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Epithelial-Mesenchymal Transitions in Human Cancer

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Epithelial-mesenchymal transition (EMT) is a type of epithelial plasticity that is characterized by long-lasting morphological and molecular changes in epithelial cells as a result of transdifferentiation towards a mesenchymal cell type. To detect possible phenotypic transitions in human cancer, surgical pathology is a useful medical discipline, examining surgical or biopsy material at the microscopic and ultrastructural level. The expression in a particular tumor of epithelial and mesenchymal markers is evaluated by means of immunohistochemistry or in situ hybridization, and this could, besides directing to a correct diagnosis, substantiate a possible transdifferentiation. Whereas EMT occurs in several stages of embryonic development and can be readily induced in (cancer) cell lines in vitro, in human cancer the phenomenon is rarely encountered. Carcinosarcoma is the tumor best studied, in which monoclonality of both epithelial and mesenchymal cell components strongly favors an EMT. A challenging hypothesis considers EMT as a more general event, providing an additional survival advantage in all types of carcinoma. By means of EMT the epithelial tumor cells would transdifferentiate into myofibroblasts that lose their malignant phenotype but constitute the desmoplastic stroma which is essential for tumor growth, invasion and metastasis.


Studying cancer cells in vitro or human tumors in the surgical pathology practice one can be confronted with morphological changes or an atypical appearance of cancer cells, which can be attributed to an epithelial-mesenchymal transition (EMT). In a broad sense, EMT encompasses all changes in cell morphology from epithelioid to mesenchymal/fibroblastoid/spindle-shaped. A more strict definition, that we will support, is formulated by Janda et al.1 It considers EMT as a type of epithelial plasticity leading to morphological changes accompanied by “drastic molecular changes” that `persist`. Merely epithelial towards spindle cell transition is termed “scattering”. “Transdifferentiation” is a term used in the context of EMT to refer to the irreversible change in differentiation of one cell type to another.2 In their clinical pratice pathologists use, rather than EMT, the terms “sarcomatous/sarcomatoid dedifferentiation” (“resembling a sarcoma”, a malignant mesenchymal tumor) or `anaplasia` (literally meaning “to form backward”).3 Instead of “transdifferentiation” the term “metaplasia” is generally used.4 This implies that the distinction between both is not made in pathology practice, namely that “transdifferentiation” is restricted to “differentiated” cells, and “metaplasia” includes both transdifferentiation and switches in stem cells.2,5

In this chapter we briefly review phenotypic cell transitions during embryonic development and the molecular basis of EMT in tumor biology. We then focus on the different features of EMT in experimental and surgical pathology, with emphasis on the significance of differentia- tion markers. Examples of tumor types in which EMT presumably occurs are given and we conclude with recent insights into stromal-tumor interactions which might widen up the concept of EMT in the future.

The Molecular Basis of EMT

From a developmental point of view, EMT and other phenotypic transitions are important processes that ultimately lead to a complex organism with its different organs and tissue types. The precisely regulated switches between epithelial and mesenchymal differentiation programs serve the creation of specific migratory cells and the formation of the mesodermal cell layer and its differentiation into specific tissue types such as muscle, skin and kidney.6 (see also chapters 1-4). In human embryo's after the second week of development, a mesodermal germ layer is formed by invagination and migration of altered epiblast cells at the primitive streak. Later on, several transitions occur in these mesodermal cells. They transiently retransform into epithelial structures, the somites, out of which migrating mesenchymal cell populations are formed again: the derma-, sclero- and myotome. Neural crest cells originate from the ectoderm and give rise to, amongst others, melanocytes, which spread over the whole body surface (see Chapter 3: Duband). Other examples of EMT are the contribution of the epicardial cells to the formation of the coronary wall7,8, see also chapter 4: Runyan et al and the cytotrophoblast cells at the implantation site of the placenta which become spindle-shaped and get the capacity to infiltrate.9 The best-studied example of the opposite, the mesenchymal-to-epithelial transition (MET), is the formation of the nephrons, the functional units in the kidney, from the metanephric mesenchyme.10,11 Similarly, the cells arranged in an epithelium that secrete the dentin layer of a tooth, the odontoblasts, originate from neural crest-derived mesenchymal cells.12 Together, these examples show that increased motility and changes in differentiation are two important consequences of EMT and that both EMT and MET may occur transiently.

