, C.W. Oncostatin M Suppresses Metastasis of Lung Adenocarcinoma by Inhibiting SLUG Expression through Coordination of STATs and PIASs Signalings. Oncotarget 2016, 7, 60395–60406.Suarez-Carmona, M.; Lesage, J.; Cataldo, D.; Gilles, C. EMT and Inflammation: Inseparable Actors of Cancer Progression. Mol. Oncol. 2017, 11, 805–823.
  23. Sarközi, R.; Hauser, C.; Noppert, S.-J.; Kronbichler, A.; Pirklbauer, M.; Haller, V.M.; Grillari, J.; Grillari-Voglauer, R.; Mayer, G.; Schramek, H. Oncostatin M Is a Novel Inhibitor of TGF-Β1-Induced Matricellular Protein Expression. Am. J. Physiol. Physiol. 2011, 301, F1014–F1025.López-Novoa, J.M.; Nieto, M.A. Inflammation and EMT: An Alliance towards Organ Fibrosis and Cancer Progression. EMBO Mol. Med. 2009, 1, 303–314.
  24. Pollack, V.; Sarközi, R.; Banki, Z.; Feifel, E.; Wehn, S.; Gstraunthaler, G.; Stoiber, H.; Mayer, G.; Montesano, R.; Strutz, F.; et al. Oncostatin M-Induced Effects on EMT in Human Proximal Tubular Cells: Differential Role of ERK Signaling. Am. J. Physiol. Physiol. 2007, 293, F1714–F1726.Dominguez, C.; David, J.M.; Palena, C. Epithelial-Mesenchymal Transition and Inflammation at the Site of the Primary Tumor. Semin. Cancer Biol. 2017, 47, 177–184.
  25. Yang, J.; Antin, P.; Berx, G.; Blanpain, C.; Brabletz, T.; Bronner, M.; Campbell, K.; Cano, A.; Casanova, J.; Christofori, G.; et al. Guidelines and Definitions for Research on Epithelial–Mesenchymal Transition. Nat. Rev. Mol. Cell Biol. 2020, 21, 341–352.Coussens, L.M.; Werb, Z. Inflammation and Cancer. Nature 2002, 420, 860–867.
  26. Zhang, J.; Ma, L. MicroRNA Control of Epithelial-Mesenchymal Transition and Metastasis. Cancer Metastasis Rev. 2012, 31, 653–662.Greten, F.R.; Grivennikov, S.I. Inflammation and Cancer: Triggers, Mechanisms, and Consequences. Immunity 2019, 51, 27–41.
  27. Gregory, P.A.; Bert, A.G.; Paterson, E.L.; Barry, S.C.; Tsykin, A.; Farshid, G.; Vadas, M.A.; Khew-Goodall, Y.; Goodall, G.J. The MiR-200 Family and MiR-205 Regulate Epithelial to Mesenchymal Transition by Targeting ZEB1 and SIP1. Nat. Cell Biol. 2008, 10, 593–601.Grivennikov, S.I.; Greten, F.R.; Karin, M. Immunity, Inflammation, and Cancer. Cell 2010, 140, 883–899.
  28. Park, S.M.; Gaur, A.B.; Lengyel, E.; Peter, M.E. The MiR-200 Family Determines the Epithelial Phenotype of Cancer Cells by Targeting the E-Cadherin Repressors ZEB1 and ZEB2. Genes Dev. 2008, 22, 894–907.Piotrowski, I.; Kulcenty, K.; Suchorska, W. Interplay between Inflammation and Cancer. Rep. Pract. Oncol. Radiother. 2020, 25, 422–427.
  29. Kim, N.H.; Kim, H.S.; Li, X.Y.; Lee, I.; Choi, H.S.; Kang, S.E.; Cha, S.Y.; Ryu, J.K.; Yoon, D.; Fearon, E.R.; et al. A P53/MiRNA-34 Axis Regulates Snail1-Dependent Cancer Cell Epithelial-Mesenchymal Transition. J. Cell Biol. 2011, 195, 417–433.Cytokines in the Balance. Nat. Immunol. 2019, 20, 1557.
  30. Siemens, H.; Jackstadt, R.; Hünten, S.; Kaller, M.; Menssen, A.; Götz, U.; Hermeking, H. MiR-34 and SNAIL Form a Double-Negative Feedback Loop to Regulate Epithelial-Mesenchymal Transitions. Cell Cycle 2011, 10, 4256–4271.Sterbova, S.; Karlsson, T.; Persson, E. Oncostatin M Induces Tumorigenic Properties in Non-Transformed Human Prostate Epithelial Cells, in Part through Activation of Signal Transducer and Activator of Transcription 3 (STAT3). Biochem. Biophys. Res. Commun. 2018, 498, 769–774.
