Journal of Cytology & Tissue Biology Category: Clinical Type: Review Article

Inducers of Epithelial Mesenchymal Transiton and Cancer Stem Cells in Malignant Pleural Effusions

Emanuela Cherubini1*, Enrico Giarnieri2, Alberto Ricci2, Salvatore Mariotta1, Maria Rosaria Giovagnoli2 and Rita Mancini3
1 Department of clinical and molecular medicine, Sapienza University of Rome, Rome, Italy
2 Department of clinical and molecular medicine, Azienda Ospedaliera Sant'Andrea, Sapienza University of Rome, Rome, Italy
3 Department of clinical and molecular medicine, Laboratory of Research and Diagnostics, Sapienza University of Rome, Rome, Italy

*Corresponding Author(s):
Emanuela Cherubini
Department Of Clinical And Molecular Medicine, Sapienza University Of Rome, Rome, Italy
Tel:+39 0633775314,
Email:emanuela.cherubini@uniroma1.it

Received Date: Sep 16, 2016
Accepted Date: Nov 01, 2016
Published Date: Nov 14, 2016
DOI:10.24966/CTB-9107/100011

Abstract

The Epithelial to Mesenchymal Transition (EMT) plays a role not only in tumor metastasis but also in tumor recurrence. This process is believed to be tightly linked to the presence of Cancer Stem Cells (CSCs) however, it is still not clear which factors could induce EMT and how it could be a source for CSCs. It has been demonstrated that Malignant Pleural Effusion (MPEs) may represent an excellent source to identify markers and molecular mechanisms involved in EMT and CSCs development. Growth factors, cell differentiation markers and molecular adhesion are involved in some of the crucial neoplastic cell events such as proliferation, metastasis, resistance to chemotherapy and EMT.In this review, we summarize the current understanding of which molecular markers can orchestrate EMT and CSCs in MPEs.

Keywords

Cancer stem cell; Epithelial mesenchymal transition; Malignant pleural effusion; Tumor markers

INTRODUCTION

Lung cancer has produced the highest mortality rate in the world, current therapy is relatively ineffective and the survival rate at 5 years is still only 15% for the advanced disease. The presence of neoplastic cells in the pleural fluid represents a common medical problem in cancer patients with advanced neoplastic disease and it leads to poor survival [1-8]. Lung and breast cancers cause approximately 75% of all MPE. However, for around 10% of MPE cases, the primary tumor is unknown [9-13]. In MPEs it has been observed that neoplastic cells produce factors that contribute to overcoming the protective mesothelial layer. For example, neoplastic cells are capable of internalizing the CD44-hyaluronan complex and hydrolyzing it in oligosaccharides showing increased permeability in the mesothelial layer and angiogenic chemotactic ability [14]. Furthermore, VEGF and bFGF produced by neoplastic cells increase the permeability of the pleural surface [15]; a low level of endostatin observed in patients with malignant pleural effusion increases endothelial cell migration, angiogenesis and tumor growth [16]. Microenvironment, hypoxia and chemokines can modify the mesothelial cell phenotype. The ability of these cells to switch dynamically between different phenotypic states led to a series of studies in which different Authors demonstrated that MPEs could be an excellent source in cancer biology investigation and the identification of potential target therapy solutions. Following this, studies identified the presence of small-sub-populations of cells, also named cancer stem cells or cancer initiating cells, within the tumor cells, causing the aggressive behaviour of cancer cells [17-19]. The presence of these sub-populations, capable of self-renewal and multipotent differentiation, could add a new element in cancer research, explain the concept of heterogeneity, relapse after treatment and resistance to conventional chemotherapies.

INDUCERS OF EMT

The expression of EMT markers and of their related transcription factors has often been studied in stabilized cell lines. So far, very limited analysis has been performed in fresh cultures from primary tumors. It is widely accepted that cancer stem cells are represented by a distinct subset of cancer cells. In fact, in comparison with cancer cells, CSCs are distinct in their ability to self-renewal, form tumors in immune-deficient mice and differentiate in other cell types. This distinct population was initially identified in leukemias, but subsequently identified in several solid malignancies (breast, lung, prostate, colon, brain, head and neck, liver) as well as in MPEs [20-25]. In pleural effusions, cancer cells are susceptible to anoikis and apoptotic triggers, grow in suspension and develop compact multicellular spheroid aggregates. These cellular aggregates can resist against anoikis and apoptosis, and probably chemotherapeutic agents. It has been observed that the presence of elevated integrin attachments, available inside the tridimensional aggregate configuration, favors the protection and survival of cells [26]. In patients with ovarian cancer, peritoneal fluids and ascites, frequently exhibit spheroid aggregates, raising interest in their formation and function [27]. An association between contractile behavior, compact spheroid-forming ability, and the invasive capacity of cancer cells in 3D has been detected [26]. Cancer cells are able to form spheroids [28-30]. It has been suggested that there could be a positive correlation between spheroid formation and tumorigenity [30], such as the possibility that spheroid cancer cells gain invasive properties by undergoing EMT [26,31]. Epithelial plasticity is the ability of the cells to switch from a different state of phenotype, and the EMT is considered a transition from epithelial to mesenchymal phenotype (Figure 1 A,B,C). On the base of function and pathways, EMT shows different subtypes: embryonic development, tissue repair, inflammation and cancer [32]. The progression of most carcinomas toward malignancy is associated with the loss of epithelial differentiation and by switching towards mesenchymal phenotype with increasing cell motility and invasion. Recent studies have demonstrated that EMT plays a critical role not only in tumor metastasis but also in tumor recurrence, which is believed to be tightly linked to the presence of CSCs [33-35]. It is still not clear which factors could induce EMT and how the EMT could be a resource for CSCs [36]. Hypoxia but also cytokines can be factors inducing EMT activation but also transcription factors and adhesion molecules are differentially expressed [37].
 