Phenotypic plasticity has been observed in different cell lines in vitro. Some cell lines transdifferentiate simply through passaging. The chemically induced rat mammary carcinoma cells RANI for instance, undergo a polygonal-to-fusiform transition, accompanied by loss of some epithelial (keratin) and gain of some mesenchymal markers (Thy-1, vimentin, fibronectin).13 Ovarian surface epithelial cells produce collagen type I and II when cultured in vitro and progressively lose cytokeratin expression with passaging.14 The formation of networks and channels, together with the expression of endothelial markers is described in ovarian carcinoma cells grown in Matrigel or collagen type I, reminiscent of the “vasculogenic mimicry” in melanomas.15,16 When explanted in vitro, retinal pigment epithelium cells become fibroblastic. 17,18 In definitive embryonic avian lens epithelium a similar phenotypic conversion is observed, triggered by a collagen type I matrix through de novo expression of integrin-β1.19 There are also reports on transdifferentiation from pancreas to liver cells,20 from myoblasts to lipocytes21 and from mesothelial cells to myoblasts.22

The cell-cell adhesion molecule E-cadherin plays a central role in the epithelial differentiation of cells. Counteracting E-cadherin expression is in most cells enough to direct them towards a mesenchymal differentiation program,23 whereas E-cadherin transfection in some fibroblastic cells makes them epithelioid.24,25 Much literature supports the idea that, besides promoting differentiation, E-cadherin also acts as an invasion suppressor molecule (see chapter 11: Berx and Van Roy). Thus, from a clinical point of view, the significance of an E—cadherin downregulation and eventually EMT in tumors, is the associated increase in invasiveness and metastatic potential and the concomitantly decreased patient survival. Alterations in E-cadherin expression or functioning, either observed in tumors or induced in cell lines in vitro, occur at different levels (reviewed by Van Aken et al26). We will focus here on those modulations that, because of their persistent nature, could fit in the EMT concept. They are at the genomic and transcriptional level. First, the E-cadherin gene CDH1 can be inactivated by mutations as has been described in lobular breast carcinoma,27,28 diffuse gastric carcinoma,29,30 endometrial,31 and thyroid carcinoma.32 Some of these are germline mutations. Second, loss of heterozygosity could be an alternative way to lose CDH1 transcription.27,28 A third level of regulation that is important in EMT, is the promoter level. Hypermethylation of the E-cadherin promoter is a well-described mechanism in tumors.33-36 Time- and tissue-specific expression of different sets of transcriptional activators and repressors mediates the above mentioned phenotypic changes during embryogenesis. The Snail family of transcriptional repressors,37 including Snail and Slug, together with SIP-1, another zinc-finger protein, play a key role in EMT during embryonic development,38 and are often re-expressed in tumor conditions. By acting on the E-boxes of the E-cadherin promoter,39-42 they downregulate E-cadherin expression, imposing an invasive and mesenchymal phenotype to the cells.43, see also Chapter 11: Berx and Van Roy Studies on tumor material demonstrated that Snail expression in invasive ductal breast carcinomas is inversely related to grade and correlates with lymph node metastasis,44 whereas a role for SIP-1 has been shown in E-cadherin downregulation in the intestinal type of gastric carcinoma.45 On the other hand, the transcription factor WT-1 (Wilms' tumor-1) which play a role in MET in the embryonic kidney,10 induces epithelial differentiation and E-cadherin expression.46,47

An important issue regarding E-cadherin modulation is the counteracting role of another classical cadherin, the neural-type or N-cadherin. Aberrant de novo expression of N-cadherin has been noted in carcinomas from the breast,48 prostate,49 bladder50 and the head and neck region,51 where it parallels a downregulation of E-cadherin and a decrease in tumor differentiation. In breast carcinoma cell lines N-cadherin expression is associated with an increased invasion potential,52-55 exerting a dominant influence on the cell's motility when co-expressed with E-cadherin.53,54 An increased fibroblast growth factor 2 (FGF2) signaling through N-cadherin-mediated FGF receptor 1 (FGFR1) stabilization, results in an elevated matrix metalloproteinase-9 production, which could account for the invasive phenotype induced by N-cadherin.55 Another proposed mechanism is the interaction of the tumor cells with N-cadherin-positive fibroblasts of the surrounding stroma.52 Although the observed decrease in differentiation does not equal per se an EMT, further study of the putative active role of N-cadherin in EMT seems relevant since N-cadherin is mentioned in several studies as a marker coming up in the mesenchymal state.1,56-58

In their list of operational criteria of EMT, Janda et al1 included the requirement for cooperation of transforming growth factor-β (TGF-β) and a hyperactive MAPkinase pathway. In Ha-Ras transformed mammary epithelial cells, they demonstrated that this pathway and not the PI3kinase pathway is responsible for the irreversible conversion.1 An active integrin-β1 signaling through interaction with the extracellular matrix is required for the EMT induced by TGF-β /MAPK.59 Others, however, found that the PI3K pathway is implicated in TGF-β-induced EMT.60,61 According to the cell system and criteria applied, i.e., if reversibility is tolerated or not, other growth factors could be involved as well. The hepatocyte growth factor /c-met pathway,62 but also the signaling pathways from other tyrosine kinase receptors, such as FGFR,63 epidermal growth factor receptor (EGFR)56,58 and insulin-like growth factor 1 receptor64 have been studied in this context. Since discussing these would be beyond the scope of this chapter, we refer to recent reviews.65-67