  31. Chang, C.J.; Chao, C.H.; Xia, W.; Yang, J.Y.; Xiong, Y.; Li, C.W.; Yu, W.H.; Rehman, S.K.; Hsu, J.L.; Lee, H.H.; et al. P53 Regulates Epithelial-Mesenchymal Transition and Stem Cell Properties through Modulating MiRNAs. Nat. Cell Biol. 2011, 13, 317–323.Smigiel, J.M.; Parameswaran, N.; Jackson, M.W. Potent EMT and CSC Phenotypes Are Induced by Oncostatin-M in Pancreatic Cancer. Mol. Cancer Res. 2017, 15, 478–488.
  32. Choi, Y.J.; Lin, C.P.; Ho, J.J.; He, X.; Okada, N.; Bu, P.; Zhong, Y.; Kim, S.Y.; Bennett, M.J.; Chen, C.; et al. MiR-34 MiRNAs Provide a Barrier for Somatic Cell Reprogramming. Nat. Cell Biol. 2011, 13, 1353–1360.Kucia-Tran, J.A.; Tulkki, V.; Smith, S.; Scarpini, C.G.; Hughes, K.; Araujo, A.M.; Yan, K.Y.M.; Botthof, J.; Pérez-Gómez, E.; Quintanilla, M.; et al. Overexpression of the Oncostatin-M Receptor in Cervical Squamous Cell Carcinoma Is Associated with Epithelial-Mesenchymal Transition and Poor Overall Survival. Br. J. Cancer 2016, 115, 212–222.
  33. Tarin, D. The Fallacy of Epithelial Mesenchymal Transition in Neoplasia. Cancer Res. 2005, 65, 5996–6000.Junk, D.J.; Bryson, B.L.; Smigiel, J.M.; Parameswaran, N.; Bartel, C.A.; Jackson, M.W. Oncostatin M Promotes Cancer Cell Plasticity through Cooperative STAT3-SMAD3 Signaling. Oncogene 2017, 36, 4001–4013.
  34. Thompson, E.W.; Newgreen, D.F. Carcinoma Invasion and Metastasis: A Role for Epithelial-Mesenchymal Transition? Cancer Res. 2005, 65, 5991–5995.West, N.R.; Murray, J.I.; Watson, P.H. Oncostatin-M Promotes Phenotypic Changes Associated with Mesenchymal and Stem Cell-like Differentiation in Breast Cancer. Oncogene 2014, 33, 1485–1494.
  35. Fischer, K.R.; Durrans, A.; Lee, S.; Sheng, J.; Li, F.; Wong, S.T.C.; Choi, H.; El Rayes, T.; Ryu, S.; Troeger, J.; et al. Epithelial-to-Mesenchymal Transition Is Not Required for Lung Metastasis but Contributes to Chemoresistance. Nature 2015, 527, 472–476.Doherty, M.R.; Parvani, J.G.; Tamagno, I.; Junk, D.J.; Bryson, B.L.; Cheon, H.J.; Stark, G.R.; Jackson, M.W. The Opposing Effects of Interferon-Beta and Oncostatin-M as Regulators of Cancer Stem Cell Plasticity in Triple-Negative Breast Cancer. Breast Cancer Res. 2019, 21, 1–12.
  36. Zheng, X.; Carstens, J.L.; Kim, J.; Scheible, M.; Kaye, J.; Sugimoto, H.; Wu, C.C.; Lebleu, V.S.; Kalluri, R. Epithelial-to-Mesenchymal Transition Is Dispensable for Metastasis but Induces Chemoresistance in Pancreatic Cancer. Nature 2015, 527, 525–530.Guo, L.; Chen, C.; Shi, M.; Wang, F.; Chen, X.; Diao, D.; Hu, M.; Yu, M.; Qian, L.; Guo, N. Stat3-Coordinated Lin-28-Let-7-HMGA2 and MiR-200-ZEB1 Circuits Initiate and Maintain Oncostatin M-Driven Epithelial-Mesenchymal Transition. Oncogene 2013, 32, 5272–5282.