Figures A and B: The EMT mechanism transform MPE cells like from epithelial to mesenchymal cell like with suppression of epithelial and activation of mesenchymal regulator markers.
Figure C: A subset of MPEs cells, known as CSCs, are tumorigenic and these cells are defined by their capacity for self renewal and differentiation plasticity. Furthermore these cells show CSCs and EMT markers suggesting that EMT is also thought to be a mechanism by which CSCs form.

Exosome

Recently, studies have evaluated the biology and composition of exosomes in cancer development has been observed that exosomes derived from tumor cells, communicate with stromal cells and vice-versa to promote tumor growth [38]. Exosomes released from cancer cells, may affect normal cells through the intercellular transfer of oncogenic materials such as DNA, mRNA, regulatory miRNA, oncoproteins and MHC class I and II proteins [39,40]. Furthermore, tumor and stromal cells can regulate the invasiveness of cancer cells through exosome-mediated delivery of protein and miRNA in the regulation of EMT-related pathways. In lung cancer cells and in late stage of lung cancer serum, an involvment of exosome as drivers of epithelial to mesenchymal transition has been recently reported, furthermore Lin et al., demonstrated that contents exosomes miR-205-5p and miR-200b were markedly increased in malignant pleural effusion [41,42].

E-cadherin

Down-regulation of E-cadherin and up-regulation of N-cadherin has been reported in tumor cells suggesting that EMT can occur heterogeneously and/or transiently within an invasive tumor [43]. On the contrary Zhao et al., observed that tumor cells in the pleural effusions mainly expressed an epithelial E-cadherin phenotype marker. The high expression of E-cadherin was associated with EGFR mutation predicting better outcome [44].

Vimentin and LASP-1

Vimentin, an intermediate filament protein normally expressed in mesenchymal cells, can be expressed in epithelial cells undergoing EMT, in both physiological and pathological conditions [45]. Vimentin and N-cadherin up-regulation and reduction of E-cadherin protein expression are representative of EMT markers in several tumor types. In breast and lung cancer, up-regulation of EMT markers like Vimentin, N-cadherin, cadherin-11, smooth- muscle-actin, and the reduction of characteristic epithelial markers like E-cadherin and cytokeratin has been frequently observed and associated with high aggressiveness and metastatic activity [37]. In papillary thyroid cancer in vitro studies demonstrated that Vimentin was required for the development and maintenance of a mesenchymal morphology and invasiveness, concluding that EMT is a common event and that Vimentin regulates EMT in thyroid cancer [46]. EMT is regulated by the activation of a cascade of transcription factors among which the most frequently involved are Snail, Slug and Twist. Twist is a highly conserved basic helix-loop-helix transcriptional factor. Its expression induces mesenchymal markers such as N-cadherin, Vimentin and fibronectin [47]. However the loss of E-cadherin expression is necessary but not sufficient to trigger EMT in cells over-expressing Twist. In addition, restoration of E-cadherin expression does not revert the mesenchymal phenotype [48]. Recently, has been reported a relationship between vimentin and LASP 1 in undifferentiated HCC cell lines. Authors Sustained that Vimentin (VIM) is a new molecular partner of LASP-1, an important hallmark of the epithelial-mesenchymal transition [49]. Further studies will be needed to verify a possible relationship between LASP-1 and cancer cells derived from malignant pleural effusion.

Twist

Twist, a highly conservative basic Helix-Loop-Helix (bHLH) transcription factor, is overexpressed in a variety of human tumors and associated to cancer invasion, metastasis and poor prognosis. Also it plays an important role in multiply processes including angiogenesis, resistance to apoptosis, multidrug resistance and EMT [50- 53]. Twist expression enhanced cell migration, tumor-sphere formation and stem-like markers [54] and up-regulation has been reported in invasive breast cancer, esophageal, parathyroid, hepatocellular and human bladder carcinoma [46,55-57]. In MPEs, Twist in adherent and spheroid cells, showed an extremely variable pattern of expression from sample to sample, which under scores the heterogeneity of malignant pleural effusion cells.

