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Invasive breast carcinomas are characterized by their strong heterogeneity, reflecting tumor histology and response to therapy. Their clinical classification has been based on histological features including the presence of differentiated tubules, proliferation rate mitotic index and anisokaryosis, bases for the Nottingham and Scarff Bloom Richardson grading systems [ 10 ].
Other properties such as hormonal receptor status have been found to correlate with disease progression and are used as markers for diagnostic and prognostic purposes [ 11 ]. Therefore, due to this heterogeneity, it is likely that the contribution of a process like EMT in cancer progression depends on the tumor type. A limitation of the clinical studies is the impossibility to state whether an undifferentiated phenotype reflects a lack of differentiation or an active EMT process during tumor progression.
However, a classification of EMT-like phenotypes based on cell—cell adhesion status has been recently proposed, without presumptions about mechanisms responsible for this phenotype [ 9 ]. In these tumors, an epithelial and a mesenchymal compartment can be distinguished based on the expression of, respectively, cytokeratins or vimentin intermediate filaments.
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Cytogenetic studies strongly indicate that these two compartments originate from a common precursor cell population undergoing a full EMT process giving rise to the mesenchymal component [ 12 ]. A more prevalent mammary tumor, the infiltrating lobular carcinoma, is also characterized by the lack of E-cadherin expression reflecting genomic and epigenetic silencing mechanisms [ 14 , 15 ]. They provide an interesting case of partial EMT producing individualized cells.
More recently, expression profiling has provided new global approaches. Based on unsupervised clustering, most studies sort breast tumors into five groups including basal-like, ERBB2-overexpressing, luminal A and B and normal-like tumors [ 17 ]. Expression profiles and signatures characterize these groups, reflecting histological features and tumor phenotype. However, no consensus has been reached yet on their precise identity.
Most of the studies have identified a group called the basal-like group. Tumor cells in this group present a phenotype reminiscent of the elusive stem-cell profile described for mammary gland.
Several authors have indicated that basal-like cancers could be generated by mammary stem cells transformed at very early stages of differentiation [ 18 ]. This observation is also relevant considering the links established between EMT and emergence of stem-cell-like cells. Several pathways activated along EMT models are also overactive in basal-like carcinomas. Also, the expression of factors of the Snail family has indicated that EMT is controlling basal-like carcinoma progression [ 20 ].
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It should be noted, however, that a basal-like tumor cell profile is distinct from a post-EMT profile. Overall, basal-like carcinomas are associated with poor relapse-free and overall survival. Another tumor group called the normal-like tumors is also characterized by the expression of some markers and pathways evoking early differentiation pathways [ 21 ]. In both cases, it is tempting to suggest that tumor cell phenotype could reflect low differentiation level from the original transformed tumor cell.
Alternatively, the initial transformation process could include a de-differentiation stage, possibly an EMT situation considering EMT-related pathways found to be activated during transformation and tumor progression. Among them, Snail genes have been studied in the context of breast carcinoma for one decade. A significant number of publications indicate overexpression linked to tumor aggressiveness [ 10 , 22 ].
Recent work using transplantations in humanized mouse mammary glands identified Slug among effectors of the Wnt pathway. In this basal-like carcinoma model, a lung metastasis signature was used to identify the Wnt pathway role for tumor cell self-renewal and proliferation, linking again EMT, stemness and seeding capacity in human mammary tumor cell [ 23 ]. Mouse models have been used to decipher the links between cell phenotype, EMT and oncogenic pathways.
Recent expression-profiling analysis has established interesting links between mammary-specific tumor-promoting pathways and the resultant phenotype and dominant active pathways [ 24 ]. These profiles evoke human classification, with notable differences.
Epithelial-mesenchymal transition and its implications for fibrosis
Basal-like, normal-like, luminal-like and mixed phenotype-based groups were identified by a clustering based on a gene signature designed by unsupervised tumor sample clustering. These phenotypes appear to result from distinct inductive pathways converging to generate a differentiation status that may also reflect transformed cell origins. Similarly to human mammary basal-like carcinomas, tumor cells from the basal-like group expressed cytokeratin 5 and c-Kit. These tumors were composed mostly of dissociated cells. Slug was also found to be overexpressed in this group and in the basal-like tumors, as reported for human mammary basal-like carcinomas.