Features of EMT in Pathology

To diagnose malignant tumors, surgical pathologists apply morphological criteria that are based on properties that these tumors share with their putative tissue of origin. Besides being classified, roughly spoken into an epithelial or mesenchymal type, the tumors are graded in a two- or three-tiered scheme, according to the extent of resemblance to their tissue of origin.3 There is a high resemblance in so-called well-differentiated (grade I) tumors. As for well-differentiated carcinomas, which are malignant epithelial tumors, the tumor cells tend to be organized in epithelial structures (show tubular differentiation and an apical-basal polarity in the case of adenocarcinomas) and the nature of their cytoplasm refers to a presumed cell of origin (containing e.g., mucus, keratin, glycogen). In poorly differentiated /undifferentiated carcinomas, the tumor cells lose their epithelial properties. In some cases this is accompanied by the acquisition of mesenchymal characteristics in a morphological and molecular sense, thereby fulfilling the criteria of EMT. Malignant transformation also involves variation in size and shape, so-called pleomorphism of cells and their nuclei, hyperchromasia of nuclei due to hyperploidy, and an increased mitotic activity. These changes reflect the differentiation status of a tumor as well and thus are also taken into account for grading.

Table 1 summarizes the most important features of EMT in vitro, their reflection in tumor tissue and the tools that are applied to study them. In the surgical pathology practice, tumors are examined macroscopically ex vivo and after fixation at the microscopic, ultrastructural (by transmission electron microscopy) or molecular level (by immunohistochemistry/ in situ hybridization). As a result of the inherently ‘static‘ nature of these practices, the observations made, i.e., in the case of EMT, can only be a reflection of the mechanisms described in vitro. Nevertheless, pathology can provide an important contribution to the study of EMT. By examining a particular tumor series or experimentally induced tumors in laboratory animals, observations in vitro can be extrapolated to the situation in vivo. Changes in morphology are readily appreciated microscopically at a routine hematoxylin/eosin (H&E) staining. Within a tumor exhibiting EMT, at least part of the tumor cells have lost their typical epithelial morphology. They lack epithelial organization in tubules, as for adenocarcinomas, or the typical organization of cells in squamous sheets, in the case of squamous cell carcinoma. Instead, the cells display either an undifferentiated mesenchymal phenotype, resembling spindle-shaped fibroblasts (hence “fibroblastoid”) and are then haphazardly oriented in a nondescript extracellular matrix, or they acquire characteristics of specialized mesenchymal tissue, like muscle, bone or cartilage. In the latter cases, cells tend to be organized in bundles or are surrounded by a specialized matrix. At the molecular level, tumor cells and stroma can be examined by immunohistochemistry or in situ hybridization for the presence/absence of proteins or their mRNA, that serve as markers of the epithelial or mesenchymal phenotype (see Table 2). In some cases additional electron microscopic analysis is needed.68-71 As is listed in Table 3, the examination focuses on the presence of cell junctions, the type of cytoplasmic intermediate filaments and the production of basement membrane or collagenous material. The latter feature brings us to the second aspect of EMT: cells that underwent EMT, synthesize a different set of extracellular matrix (ECM) molecules, such as different types of collagen, proteoglycans and hyaluronic acid. Although in general a routine staining suffices to appreciate the presence and extent of ECM in a tumor, immunohistochemistry is needed to identify the different types of matrix molecules. For instance, a chondroid matrix is rich in hyaluronic acid and shows immunospecificity for the matrix-associated proteins S100 and bone morphogenic protein.72 Finally, an important feature of EMT is the increased cell motility. In a pathology perspective, this implies the abnormal presence of epithelium-derived cells in the connective tissue after crossing the basement membrane boundary (invasion), or in an organ at distance of the primary tumor mass (metastasis). Again, immunohistochemical markers can be of help. For instance, a laminin staining can show discontinuities of the basement membrane and metastatic tumor cells are better distinguished from their surrounding tissue when a tumor-specific panel of antibodies is applied. Carcinosarcomas, that very likely exemplify an EMT as we will discuss below, are in general highly infiltrative and metastasizing. The fact that these tumors usually behave similarly to poorly differentiated carcinomas, indicates once more that tumor grade rather than the EMT in se determines the tumor's potential to invade and metastasize and eventually the patient's survival. As extensively studied in breast carcinoma, some markers of mesenchymal differentiation such as vimentin, tenascin-C and stromelysin-3 may be predictive for an adverse outcome.73-75

Table 1. Features of EMT in vitro and in tumor pathology.

Table 1

Features of EMT in vitro and in tumor pathology.

Table 2. Features of EMT in vitro and in tumor pathology.

Table 2

Features of EMT in vitro and in tumor pathology.

Table 3. Ultrastuctural markers of the epithelial and mesenchymal phenotype.

Table 3

Ultrastuctural markers of the epithelial and mesenchymal phenotype.