Snail and slug

Snail (Snai1) and Slug (Snai2), evolutionarily conserved members of the Snail family of zinc finger transcription factors, play an important role in embryonic development. They regulate the process of EMT, characterized by loss of intercellular adhesions and acquisition of a migratory phenotype [58]. Snail and Slug have been shown to be involved in pancreatic cancer development [59] and their effects were observed to be most active at the invasive front of tumors in invasive human breast cancers [60].

TGF-β

Inflammatory cells are the main source of growth factors. In MPEs, neoplastic cells are frequently associated to a variable presence of inflammatory cells. TGF-β1 is an inductor of pleurodes and regulate proliferation, migration and differentiation cell, and a potent chemoattractant for fibroblasts. Authors observed that mesothelial cells stimulated by TGF-β leads to collagen synthesis, matrix proteins, matrix metalloproteinase-1 and 9, and tissue inhibitor of matrix metalloproteinases-2 [61,62]. EMT can be induced or regulate by TGF-β not only during embryogenesis but also in fibrosis and cancer. TGF-β is considered a key effector of EMT during cancer progression and metastasis. Studies showed that transgenic expression of activated TGF-β1 correlates with invasive spindle cell carcinomas. TGF-β1 production by cancer cell triggers EMT, enhances angiogenesis providing an exit route for migratory mesenchymal cells [63].

VEGF

Vascular Endothelial Growth Factor (VEGF) is a permeability and angiogenic factor mediating neovascularization [64]. Its expression is up-regulated in activated pleural mesothelial cells and produced in large amount in inflammatory and malignant effusions [65-67]. VEGF control mesothelial cells permeability throught phosphorylation of adherens junction proteins and dynamic interactions between molecular adhesions. Exposure to noxious stimuli, the interaction of surface ligands with intercellular molecules expressed on mesothelial cells can cause cell migration and dispersion of high molecular weight proteins across the pleural membrane leading pleural effusion creation VEGF stimulation of normal epithelial cells and differentiated carcinoma cells can induce EMT [68,69], at the same time, hypoxia induces EMT in mesothelial cells by activation of HIF-1α, the major driver of VEGF expression in tumors [70,71].

PDGF

Mesothelial cells are able to produce Platelet-Derived Growth Factor (PDGF) a mitogenic cytochine that stimulate hyaluronan production and stimulate growth of fibroblast. Among PDGF family polypeptide chains encoded by four genes known as PDGF-A, B, C, D, PDGF factor D (PDGF-D) overexpression has observed in a variety of cancers. Overexpression of PDGF-D cells showed loss or relocation of E-cadherin, increased expression levels of vimentin that taken together contributes to EMT in human cancer [72].

Neurotrophins and TrK receptors

Recently, particular interest is given to the neurotrophin growth factor family. The term Neurotrophins (NTs), including Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3), NT-4/5 and NT-6, refers to a family of related polypeptide growth factors whose activities were originally related to a variety of neural cell types. The biological effects of NTs are mediated through two unrelated classes of cell-surface membrane receptors characterized by different binding affinities and molecular weights [73,74]. All the NTs interact with a transmembrane glycol-protein without a direct catalytic function, the 75 kDa low-affinity p75 receptor [75]. p75 receptor belongs to the tumor necrosis factor receptor family. NTs also bind distinct members of a superfamily of 140 - 145 kDa high affinity transmembrane tyrosine kinase receptors known as Trks [76]. NGF interacts with TrkA, BDNF and NT-4/5 with TrkB and NT-3 with TrkC receptor. Nts are involved in the transformation and tumor progression of many types of solid tumors and hematological malignancies [77]. NTs and their receptors are widely expressed in many lung cancers [78] and this expression suggests that NTs may be involved in controlling growth and differentiation of human lung cancer. In particular, the TrkB/ BDNF axis has a very important role in the proliferation, differentiation and tumor invasion and, furthermore, has been reported that TrkB is a negative prognostic factor in lung cancer [79]. Despite the growing interest in the NT system in several lung diseases and in lung cancer [80-84], their role in malignant pleural effusion has been investigated only sparsely [85]. in vitro cell cultures obtained from lung adenocarcinoma pleural effusion showed that TrkB is required for the maintenance of cells with slow proliferation that are still capable of growing in non-adherent conditions, rather than for the survival of progenitor and terminally differentiated cells [86]. TrkB is considered a promoter of EMT and anoikis resistance. Authors reported that TrkB is an inducer of EMT in head and neck, colorectal cancer and, recently, in human salivary adenoid cystic and endometrial carcinoma [87-89]. In metastatic breast cancers, the acquisition of metastatic ability, which leads to clinically incurable disease and poor survival, has been associated with acquisition of EMT program and CSCs via activation of PI3K/AKT and IL6/JAK2/STAT3 signaling pathways [90].