  37. Ye, X.; Brabletz, T.; Kang, Y.; Longmore, G.D.; Nieto, M.A.; Stanger, B.Z.; Yang, J.; Weinberg, R.A. Upholding a Role for EMT in Breast Cancer Metastasis. Nature 2017, 547, E1–E6.Onishi, K.; Zandstra, P.W. LIF Signaling in Stem Cells and Development. Development 2015, 142, 2230–2236.
  38. Aiello, N.M.; Kang, Y. Context-Dependent EMT Programs in Cancer Metastasis. J. Exp. Med. 2019, 216, 1016–1026.Liu, S.C.; Hsu, T.; Chang, Y.S.; Chung, A.K.; Jiang, S.S.; OuYang, C.N.; Yuh, C.H.; Hsueh, C.; Liu, Y.P.; Tsang, N.M. Cytoplasmic LIF Reprograms Invasive Mode to Enhance NPC Dissemination through Modulating YAP1-FAK/PXN Signaling. Nat. Commun. 2018, 9, 333.
  39. Williams, E.D.; Gao, D.; Redfern, A.; Thompson, E.W. Controversies around Epithelial–Mesenchymal Plasticity in Cancer Metastasis. Nat. Rev. Cancer 2019, 19, 716–732.Bian, S.; Yang, Y.; Liang, W.; Zhang, K.; Chen, L.; Zhang, Z. Leukemia Inhibitory Factor Promotes Gastric Cancer Cell Proliferation, Migration, and Invasion via the LIFR–Hippo–YAP Pathway. Ann. N. Y. Acad. Sci. 2021, 1484, 74–89.
  40. Mittal, V. Epithelial Mesenchymal Transition in Tumor Metastasis. Annu. Rev. Pathol. Mech. Dis. 2018, 13, 395–412.Lin, W.H.; Chang, Y.W.; Hong, M.X.; Hsu, T.C.; Lee, K.C.; Lin, C.; Lee, J.L. STAT3 Phosphorylation at Ser727 and Tyr705 Differentially Regulates the EMT–MET Switch and Cancer Metastasis. Oncogene 2021, 40, 791–805.
  41. Tawara, K.; Scott, H.; Emathinger, J.; Wolf, C.; LaJoie, D.; Hedeen, D.; Bond, L.; Montgomery, P.; Jorcyk, C. HIGH Expression of OSM and IL-6 Are Associated with Decreased Breast Cancer Survival: Synergistic Induction of IL-6 Secretion by OSM and IL-1β. Oncotarget 2019, 10, 2068–2085.Chen, D.; Sun, Y.; Wei, Y.; Zhang, P.; Rezaeian, A.H.; Teruya-Feldstein, J.; Gupta, S.; Liang, H.; Lin, H.K.; Hung, M.C.; et al. LIFR Is a Breast Cancer Metastasis Suppressor Upstream of the Hippo-YAP Pathway and a Prognostic Marker. Nat. Med. 2012, 18, 1511–1517.
  42. Zheng, X.; Lu, G.; Yao, Y.; Gu, W. An Autocrine IL-6/IGF-1R Loop Mediates Emt and Promotes Tumor Growth in Non-Small Cell Lung Cancer. Int. J. Biol. Sci. 2019, 15, 1882–1891.Wang, M.; Wang, M.; Wang, Z.; Yu, X.; Song, Y.; Wang, C.; Xu, Y.; Wei, F.; Zhao, Y.; Xu, Y. Long Non-Coding RNA-CTD-2108O9.1 Represses Breast Cancer Metastasis by Influencing Leukemia Inhibitory Factor Receptor. Cancer Sci. 2018, 109, 1764–1774.
  43. Korkaya, H.; Kim, G., II; Davis, A.; Malik, F.; Henry, N.L.; Ithimakin, S.; Quraishi, A.A.; Tawakkol, N.; D’Angelo, R.; Paulson, A.K.; et al. Activation of an IL6 Inflammatory Loop Mediates Trastuzumab Resistance in HER2+ Breast Cancer by Expanding the Cancer Stem Cell Population. Mol. Cell 2012, 47, 570–584.Seeneevassen, L.; Giraud, J.; Molina-Castro, S.; Sifré, E.; Tiffon, C.; Beauvoit, C.; Staedel, C.; Mégraud, F.; Lehours, P.; Martin, O.C.B.; et al. Leukaemia Inhibitory Factor (LIF) Inhibits Cancer Stem Cells Tumorigenic Properties through Hippo Kinases Activation in Gastric Cancer. Cancers 2020, 12, 2011.