Morphological Markers of Cell Differentiation

Table 2 gives an overview of the most common markers applied in the study of EMT and epithelial plasticity in general. Neither marker on itself has, when present in a cell, an absolute predictive value as to its reflection of an epithelial or mesenchymal phenotype.76,77 Intermediate filaments, intracellular cytoskeleton proteins, have classically been used to distinguish between these phenotypes.78 The cytokeratin subgroup is almost exclusively expressed in epithelia and consists of at least 20 different proteins varying in molecular weight (from 40 to 70kD) and showing some epithelium-, organ-, or tumor-specificity.79-82 For routine immunohistochemistry purposes ‘cocktails” of antibodies, such as AE1/AE3 covering most keratin subtypes, have been commercialized. On the other hand, CAM5.2 reactivity is restricted to ‘simple” or ductal epithelia (as in adenocarcinomas).83 Cytokeratins are relatively stable in vivo, as they remain expressed in most high-grade carcinomas and traces of it can even be detected in the sarcomatous component of a mixed tumor. Decreased differentiation however, is in some epithelial cell types like in breast epithelium, accompanied by the emergence of vimentin, a mesenchymal type of intermediate filaments.84-89 In vitro studies indicated a link between vimentin and increased motility or invasion in e.g., breast,90-93 prostate94 and cervical95,96 cancer cell lines. Sommers et al97 suggested that vimentin is a marker but not an inducer of the fibroblastic phenotype in vitro, as transfection of MCF-7 mammary cancer cells did not alter their epithelial morphology, neither the expression of epithelial markers. In line with this is the study of Hendrix et al92 showing that vimentin expression alone does not suffice for metastasis formation. Many reports discuss the prognostic significance of vimentin expression in carcinomas in vivo. In breast cancer, some groups found a correlation with a lower post-operative survival.73,98-100 Other studies however, could not confirm this.89,101,102 Remarkably, Thomas et al103 suggested that a keratin/vimentin expression ratio is more predictive for a worse prognosis than vimentin expression alone; the tumors with a high keratin level in addition to vimentin were associated with the poorest survival. In cervical cancer, vimentin expression was noted in invasive carcinomas and in their lymph node metastases, but not in the intra-epithelial neoplasia precursor lesions.104 That intermediate filament markers are in a sense ‘promiscuous” is best illustrated by vimentin immunostaining. Vimentin/keratin co-expression is found in some carcinoma types without evidence of dedifferentiation or EMT, and even in normal epithelium. This is particularly true for epithelia that have evolved from mesenchymal precursors like the urogenital organs.105,106 In a way, these epithelial cells seem to recall their mesenchymal roots. Ovarian surface epithelial cells for instance, consistently express vimentin.14,107 Normal endometrial glands, like the ovary derived from the mesodermal celomic epithelium, also express vimentin, though mainly in their proliferative phase.108 In series of renal cell carcinomas up to half of the tumors expressed vimentin.109,110 Although a spindled morphology correlated with the vimentin expression, 32% of the well-differentiated carcinomas showed immunoreactivity as well.109 Aberrant expression of keratins also occurs, e.g., in soft tissue tumors, though to a lesser extent than aberrant vimentin expression in carcinomas.111,112

Another class of differentially expressed markers is the cadherins. The switch from E- to N-cadherin has been discussed above. Another cadherin of interest is OB-cadherin or cadherin-11, belonging to the atypical class II cadherin family.113 During embryonic development cadherin-11 is exclusively expressed in mesenchymal cells, in which it assists together with other cadherins in cell sorting.114,115 In adult tissue, cadherin-11 is a quite specific marker for mesenchymal cells, with the exception of the endometrial epithelium and the trophoblast. Aberrant expression of cadherin-11 and its splice variant in breast carcinomas seems restricted to the more aggressive, invasive cell lines such as MDA-MB-231.116 Transfection experiments with MCF-7117 or BT-2054 mammary carcinoma cells indicated an invasion promoter role, while in SKBR3 mammary carcinoma cells the induced epithelial morphology upon transfection would suggest a role in cell differentiation.117 Of interest in the EMT context is the finding that decidualization of endometrial stromal cells coincides with upregulation of cadherin-11 expression.118 Decidualization is the process of morphological changes in endometrial stromal cells towards an epithelioid cell type that occurs in normal women at the late secretory phase of the menstrual cycle, when progesteron levels are high. In the placenta, cadherin-11 is switched on in certain types of trophoblasts, that is, in the syncytiotrophoblasts (after cell fusion) and in the terminally differentiated cytotrophoblasts (after transdifferentiation towards stromal infiltrative cells).119,120 The latter interact with the pregnancy-induced decidual stromal cells of the endometrium, possibly through cadherin-11.119

Changes in the expression level or pattern of desmosomal cadherins121 and of other components of intercellular junctions, such as occludin56,122 or ZO-160 are looked at to substantiate EMT-related loss of polarity. Desmosome dissociation in the NBT-II rat bladder carcinoma cell line is an initial step of the EMT induced by the zinc-finger protein Slug.121

An important role in EMT is played by integrins, as mentioned above. Switches have been described towards fibronectin- or collagen type I-interacting integrins.123-125