CANCER STEM CELL MARKERS

It has been recently demonstrated that MPEs could be an excellent source for growing in vitro and in vivocell cultures reproducing the natural heterogeneity of primary lung adenocarcinomas. Furthermore, the presence and proliferation of cancer cells in pleural effusion may be mediated by cancer stem cells, which also risk undergoing Epithelial Mesenchymal Transition (EMT). In the case of MPEs, fluids contain a population with enormous self-renewal and regeneration capacity, ability to escape apoptosis and resistance to anoikis. In MPEs, putative CSCs have been identified using a variety of markers. The identification of CSCs is carried out on the basis of molecular expression markers. However, these markers are not always and uniformly expressed across tumor types, for this reason the topic is still under discussion.

ALDH

Aldehyde Dehydrogenase (ALDH) is a marker frequently used to distinguish normal and malignant stem/progenitor cells. Through oxidation of retinol to retinoic acid, ALDH is involved in early stem cell development [91]. Initially used to sort haematopoietic stem cells [92], ALDH contributes to drug resistance through the detoxification of many cytotoxic agents and has been reported as a reliable CSC marker in several tumor types [92-94]. Isolated ALDH1- positive cells from stable cell lines show features of CSC. This has been correlated with poor prognosis for patients with early-stage NSCLC [95]. Recently, through primary cultures obtained from MPEs, authors have described the existence of cells with ALDH1 activity by FACS analysis both in adherent and spheroid culture [96]. Results showed that in the majority of samples analyzed, the percentage of ALDHbr (ALDH-bright) cells increased upon culturing in spheroid conditions, providing information about the presence of putative CSC in MPE primary cultures [29].

CD133

Another marker used to identify CSCs is the CD133, a member of transmembrane glycoproteins. CD133, also known as prominin-1, is a cell-surface transmembrane glycoprotein that has been used in the identification of putative CSCs in several malignant tumors. These cells have shown increased tumorigenic potential in transplantation studies in vitro and in vivo and, in clinical studies, an association with poor prognoses and distant metastases [97-99] however, the exact function of CD133 has not yet been established. In NSCLC patients, significant increase in CD133 cells has been observed suggesting the involvment of this cell population in tumor growth vasculogenesis. Eramo et al., were able to isolate small niche of CD133 from SCLC and NSCLC observing that CD133 cell population showed ability to self-renew but were not tumorigenic [100]. In a study of CSCs markers in MPEs, authors observed three different combination patterns of positive or negative protein expression of Nanog, OCT-4 and CD133 observing that the rates of immunoreactivity for these three CSC-representative markers range were from 15% to 90% associated to variations and combinations of their expression probably due to pleural effusion intratumoral heterogeneity [101].

OCT-4

OCT-4 and Nanog are both transcription factors essential for normal pluripotent cell development. Nanog is chiefly responsible for differentiation during embryogenesis whereas OCT-4 may have long-term influences on both tissue proliferation and differentiation [102]. OCT-4 is especially expressed in embryonic stem cells and germ cells, and has been detected in specific types of testicular germ-cell tumors. Moreover, it is also preferentially expressed in undifferentiated human ESCs, pancreatic islets, and diffuse-type gastric cancers. Therefore, it has been suggested that OCT-4 contributes to maintaining stem cell properties. However, several recent reports have suggested that as many as 25% of the cancer cells within certain tumors have the properties of CSCs [102]. Data suggested that cancer cells show various cell surface markers and the use of more than one marker to isolate CSCs might increase the possibility to detect cell sub-population. Therefore more investigation should be done in order to detect more markers to identify CSCs in MPEs.

CONCLUSION

The identification of more efficient therapies for the treatment of malignant pleural effusion in patients with metastatic lung cancer is crucial to understand the mechanisms that cause current fail treatment. Characterization of CSCs in malignant pleural effusion and recent understanding of EMT contributed to better know about environment, behavior and prognosis of this tumor. Advances have been made towards elucidating causes and mechanisms of EMT in malignant pleural effusion considering EMT process as one of possible mechanisms through which CSCs are generated. However, beyond identification and characterization of cell surface markers, there is still much that remains unknown about CSCs and EMT interaction including the mechanisms they utilize to maintain their chemoresistance.

ACKNOWLEDGEMENT

This work was supported by AIRC Grant IG 17009 to R. Mancini.