This work indicates that the EMT-like phenotype can result from oncogenically controlled activation.
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This was demonstrated more clearly in an intricate mouse model. This clear localization illustrated an extensive EMT process affecting a significant proportion of tumor cells. In this model, a good proportion of the peritumoral stroma was actually generated by EMT from the original mouse mammary epithelial cells. This work represents a clear demonstration of an EMT process involved in tumor progression and emphasizes the specific role of some oncogenic pathways such as myc and ras in triggering this process.
This is reminiscent of the role of the myc pathway mentioned before in human basal-like mammary carcinomas. Besides the modification of the phenotype, EMT also results in the acquisition of other properties involved in carcinoma progression, such as an increased ability to migrate, a higher resistance to apoptosis and the already mentioned acquisition of stemness properties. The onset of both EMT and EMT-like events is associated with loss of cellular polarity, partial to total destabilization of cell—cell junctions, remodeling and replacement of cytoskeletal components, the onset of cell motility and the suppression of apoptosis.
In vitro and in vivo model systems have allowed the characterization of various pathways leading to EMT and EMT-like phenotypes. Such pathways are referred to as EMT pathways in this review, without assuming functional specificity. A distinct EMT pathway has also been recently described involving the protein tyrosine phosphatase Pez.
Transcriptional down-regulation of junctional components accompanies the EMT process in several systems [ 1 , 3 ] and may be either a cause or an effect of EMT-like events. Down-regulation of E-cadherin is linked to cell—cell dissociation and invasion in pancreas, prostate and mammary gland mouse cancer models [ 30 ]. These factors appear to be involved in most physiological EMT situations, and their overexpression in epithelial cell lines usually induces an EMT [ 16 , 22 , 33 ].
At the same time, detailed mechanism s of their effects remain unclear; cellular co-expression of Snail and E-cadherin has been described in breast and colon carcinomas by several groups [ 10 , 34 ]. In addition, specificity of these transcription factors is clearly not restricted to E-cadherin regulation and the EMT process. For example, members of the Snail family have been shown to be involved in cell motility, proliferation control, differentiation and apoptotic regulation in vivo and in cell models [ 22 , 35 ].
Distinct pathways inducing EMT have been uncovered recently, emphasizing functional links between EMT-like phenotypes and inductive pathways specifically activated during tumor growth and progression.
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Tumor cell growth requires an increase in local vasculature to provide metabolites and oxygen. Cells adjust to a nutritionally impoverished and hypoxic environment by activating specific pathways associated with hypermetabolism, glycolysis and resistance to acidosis-induced toxicity, and neoangiogenesis. Hypoxia genes have been found to be expressed locally within solid tumors, probably contributing to tumor heterogeneity [ 36 ]. The link between hypoxia and EMT has been recently strengthened by the observed activation of Snail and Twist expression by HIF-1, a key hypoxia effector [ 37 ].
Another hypoxia-related gene, lysyl oxidase, was found to interact directly with Snail [ 38 ]. Another specific feature of the tumor microenvironment is the stromal reaction through which epithelial—mesenchymal interactions activate or regulate several pathways involving integrins, cytokines and growth factors that are critical for tumor growth and metastasis [ 39 ].
A putative role of macrophages in supporting the movement of individualized cells from mammary tumors into the bloodstream has recently been indicated in striking movies [ 41 ]. In conclusion, the concept of EMT has been very fruitful in emphasizing new pathways controlling cell fate and tissue morphogenesis. Based on clinical observations, it appears more appropriate in most cases to describe the emergence of an EMT-like phenotype during tumor progression.
This descriptive term does not necessarily imply an active dedifferentiation process but emphasizes an intermediary phenotype resulting from tumor cell renewal and adaptation to specific microenvironments. Several transcription factor families have proved to be powerful regulators of cell phenotype, also involved in apparently unrelated cell processes such as apoptosis and acquisition of stemness properties. In vivo studies show functional links between these processes along developmental stages, stress response and indeed carcinoma progression. Although many questions remain to be answered, the remarkable advances during the last years in the mechanism controlling EMT opens new hopes about the use of inhibitors of this process as an antitumoral drug, alone or in combination with other compounds targeting epithelial cells [ 2 , 42 ].
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