The type of extracellular proteins produced changes also during EMT. A decrease in the production of laminin and collagen type IV, components of the basement membrane, parallels an increase in collagen type I, III, and V, fibronectin and/or tenascin-C (TN-C). The latter molecule is a hexameric glycoprotein,126-129 that is produced by (myo)fibroblasts at the stroma-epithelium interface.130,131 During wound healing and in neoplasia an elevated TN-C expression is noted.131-135 In these pathological conditions TN-C expression is also switched on in a small amount of the epithelial cells, particularly those bordering the stroma.131-133,136-139 This expression pattern may relate to its known interference with (tumor) cell-matrix interactions. In a panel of mouse mammary epithelial cells TN-C expression was inversely correlated with the degree of epithelial differentiation, i.e., polarization, and could be induced by TGF-β.140 An inverse correlation with survival was found in human breast tumors,141 and TN-C expression in the tumor stroma at the invasive border was predictive for tumor recurrence, metastasis and decreased survival.74

The epithelial membrane antigen (EMA) is the mixture of antigenic glycoproteins from human mammary epithelial cells present in milk through reverse pinocytosis. Antibodies raised against these antigens are reactive in most epithelia and carcinomas and thus are routinely used in pathology together with keratin antibodies.142

The tumor suppressor gene adenovirus E1a induces an epithelial phenotype in mesenchymal tumor cell lines and fibroblasts, probably by globally reprogramming transcription.143,144

Fibroblast-specific protein-1 (FSP1) is a calcium-binding protein belonging to the S100 family, isolated by comparative transcript analysis from mouse renal interstitial fibroblasts and is characterized as highly specific for fibroblasts.145 FSP1 is used as a marker for EMT in the mouse model of kidney fibrogenesis, which we will describe below.

Finally, ‘stromal type” MMPs can be produced by tumor cells undergoing an EMT, i.e., stromelysin-1 (Str-1, MMP-3)146,147 stromelysin-3 (Str-3, MMP-11),148-150 gelatinase A (MMP-2),95 and membrane type 1 (MT1)-MMP.151 That these MMPs play an active role in EMT was demonstrated in the normal mouse mammary cell line SCp2, in which Str-1 expression was sufficient to trigger an EMT.152 In transgenic mice, Str-1 promoted the development of mammary tumors with a mesenchymal phenotype.153 Str-1 expression in mouse skin carcinomas was observed in association with a squamous to spindle cell conversion.154 As for Str-3, protein and mRNA were demonstrated in both the epithelial and mesenchymal compartment of metaplastic mammary carcinomas, which are examples of EMT,148 but occasionally also in the tumor cells of common mammary ductal carcinomas.155 The Str-3 level, either stromal75,148 or epithelial,149 is a prognostic parameter in breast cancer since a strong correlation has been shown with decreased postoperative (disease-free) survival.

We can conclude that assessing the expression of a panel of differentiation markers on tumor cells enables one in most cases to discriminate between the epithelial and mesenchymal phenotype. In the diagnostic pathology practice, mesenchymal differentiation of a tumor is rather documented by a loss of epithelial markers (keratins and EMA) or a gain of specific mesenchymal differentiation markers, e.g., α-smooth muscle actin (α-SMA), desmin, S100 and CD31 for smooth muscle, skeletal muscle, neuroid/chondroid and vascular differentiation respectively.

Examples of EMT

Carcinosarcoma/Sarcomatoid Carcinoma

First of all, it should be stressed that in the great majority of human tumors no EMT seems to occur. This is unlike the situation in vitro, in which phenotypic plasticity is common. One can argue that EMT is an artefact of in vitro culturing.156 Alternatively, it may be that pathologists only detected the tip of the iceberg so far. The tumor stroma being an integral part of a malignant tumor could imply that virtually every carcinoma underwent an EMT while creating its own stroma. We will discuss this hypothesis further on. Yet, for the moment, the most convincing examples of EMT in tumor pathology are those neoplasms exhibiting both an epithelial and mesenchymal component (Table 4) (for a review see ref. 157). Together, they represent less than one percent of the total number of cancers.

Table 4. Examples of EMT in tumor pathology.

Table 4

Examples of EMT in tumor pathology.

Carcinosarcomas make up a rare group of malignant mixed tumors that can occur in the vicinity of all kinds of epithelium anywhere in the body.158-164 The epithelial component is usually an adenocarcinoma. The mesenchymal component consists either of nondescript, undifferentiated spindle cells, or of pleomorphic cells featuring a particular line of differentiation such as rhabdoid (skeletal muscle),165 osteoid (bone)162,166 or chondroid72 (cartilage) differentiation. (fig.1, 2) The terminology of this group of tumors is diverse. When such a specific mesenchymal cell differentiation is present (in a large extent) the tumors are usually termed ‘carcinosarcoma”. On the other hand, if transitions between the two cell populations are obvious, i.e., if there is a hybrid epithelial-mesenchymal cell type, the term ‘sarcomatoid carcinoma” is often preferred. However, merely referring to the anatomical site, mixed tumors in the breast are usually termed ‘spindle” or ‘metaplastic” cell carcinoma, in the esophagus ‘pseudosarcoma”, and in the lining of the female genital tract ‘malignant mixed M_an tumor”. Different opinions on the histogenesis of mixed tumors, which are nicely reviewed by Wick and Swanson,167 to some extent account for this quite inconsistent classification. The debate focuses on two hypotheses. There is the convergence, polyclonal hypothesis in which mixed tumors consist of two separate, concurrent populations, hence the old term ‘collision tumors”. Alternatively, the divergence, monoclonal hypothesis assumes that both epithelial and mesenchymal components are derived from a single uncommitted, totipotent cell which, after transformation, has proliferated towards separate differentiation lineages. Although rare cases of polyclonal mixed neoplasms might exist, most evidence in literature is favoring the divergence hypothesis.