REFERENCES

  1. Lambert MP, Herceg Z (2008) Epigenetics and cancer, 2nd IARC meeting, Lyon, France, 6 and 7 December 2007. Mol Oncol 2: 33-40.
  2. Uzbeck MH, Almeida FA, Sarkiss MG, Morice RC, Jimenez CA, et al. (2010) Management of malignant pleural effusions. Adv Ther 27: 334-347.
  3. Gompelmann D, Eberhardt R, Herth FJ (2011) Advanced malignant lung disease: what the specialist can offer. Respiration 82: 111-123.
  4. Kastelik JA (2013) Management of malignant pleural effusion. Lung 191: 165-175.
  5. Burrows CM, Mathews WC, Colt HG (2000) Predicting survival in patients with recurrent symptomatic malignant pleural effusions: an assessment of the prognostic values of physiologic, morphologic, and quality of life measures of extent of disease. Chest 117: 73-78.
  6. Froudarakis ME (2008) Diagnostic work-up of pleural effusions. Respiration 75: 4-13.
  7. Froudarakis ME (2012) Pleural diseases in the molecular era - time for more answers: introduction. Respiration 83: 2-4.
  8. Antony VB, Loddenkemper R, Astoul P, Boutin C, Goldstraw P, et al. (2001) Management of malignant pleural effusions. Eur Respir J 18: 402-419.
  9. Musani AI (2009) Treatment options for malignant pleural effusion. Curr Opin Pulm Med 15: 380-387.
  10. Salyer WR, Eggleston JC, Erozan YS (1975) Efficacy of pleural needle biopsy and pleural fluid cytopathology in the diagnosis of malignant neoplasm involving the pleura. Chest 67: 536-539.
  11. Johnston WW (1985) The malignant pleural effusion. A review of cytopathologic diagnoses of 584 specimens from 472 consecutive patients. Cancer 56: 905-909.
  12. Hsu C (1987) Cytologic detection of malignancy in pleural effusion: a review of 5,255 samples from 3,811 patients. Diagn Cytopathol 3: 8-12.
  13. Sears D, Hajdu SI (1987) The cytologic diagnosis of malignant neoplasms in pleural and peritoneal effusions. Acta Cytol 31: 85-97.
  14. Nasreen N, Mohammed KA, Hardwick J, Van Horn RD, Sanders K, et al. (2002) Low molecular weight hyaluronan induces malignant mesothelioma cell (MMC) proliferation and haptotaxis: role of CD44 receptor in MMC proliferation and haptotaxis. Oncol Res 13: 71-78.
  15. Sriram PS, Mohammed KA, Nasreen N, Hardwick J, Van Horn R, et al. (2002) Adherence of ovarian cancer cells induces pleural mesothelial cell (PMC) permeability. Oncol Res 13: 79-85.
  16. Nasreen N, Mohammed KA, Sanders K, Hardwick J, Van Horn RD, et al. (2003) Pleural mesothelial cell (PMC) defense mechanisms against malignancy. Oncol Res 14: 155-161.
  17. Basak SK, Veena MS, Oh S, Huang G, Srivatsan E, et al. (2009) The malignant pleural effusion as a model to investigate intratumoral heterogeneity in lung cancer. PLoS One 4: 5884.
  18. Chen SF, Lin YS, Jao SW, Chang YC, Liu CL, et al. (2013) Pulmonary Adenocarcinoma in Malignant Pleural Effusion Enriches Cancer Stem Cell Properties during Metastatic Cascade. PLoS One 8: 54659.
  19. Giarnieri E, De Vitis C, Noto A, Roscilli G, Salerno G, et al. (2013) EMT markers in lung adenocarcinoma pleural effusion spheroid cells. J Cell Physiol 228: 1720-1726.
  20. Eppert K, Takenaka K, Lechman ER, Waldron L, Nilsson B, et al. (2011) Stem cell gene expression programs influence clinical outcome in human leukemia. Nat Med 17: 1086-1093.
  21. Tang C, Ang BT, Pervaiz S (2007) Cancer stem cell: target for anti-cancer therapy. FASEB J 21: 3777-3785.
  22. Ma S, Chan KW, Hu L, Lee TK, Wo JY, et al. (2007) Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology 132: 2542-2556.
  23. O'Brien CA, Pollett A, Gallinger S, Dick JE (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445: 106-110.
  24. Kim CF, Jackson EL, Woolfenden AE, Lawrence S, Babar I, et al. (2005) Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121: 823-835.
  25. Mancini R, Giarnieri E, De Vitis C, Malanga D, Roscilli G, et al. (2011) Spheres derived from lung adenocarcinoma pleural effusions: Molecular characterization and tumor engraftment. PLoS ONE 6: 21330
  26. Sodek KL, Murphy KJ, Brown TJ, Ringuette MJ (2012) Cell-cell and cell-matrix dynamics in intraperitoneal cancer metastasis. Cancer Metastasis Rev 31: 397-414.
  27. Allen HJ, Porter C, Gamarra M, Piver MS, Johnson EA (1987) Isolation and morphologic characterization of human ovarian carcinoma cell clusters present in effusions. Exp Cell Biol 55: 194-208.