  44. Giladi, N.D.; Ziv-Av, A.; Lee, H.K.; Finniss, S.; Cazacu, S.; Xiang, C.; Ben-Asher, H.W.; de Carvalho, A.; Mikkelsen, T.; Poisson, L.; et al. RTVP-1 Promotes Mesenchymal Transformation of Glioma via a STAT-3/IL-6-Dependent Positive Feedback Loop. Oncotarget 2015, 6, 22680–22697.Pan, C.M.; Wang, M.L.; Chiou, S.H.; Chen, H.Y.; Wu, C.W. Oncostatin M Suppresses Metastasis of Lung Adenocarcinoma by Inhibiting SLUG Expression through Coordination of STATs and PIASs Signalings. Oncotarget 2016, 7, 60395–60406.
  45. Zhao, Y.; Xu, Y.; Li, Y.; Xu, W.; Luo, F.; Wang, B.; Pang, Y.; Xiang, Q.; Zhou, J.; Wang, X.; et al. NF-ΚB-Mediated Inflammation Leading to EMT via MiR-200c Is Involved in Cell Transformation Induced by Cigarette Smoke Extract. Toxicol. Sci. 2013, 135, 265–276.Kang, Y.; He, W.; Tulley, S.; Gupta, G.P.; Serganova, I.; Chen, C.R.; Manova-Todorova, K.; Blasberg, R.; Gerald, W.L.; Massagué, J. Breast Cancer Bone Metastasis Mediated by the Smad Tumor Suppressor Pathway. Proc. Natl. Acad. Sci. USA 2005, 102, 13909–13914.
  46. Smigiel, J.; Parvani, J.G.; Tamagno, I.; Polak, K.; Jackson, M.W. Breaking the Oncostatin M Feed-Forward Loop to Suppress Metastasis and Therapy Failure. J. Pathol. 2018, 245, 6–8.Deckers, M.; Van Dinther, M.; Buijs, J.; Que, I.; Löwik, C.; Van Der Pluijm, G.; Ten Dijke, P. The Tumor Suppressor Smad4 Is Required for Transforming Growth Factor β-Induced Epithelial to Mesenchymal Transition and Bone Metastasis of Breast Cancer Cells. Cancer Res. 2006, 66, 2202–2209.
  47. Zhong, Z.; Hu, Z.; Jiang, Y.; Sun, R.; Chen, X.; Chu, H.; Zeng, M.; Sun, C. Interleukin-11 Promotes Epithelial-Mesenchymal Transition in Anaplastic Thyroid Carcinoma Cells through PI3K/Akt/GSK3β Signaling Pathway Activation. Oncotarget 2016, 7, 59652–59663.
  48. Zhao, M.; Liu, Y.; Liu, R.; Qi, J.; Hou, Y.; Chang, J.; Ren, L. Upregulation of IL-11, an IL-6 Family Cytokine, Promotes Tumor Progression and Correlates with Poor Prognosis in Non-Small Cell Lung Cancer. Cell. Physiol. Biochem. 2018, 45, 2213–2224.
  49. Peng, N.; Lu, M.; Kang, M.; Liu, X.; Li, B.; Dong, C. Recombinant Human IL-11 Promotes Lung Adenocarcinoma A549 Cell Growth and EMT through Activating STAT3/HIF-1α/EMT Signaling Pathway. Anticancer Agents Med. Chem. 2020, 21, 1–10.
  50. Bockhorn, J.; Dalton, R.; Nwachukwu, C.; Huang, S.; Prat, A.; Yee, K.; Chang, Y.F.; Huo, D.; Wen, Y.; Swanson, K.E.; et al. MicroRNA-30c Inhibits Human Breast Tumour Chemotherapy Resistance by Regulating TWF1 and IL-11. Nat. Commun. 2013, 4, 1–14.
  51. Wu, J.; Wang, Y.; Xu, X.; Cao, H.; Sahengbieke, S.; Sheng, H.; Huang, Q.; Lai, M. Transcriptional Activation of FN1 and IL11 by HMGA2 Promotes the Malignant Behavior of Colorectal Cancer. Carcinogenesis 2016, 37, 511–521.
  52. Al-Ismaeel, Q.; Neal, C.P.; Al-Mahmoodi, H.; Almutairi, Z.; Al-Shamarti, I.; Straatman, K.; Jaunbocus, N.; Irvine, A.; Issa, E.; Moreman, C.; et al. ZEB1 and IL-6/11-STAT3 Signalling Cooperate to Define Invasive Potential of Pancreatic Cancer Cells via Differential Regulation of the Expression of S100 Proteins. Br. J. Cancer 2019, 121, 65–75.
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