Figure 1. Malignant mixed Müan tumor (carcinosarcoma) of the ovary.

Figure 1

Malignant mixed Müan tumor (carcinosarcoma) of the ovary. The cells of the carcinomatous (arrows) and sarcomatous (arrowheads) component show malignant features: their nuclei are enlarged, pleomorphic and hyperchromatic. Formaldehyde fixed, paraffin (more...)

Figure 2. Carcinosarcoma of the bladder.

Figure 2

Carcinosarcoma of the bladder. A) area in which the mesenchymal (sarcomatous) component predominates. It is composed of disorganized spindle cells surrounded by a nondescript matrix, with an area of chondroid differentiation (arrowheads). Adjacent, the (more...)

First, at the light microscopic level, the epithelial and mesenchymal components are often not well demarcated. The tumor mass rather consists of a mixture of cells with smooth transitions in between the different cell types. Second, spindle cells frequently exhibit (at least minor) epithelial features, as is shown by immunohistochemical positivity for keratin and EMA, or by electron microscopy. Also, in some reports on the (lymph node) metastases of carcinosarcomas, the epithelial component predominates or is the only component,168-170 which would not be expected in a true polyclonal neoplasm. In line with this is the fact that the clinical prognosis of mixed tumors in general equals that of poorly differentiated epithelial neoplasms.170 Strong evidence of monoclonality is provided by the analysis of commonly mutated p53 exons,171-173 allelic polymorphisms,174 loss of heterozygosity173 or the level of homology in chromosomal aberrations by comparative genomic hybridization.175 These studies demonstrated identical genotypic changes in both components.

EMT in Other Human Tumors

Table 4 lists other examples of EMT in tumors. The most prevalent tumor is the malignant mesothelioma, a locally aggressive tumor that is related to asbestos exposure. It originates from the mesothelium which lines the pleural and peritoneal cavities. The tumor cells display either an epithelial or a mesenchymal phenotype and often, in so-called ‘biphasic mesothelioma”, both cell types are present (fig.3), probably representing cell plasticity.176-178

Figure 3. Biphasic malignant mesothelioma.

Figure 3

Biphasic malignant mesothelioma. Both the epithelial (upper right field) and mesenchymal (lower left field, arrowheads) component show intracytoplasmic immunoreactivity with the pan-cytokeratin AE1/AE3 antibody. Hematoxylin counterstaining. (scale bar: (more...)

Sex cord-stromal tumors represent a group of rare ovarian stromal tumors probably derived from the ovarian surface epithelium.105 This is a monolayered cuboidal epithelium, showing epithelial characteristics such as cytokeratin expression, desmosomes, and the production of the basement membrane molecules collagen type IV and laminin. However, concurrent vimentin and N-cadherin rather than E-cadherin expression suggests a dual epithelial-mesenchymal differentiation capacity,105 which is also reflected by the plasticity of the ovarian surface epithelial cells in vitro, as mentioned above. This dual differentiation capacity might explain why as diverse tumor types as ovarian surface carcinomas and sex cord-stromal tumors could originate from them.

The last example of EMT illustrates that tumors might recapitulate embryonic development by showing differentiation along the same lineages. In the ameloblastoma, a tumor usually arising from remnants of the dental lamina or the enamel organ in the jaw, the so-called ‘stellate reticulum” constitutes the tumor stroma adjacent to the ameloblastic tumor epithelium. These stromal cells share epithelial features with the ameloblastoma cells, as has been demonstrated ultrastructurally,179 immunohistochemically and by in situ hybridization.180 Both cell types are encountered in a similar context in the developing dental root.181 In the more rare mixed odontogenic tumors, there is evidence for an EMT as well.182

Finally, Putz et al183 investigated the marker profiles of cell lines that were established from bone marrow aspirates of stage M0 cancer patients and found that they were consistent with cancer cells that underwent an EMT, thereby underscoring the hypothesis that (micro)metastasized carcinoma cells have gone through an EMT.

EMT in Non-Tumoral Pathologies

Besides during embryogenesis and in tumors, EMT also occurs in certain non-tumoral pathologies, namely in some chronic inflammatory processes (see Table 5). Best studied is the transition in kidney fibrogenesis. Iwano et al induced a chronic inflammatory response in the kidney interstitium of transgenic mice by imposing a unilateral ureteral obstruction.184 They demonstrated that a substantial number of the fibroblasts appearing in the induced fibrotic tissue were derived from the proximal tubular epithelium, which had been specifically LacZ-labeled through cell type specific gene targeting. Other reports focused on the underlying mechanisms; TGF-β, EGF and FGF2 secreted by inflammatory stromal cells, appeared inducers of this type of EMT.63,185,186 In renal biopsies from patients suffering from tubulointerstitial fibrosis a switch was observed in the morphological markers, compatible with EMT.187,188

Table 5. Transitions in physiology and non-tumoral pathology.