  28. Sodek KL, Ringuette MJ, Brown TJ (2009) Compact spheroid formation by ovarian cancer cells is associated with contractile behavior and an invasive phenotype. Int J Cancer 124: 2060-2070.
  29. Casey RC, Burleson KM, Skubitz KM, Pambuccian SE, Oegema TR Jr, et al. (2001) Beta 1-integrins regulate the formation and adhesion of ovarian carcinoma multicellular spheroids. Am J Pathol 159: 2071-2080.
  30. Kelm JM, Timmins NE, Brown CJ, Fussenegger M, Nielsen LK (2003) Method for generation of homogeneous multicellular tumor spheroids applicable to a wide variety of cell types. Biotechnol Bioeng 83: 173-180.
  31. Ahmed N, Thompson EW, Quinn MA (2007) Epithelial-mesenchymal interconversions in normal ovarian surface epithelium and ovarian carcinomas: An exception to the norm. J Cell Physiol 213: 581-588.
  32. Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119: 1420-1428.
  33. Thiery JP (2002) Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2: 442-454.
  34. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, et al. (2008). The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133: 704-715.
  35. Kasper S (2009) Identification, characterization, and biological relevance of prostate cancer stem cells from clinical specimens. Urol Oncol 27: 301-303.
  36. Gupta GP, Massagué J (2006) Cancer metastasis: building a framework. Cell 127: 679-695.
  37. Sarrió D, Rodriguez-Pinilla SM, Hardisson D, Cano A, Moreno-Bueno G, et al. (2008) Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res 68: 989-997.
  38. Vella LJ (2014) The emerging role of exosomes in epithelial-mesenchymal-transition in cancer. Front Oncol 4: 361.
  39. Kim J, Kim TY, Lee MS, Mun JY, Ihm C, et al. (2016) Exosome cargo reflects TGF-β1-mediated Epithelial-to-Mesenchymal Transition (EMT) status in A549 human lung adenocarcinoma cells. Biochem Biophys Res Commun 478: 643-648.
  40. Bard MP, Hegmans JP, Hemmes A, Luider TM, Willemsen R, et al. (2004). Proteomic analysis of exosomes isolated from human malignant pleural effusions. Am J Respir Cell Mol Biol 31: 114-121.
  41. Rahman MA, Barger JF, Lovat F, Gao M, Otterson GA, et al. (2016) Lung cancer exosomes as drivers of epithelial mesenchymal transition. Oncotarget .
  42. Lin J, Wang Y, Zou YQ, Chen X, Huang B, et al. (2016). Differential miRNA expression in pleural effusions derived from extracellular vesicles of patients with lung cancer, pulmonary tuberculosis, or pneumonia.Tumour Biol.
  43. Zhao C, Li X, Su C, Li J, Cheng N, et al. (2015) High expression of E-cadherin in pleural effusion cells predicts better prognosis in lung adenocarcinoma patients. Int J Clin Exp Pathol 8: 3104-3109.
  44. Agiostratidou G, Hulit J, Phillips GR, Hazan RB (2007) Differential cadherin expression: Potential markers for epithelial to mesenchymal transformation during tumor progression. J Mammary Gland Biol Neoplasia 12: 127-133.
  45. Vasko V, Espinosa AV, Scouten W, He H, Auer H, et al. (2007) Gene expression and functional evidence of epithelial-to-mesenchymal transition in papillary thyroid carcinoma invasion. Proc Natl Acad Sci USA 104: 2803-2808.
  46. Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, et al. (2004) Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117: 927-939.
  47. Kang Y, Massagué J (2004) Epithelial-mesenchymal transitions: twist in development and metastasis. Cell 118: 277-279.
  48. Acloque H, Thiery JP, Nieto MA (2008) The physiology and pathology of the EMT. Meeting on the epithelial-mesenchymal transition. EMBO Rep 9: 322-326.
  49. Salvi A, Bongarzone I, Ferrari L, Abeni E, Arici B, et al. (2015) Molecular characterization of LASP-1 expression reveals vimentin as its new partner in human hepatocellular carcinoma cells. Int J Oncol 46: 1901-1912.
  50. D'Angelo RC, Liu XW, Najy AJ, Jung YS, Won J, et al. (2014) TIMP-1 via TWIST1 induces EMT phenotypes in human breast epithelial cells. Mol Cancer Res 12: 1324-1333.
  51. Yang Z, Zhang X, Gang H, Li X, Li Z, et al. (2007) Up-regulation of gastric cancer cell invasion by Twist is accompanied by N-cadherin and fibronectin expression. Biochem Biophys Res Commun 358: 925-930.
  52. Li J, Zhou BP (2011) Activation of β-catenin and Akt pathways by Twist are critical for the maintenance of EMT associated cancer stem cell-like characters. BMC Cancer 11: 49.
  53. Sasaki K, Natsugoe S, Ishigami S, Matsumoto M, Okumura H, et al. (2009) Significance of Twist expression and its association with E-cadherin in esophageal squamous cell carcinoma. J Exp Clin Cancer Res 28: 158.
  54. Zhang Z, Xie D, Li X, Wong YC, Xin D, et al. (2007) Significance of TWIST expression and its association with E-cadherin in bladder cancer. Hum Pathol 38: 598-606.
  55. Yu Q, Zhang K, Wang X, Liu X, Zhang Z (2010) Expression of transcription factors snail, slug, and twist in human bladder carcinoma. J Exp Clin Cancer Res 29: 119.
  56. Cano A, Pérez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, et al. (2000) The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2: 76-83.
  57. Hotz B, Arndt M, Dullat S, Bhargava S, Buhr HJ, et al. (2007) Epithelial to mesenchymal transition: expression of the regulators snail, slug, and twist in pancreatic cancer. Clin Cancer Res 13: 4769-4776.
  58. Vincent T, Neve EP, Johnson JR, Kukalev A, Rojo F, et al. (2009) A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-beta mediated epithelial-mesenchymal transition. Nat Cell Biol 11: 943-950.
  59. Ma C, Tarnuzzer RW, Chegini N (1999) Expression of matrix metalloproteinases and tissue inhibitor of matrix metalloproteinases in mesothelial cells and their regulation by transforming growth factor-beta1. Wound Repair Regen 7: 477-485.
  60. Cui W, Fowlis DJ, Bryson S, Duffie E, Ireland H, et al. (1996) TGFbeta1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice. Cell 86: 531-542.
  61. Derynck R, Akhurst RJ, Balmain A (2001) TGF-beta signaling in tumor suppression and cancer progression. Nat Genet 29: 117-129.
  62. Thickett DR, Armstrong L, Millar AB (1999) Vascular endothelial growth factor (VEGF) in inflammatory and malignant pleural effusions. Thorax 54: 707-710.
  63. Becker PM, Alcasabas A, Yu AY, Semenza GL, Bunton TE (2000) Oxygen-independent upregulation of vascular endothelial growth factor and vascular barrier dysfunction during ventilated pulmonary ischemia in isolated ferret lungs. Am J Respir Cell Mol Biol 22: 272-279.
  64. Mohammed KA, Nasreen N, Hardwick J, Logie CS, Patterson CE, et al. (2001) Bacterial induction of pleural mesothelial monolayer barrier dysfunction. Am J Physiol Lung Cell Mol Physiol 281: 119-125.
  65. Ishimoto O, Saijo Y, Narumi K, Kimura Y, Ebina M, et al. (2002) High level of vascular endothelial growth factor in hemorrhagic pleural effusion of cancer. Oncology 63: 70-75.
  66. Batra H, Antony VB (2015) Pleural mesothelial cells in pleural and lung diseases. J Thorac Dis 7: 964-980.
  67. Mak P, Leav I, Pursell B, Bae D, Yang X, et al. (2010) ERbeta impedes prostate cancer EMT by destabilizing HIF-1alpha and inhibiting VEGF-mediated snail nuclear localization: implications for Gleason grading. Cancer Cell 17: 319-332.
  68. Wanami LS, Chen HY, Peiró S, García de Herreros A, Bachelder RE (2008) Vascular Endothelial Growth Factor-A stimulates Snail expression in breast tumor cells: Implications for tumor progression. Exp Cell Res 314: 2448-2453.
  69. Morishita Y, Ookawara S, Hirahara I, Muto S, Nagata D (2016) HIF-1α mediates Hypoxia-induced epithelial-mesenchymal transition in peritoneal mesothelial cells. Ren Fail 38: 282-289.
  70. Kong D, Wang Z, Sarkar SH, Li Y, Banerjee S, et al. (2008) Platelet-derived growth factor-D overexpression contributes to epithelial-mesenchymal transition of PC3 prostate cancer cells. Stem Cells 26: 1425-1435.
  71. Barbacid M (1994) The Trk family of neurotrophin receptors. J Neurobiol 25: 1386-1403.
  72. Lei L, Parada LF (2007) Transcriptional regulation of Trk family neurotrophin receptors. Cell Mol Life Sci 64: 522-532.
  73. Underwood CK, Coulson EJ (2008) The p75 neurotrophin receptor. The International Journal of Biochemistry & Cell Biology 40: 1664-1668.
  74. Li Z, Beutel G, Rhein M, Meyer J, Koenecke C, et al. (2009) High-affinity neurotrophin receptors and ligands promote leukemogenesis. Blood 113: 2028-2037.
  75. Nakagawara A (2001) Trk receptor tyrosine kinases: a bridge between cancer and neural development. Cancer Lett 169: 107-114.
  76. Ricci A, Mariotta S, Pompili E, Mancini R, Bronzetti E, et al. (2010) Neurotrophin system activation in pleural effusions. Growth Factors 28: 221-231.
  77. Okamura K, Harada T, Wang S, Ijichi K, Furuyama K, et al. (2012) Expression of TrkB and BDNF is associated with poor prognosis in non-small cell lung cancer. Lung Cancer 78: 100-106.