Table 5

Transitions in physiology and non-tumoral pathology.

Another example of chronic inflammation is the peritoneal fibrosis that occurs during long-standing continuous ambulatory peritoneal dialysis of patients with renal failure. A recent study showed that in peritoneal biopsies of such patients the normal mesothelium and submesothelial connective tissue was replaced by fibrotic tissue and embedded in it, a population of elongated, fibroblast-like though still cytokeratin-positive cells.189 In cultures of the mesothelial cells that were shedded into the dialysis fluid, a comparable phenotypic switch was found to be paralleled by an increase in vimentin expression and a downregulation of cytokeratin and E-cadherin. Similar cellular changes could be induced in vitro by treating normal mesothelium with TGF-β and IL1-β. Although in these cell cultures the transitions were reversible, so rather an example of scattering according to our definition, the persistent scar tissue observed in vivo could be attributed to an EMT.

A comparable transient phenotypic switch is described in repair mechanisms of human respiratory epithelial cells in vitro.150 Motile, elongated cells emerging at the wound edge co-expressed cytokeratins and vimentin. The transition is possibly related to Str-3 (MMP-11) production in neighboring epithelial cells.

As mentioned above, retinal pigment epithelial cells show phenotypic plasticity in vitro. This cell type can be the key player in the ‘proliferative vitreoretinal disorders”, which are characterized by proliferation of scar-like tissue in response to inflammatory stimuli.190

Other Transitions

Examples of cell plasticity in adult tissue other than the epithelial-to-mesenchymal transition are listed in Tables 5 and 6. Concerning the non-tumoral pathologies, Barrett esophagus, caused by chronic gastro-esophageal reflux, is clinically the most important example, since it imposes a high risk for developing adenocarcinoma.191,192

Table 6. Transitions in tumor pathology.

Table 6

Transitions in tumor pathology.

Blood vessels, when activated during inflammation, could become lined by an epithelioid instead of the normal flattened endothelium. An epithelioid morphology is also adapted by the macrophages in epithelioid granulomas, representing a type of chronic inflammation characterized by aggregates of activated macrophages. An electron microscopy study revealed that each epithelioid granuloma, irrespective of the underlying disease, consists of a heterogeneous population of macrophages. The cells have a large amount of eosinophilic cytoplasm due to the accumulation of different types of lysosomes and vesicles and the prominence of the rough endoplasmic reticulum and Golgi apparatus.193 The cadherin expression detected in such epithelioid macrophages by immunohistochemistry, favors a process of true transdifferentiation.194

In contrast to the active changes in EMT, alterations in the epithelial cell shape can be the result of an accumulation of foreign material in the cytoplasm or the cytopathic effect of a viral infection. Besides nuclear alterations, cytoplasmic vacuolization and accumulation of keratohyaline granules are seen in Papilloma virus infections (cervix condylomata or warts of the skin), whereas epithelial cells transform to large, multinucleated cells in Herpes virus infections.

Concerning examples of cell plasticity in tumors (Table 6), epithelioid sarcoma is a clear example of a soft tissue tumor with a mixed marker expression pattern (EMA-, keratin- and vimentin-positive) but with an epithelioid cell morphology.195,196 Synovial sarcoma is a ‘biphasic” soft tissue tumor with a spindle-shaped and a variable epithelioid cell component.197,198 Wilms' tumors are aggressive tumors of infancy and childhood exhibiting epithelial and stromal elements that are genetically related and that mimick immature renal structures.199,200 Unlike low-grade lymphomas, anaplastic large cell lympomas (ALCL) are characterized by large, apparently cohesive cells with abundant cytoplasm which are sometimes mistaken for carcinoma cells. Interestingly, strong pan-cadherin immunoreactivity was found in a series of ALCL, probably accounting for the epithelioid phenotype of the lymphoma cells.194