  78. Prakash Y, Thompson MA, Meuchel L, Pabelick CM, Mantilla CB, et al. (2010) Neurotrophins in lung health and disease. Expert Rev Respir Med 4: 395-411.
  79. Olgart Höglund C, de Blay F, Oster JP, Duvernelle C, Kassel O, et al. (2002) Nerve growth factor levels and localisation in human asthmatic bronchi. Eur Respir J 20: 1110-1116.
  80. Ricci A, Graziano P, Bronzetti E, Saltini C, Sciacchitano S, et al. (2007) Increased pulmonary neurotrophin protein expression in idiopathic interstitial pneumonias. Sarcoidosis Vasc Diffuse Lung Dis 24: 13-23.
  81. Dagnell C, Grunewald J, Idali F, Wikén M, Kemi C, et al. (2008) Increased levels of nerve growth factor in the airways of patients with sarcoidosis. J Intern Med 264: 463-471.
  82. Freund-Michel V, Frossard N (2008) The nerve growth factor and its receptors in airway inflammatory diseases. Pharmacol Ther 117: 52-76.
  83. Davidson B, Suo Z, Nesland JM (2004) Malignant mesothelioma. Ultrastruct Pathol 28: 179-180.
  84. Ricci A, De Vitis C, Noto A, Fattore L, Mariotta S, et al. (2013) TrkB is responsible for EMT transition in malignant pleural effusions derived cultures from adenocarcinoma of the lung. Cell Cycle 12: 1696-1703.
  85. Kupferman ME, Jiffar T, El-Naggar A, Yilmaz T, Zhou G, et al. (2010) TrkB induces EMT and has a key role in invasion of head and neck squamous cell carcinoma. Oncogene 29: 2047-2059.
  86. Fujikawa H, Tanaka K, Toiyama Y, Saigusa S, Inoue Y, et al. (2012) High TrkB expression levels are associated with poor prognosis and EMT induction in colorectal cancer cells. J Gastroenterol 47: 775-784.
  87. Jia S, Wang W, Hu Z, Shan C, Wang L, et al. (2015) BDNF mediated TrkB activation contributes to the EMT progression and the poor prognosis in human salivary adenoid cystic carcinoma. Oral Oncol 51: 64-70.
  88. Kim MS, Lee WS, Jeong J, Kim SJ, Jin W, et al. (2015) Induction of metastatic potential by TrkB via activation of IL6/JAK2/STAT3 and PI3K/AKT signaling in breast cancer. Oncotarget 6: 40158-40171.
  89. Chute JP, Muramoto GG, Whitesides J, Colvin M, Safi R, et al. (2006) Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells. Proc Natl Acad Sci USA 103: 11707-11712.
  90. Moreb JS (2008) Aldehyde dehydrogenase as a marker for stem cells. Curr Stem Cell Res Ther 3: 237-246.
  91. Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, et al. (2007) ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1: 555-567.
  92. Matsui W, Huff CA, Wang Q, Malehorn MT, Barber J, et al. (2004) Characterization of clonogenic multiple myeloma cells. Blood 103: 2332-2336.
  93. Hiratsuka S, Watanabe A, Aburatani H, Maru Y (2006) Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat Cell Biol 8: 1369-1375.
  94. O'Brien CA, Pollett A, Gallinger S, Dick JE (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445: 106-110.
  95. Yin S, Li J, Hu C, Chen X, Yao M, et al. (2007) CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity. Int J Cancer 120: 1444-1450.
  96. Horst D, Scheel SK, Liebmann S, Neumann J, Maatz S, et al. (2009) The cancer stem cell marker CD133 has high prognostic impact but unknown functional relevance for the metastasis of human colon cancer. J Pathol 219: 427-434.
  97. Ishigami S, Ueno S, Arigami T, Uchikado Y, Setoyama T, et al. (2010) Prognostic impact of CD133 expression in gastric carcinoma. Anticancer Res 30: 2453-2457.
  98. Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, et al. (2008) Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ 15: 504-514.
  99. Chambers I, Colby D, Robertson M, Nichols J, Lee S, et al. (2003) Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113: 643-655.
  100. Hochedlinger K, Yamada Y, Beard C, Jaenisch R. (2005) Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues. Cell 121: 465-477.
  101. Freberg CT, Dahl JA, Timoskainen S, Collas P (2007) Epigenetic reprogramming of OCT4 and NANOG regulatory regions by embryonal carcinoma cell extract. Mol Biol Cell 18: 1543-1553.
  102. Gupta PB, Chaffer CL, Weinberg RA (2009) Cancer stem cells: mirage or reality? Nat Med 15: 1010-1012.

Citation: Cherubini E, Giarnieri E, Ricci A, Mariotta S, Giovagnoli MR et al. (2016) Inducers of Epithelial Mesenchymal Transiton and Cancer Stem Cells in Malignant Pleural Effusions. J Cytol Tissue Biol 3: 011.

Copyright: © 2016  Emanuela Cherubini, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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