Epithelium- Stroma Interactions

EMT in tumors should be considered as a possible phenotypic event occurring in a context of epithelial-mesenchymal interactions, which lead to homeostasis sustaining tumor progression. An important manifestation of these interactions in tumor pathology is the so-called ‘desmoplastic stroma”. This is the reactive connective tissue found in most malignant tumors that surrounds to a variable extent the infiltrating tumor cells (fig.4). It mainly consists of activated myofibroblastic cells and an altered extracellular matrix (ECM). The stromal changes are the result of interactions during tumor progression between malignant cells, ECM, and the fibroblasts that normally populate the connective tissue, and involve also inflammatory cells and blood vessels.201,202-204 In breast carcinoma, paracrine factors such as platelet derived growth factor205 and TGF-β206,207 secreted by the tumor cells, could account for the initiation of the desmoplastic response. Fibroblasts are converted to α-SMA-reactive myofibroblastic cells,208 and produce a different set of ECM proteins, such as tenascin-C,209 fibronectin,210 hyaluronic acid,211 as well as increased amounts of collagen type I, III and V.212,213 The myofibroblastic cells also overexpress matrix metalloproteinases like MMP-9, MMP-3, MMP-2 and/or MMP-11,214-216 and secrete growth factors such as FGF2, vascular endothelial growth factor-D and HGF,217,218 which act on their turn on the tumor cells. Tumor-derived (myo)fibroblasts exerted a differential tumorigenic influence on breast219 and prostate220 cancer cells as compared to stromal cells from non-tumoral tissue. Benign stromal cells induced a differentiated, less tumorigenic phenotype in the rat Dunning prostatic adenocarcinoma cells.221 A dominance of the stromal phenotype over the cancer cells' genotype was suggested in a mouse prostate model of ras+myc-induced carcinogenesis222 and in the HMT-3522 breast cancer cell line, in which integrin-blocking antibodies were able to revert its malignant phenotype.223 Serial analysis of gene expression (SAGE) and in situ hybridization studies described panels of genes that are differentially expressed in the desmoplastic stroma of breast and pancreas carcinoma, some of which appear to be organ-specific or restricted to specific regions within the tumors.224,225 The interactions of the desmoplastic stroma with the tumor cells are reminiscent to the crosstalk observed in wound healing, in which the different components of the granulation tissue induce epithelial cell proliferation and migration necessary for wound closure.204,226 Parallels can also be drawn with the epithelium-stroma interactions during the embryogenesis of e.g., breast or prostate.227,228

Figure 4. Desmoplastic stroma in an invasive ductal adenocarcinoma of the breast.

Figure 4

Desmoplastic stroma in an invasive ductal adenocarcinoma of the breast. It contains a high number of ‘non-tumoral” myofibroblasts (arrowheads), of which the elongated nuclei are regular in size and shape compared to the pleomorphic nuclei (more...)

As for the myofibroblastic cells of the desmoplastic stroma, they most probably derive from quiescent stromal fibroblasts in response to TGF-β.229-233 Concerning human prostate carcinoma however, Hayward et al suggests that the smooth muscle cells which make up the normal prostatic stroma are the cells of origin.234 Since this transition would be accompanied by a loss of the smooth muscle markers myosin and desmin, it represents a type of dedifferentiation. In recent literature, the alternative hypothesis is brought up that the myofibroblasts in the desmoplastic stroma of a classical carcinoma, originate from the carcinoma cells themselves through a process of EMT.235 A recent study by Petersen at al236 addresses this subject indirectly. They examined two cell lines, established from the epithelial and mesenchymal component of a metaplastic breast carcinoma. Besides evidence for an EMT and for the clonality of both components, they showed that the fibroblastoid cell line behaved on itself in an indolent way. Although the cells were immortal, they were not tumorigenic in vivo and resembled normal fibroblasts in responding to TGF-β by de novo expression of α-SMA. The authors conclude that EMT-derived mesenchymal cells may differentiate into non-malignant myofibroblast-like cells. In a sense these results subscribe to a third theory concerning the origin of mixed tumors (besides the poly- and monoclonal theory discussed above): the stromal induction/metaplasia theory. According to this theory the stromal component of a mixed tumor is a non-malignant response to the growth of the epithelial malignant component. This particular case of a mixed breast carcinoma could also exemplify a tumor mechanism of carcinomas in general. One could hypothesize that in order to progress, the transformed epithelial cells of a carcinoma need the inductive signals of a surrounding stroma that they create themselves by undergoing a mesenchymal transition towards non-tumorigenic myofibroblastic cells (fig.4). In breast carcinomas, this could occur via an intermediate myoepithelial cell type. The fact that similar loci of loss of heterozygozity could be found in both mammary carcinoma and desmoplastic stromal cells from the same tumor, points to a similar genetic background, possibly indicating that both cell types derive from the same progenitor cell.237-239

In summary, epithelial-mesenchymal transitions are precisely regulated events. Reflected by changes in morphology (differentiation), cells exhibit altered functional properties in terms of motility, extracellular matrix remodeling and interactions with other cell types. In embryonic life, by means of EMT, the cells obtain the potential to create a wide range of different tissues, whereas in adult life, it helps maintaining a homeostasis, e.g., in adequate wound healing. In non-physiological conditions, EMT can also occur. Besides its suggested role in human chronic inflammatory disorders, EMT is described in malignant tumors. Much less numerous than the observations in vitro are the examples of EMT in human tumor pathology. In addition to the rare cases of mixed epithelial/mesenchymal tumors, we discussed the tempting hypothesis that EMT is a common event in carcinomas in general. By means of EMT the epithelial tumor cells would obtain the ability to transdifferentiate into myofibroblasts that lose their malignant phenotype but constitute the desmoplastic stroma which is essential for tumor growth, invasion and metastasis. Thus, by creating their own stroma, carcinoma cells would obtain an additional survival advantage.


We would like to thank M. Mareel, C. Stove and L. Derycke for critical reading of the manuscript, G. Debruyne for his help with the references and J. Roels and E. Van Marck for assistance with the illustrations. V. Van Marck is a research assistant of the Fund for Scientific Research- Flanders (F.W.O- Kom op Tegen Kanker, Belgium).


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