Control of differentiation
in progression of epithelial tumors

This point can be illustrated by the investigations of HCC progression mechanisms performed in our laboratory in the last few years. HCC is the prevalent liver tumor and one of the world's most common cancers. The major risk factors for the development of HCC are chronic infection with hepatitis B or C viruses and prolonged exposure to hepatocarcinogenes (Bosch et al., 1999). HCC development is a continuous multi-step process that results from the accumulation of genetic alterations leading to the acquisition of more aggressive tumor phenotype. The analysis of genetic abnormalities and gene expression alterations in HCC revealed some candidate genes and signaling pathways possibly implicated in hepatocarcinogenesis (Thorgeirsson and Grisham, 2002). These genes encode growth factors (TGF-α and -β, hepatocyte growth factor (HGF) and their receptors), tumor suppressors (Rb and p53), components of the Wnt/catenin pathway, and other cell communication and adhesion molecules (Buendia, 2000). However, the molecular basis of hepatic tumor progression and its relationship to normal cell differentiation remain obscure.

To elucidate the role of liver-enriched transcription factors in HCC progression, we have developed an experimental model in which a chemically induced slow-growing transplantable mouse HCC (sgHCC) rapidly gave rise in vivo to a highly invasive dedifferentiated fast-growing variant (fgHCC) (Lazarevich et al., 2004).

sgHCC is a highly differentiated tumor with a pattern of gene expression that closely resembles normal hepatocytes. The progression of sgHCC was accompanied by loss of epithelial morphology, activation of telomerase, extinction of liver-specific gene expression, invasion, and ultimately metastasis (Varga et al., 2001; Lazarevich et al., 2004).

The loss of epithelial morphology in fgHCC comprises a complete loss of cell polarity and a decrease in cell-cell and cell-matrix adhesion. sgHCC has a typical basal membrane which consists of type IV collagen, laminin, entactin, and fibronectin; each cell interacts with the basal membrane. In contrast, in fgHCC, all ECM components are synthesized but not associated with the membranes, thus, cell-matrix interactions are completely disarranged. The tight junction marker protein ZO-1 is present on the membrane of sgHCC, while fgHCC cells exhibit no membrane staining of ZO-1. This fact together with the redistribution of domain-specific markers indicates the loss of epithelial polarity in fgHCC (Engelhardt et al., 2000; Kudryavtseva et al., 2001).

The morphological changes observed during a one-step progression meet the criteria of the EMT (Thiery, 2002). It is accompanied by alterations in the expression of several genes coding for the cell-cell and cell-ECM communication components (Lazarevich et al., 2004). Noteworthily, sgHCC, characterized by extremely strong cell-cell and cell-matrix contacts, overexpresses E-cadherin and β-catenin mRNA as compared to normal liver. fgHCC shows significantly decreased steady state mRNA levels of the major liver gap junctional protein Cx32 and E-cadherin, and an overexpressed α3 integrin subunit, which is expressed in immature or transformed hepatocytes and in biliary cells and mediates ECM-induced differentiation (Lora et al., 1998). Downregulation of E-cadherin transcription is accompanied by a significant increase of mRNA steady state level of Snail, a zinc finger transcription factor involved in the epithelial-to-mesenchymal transition through repression of the E-cadherin promoter (reviewed in Peinado et al., 2004). In the mouse HCC model, EMT was also mediated by increased levels of the mesenchymal cell marker vimentin and splice form of fibronectin containing extra domain A (EDA). EDA form of fibronectin promotes the increase of cell spreading and migration (Manabe et al., 1997).

In addition to the loss of epithelial morphology, fgHCC cells demonstrate reduced expression of most markers of mature hepatocytes (albumin, α1-antitrypsin, transthyretin, phenylalanine hydroxylase, apolipoproteins, L-type pyruvate kinase, glucokinase, etc.) as well as the expression of AFP normally restricted to fetal hepatoblasts and induced in sgHCC as compared to normal liver. Thus, according to the expression pattern, the one-step progression caused severe dedifferentiation of fgHCC as compared to sgHCC. These alterations were coupled with the reduced expression of the entire block of liver transcription factors that are essential for hepatocyte differentiation, namely, HNF1α, HNF1β, HNF3γ, C/EBPα, HNF4α (both α1 and α7 isoforms), and HNF6 (Lazarevich et al., 2004). The retained expression of several liver-specific genes in fgHCC confirms the hepatic origin of these cells (Lazarevich et al., 2004).

Multiple phenotypic changes defining the development of a highly malignant phenotype occur rapidly implying that HCC progression in this model is a consequence of a limited set of molecular events. We suppose that HCC progression can result from dysfunction of liver-specific transcription factors which control hepatic gene expression and differentiation. Extensive investigations on animal models indicate that the key liver-specific transcription factors providing for mature hepatic phenotype are HNF4α1, HNF1α, and C/EBPα (Section II.B.1).

The relevance of these factors for the maintenance of hepatic differentiation is confirmed for hepatoma cell cultures. The expression of HNF4α1 as well as of its direct transcriptional target HNF1α is generally restricted to differentiated hepatomas, while HNF1β and HNF4α7 are mainly expressed in dedifferentiated cells (Cereghini et al., 1988; Spath and Weiss, 1998; Nakhei et al., 1998; Torres-Padilla, 2001). In concordance with these data, a significant decrease of HNF1α expression was revealed in poorly differentiated human HCCs relative to well-differentiated tumors (Wang et al., 1998).

Similarly, the expression of C/EBPα, associated with the maintenance of a quiescent differentiated state of hepatocytes, is very low or undetectable in liver nodules and HCC tumor samples (Flodby et al., 1995). Forced expression of C/EBPα in human hepatoma cell lines results in impaired proliferation and suppressed tumorigenicity (Watkins et al., 1996).

The expression of exogenous HNF4α1 in a dedifferentiated hepatoma cell culture H5 induces the expression of several hepatic genes and re-establishment of epithelial cell morphology. This transition is associated with re-expression of cytokeratins and E-cadherin production. These findings indicate that HNF4α may be a key regulator of hepatic differentiation which integrates tissue-specific gene expression and epithelial morphogenesis (Spath and Weiss, 1998).

The studies on the one-step model of HCC progression in mice confirmed the essential role of HNF4α dysfunction in hepatocarcinogenesis (Lazarevich et al., 2004). Forced expression of HNF4α1 in cultured fgHCC cells partially restored epithelial morphology. fgHCC cells expressing HNF4α1 formed epithelial sheets with tight junctions marked by ZO-1 plasma membrane staining. In addition, fibrils of ECM components were located along cell-cell interfaces indicating the formation of cell-matrix contacts. At the same time, E-cadherin was not revealed on the cell membranes of epithelial islands suggesting that epithelial conversion in this case is an E-cadherin independent process.

HNF4α1 re-expression in fgHCC cell culture also restored the expression of several functional hepatic proteins (apolipoproteins, α1-antitrypsin, Cx32, etc.) and transcription factors (HNF1α, HNF6, HNF4α7, and HNF3γ), reduced the proliferation rate in vitro, and dramatically inhibited tumor formation and metastasis in congenic recipient mice. The multiple effects of HNF4α1 on tumor cell characteristics can be mediated by the activation of other HNF4α-regulated liver-enriched transcription factors. Nevertheless, the re-expression of individual transcription factors that were HNF4α-inducible did not result in obvious changes in fgHCC cell proliferation and morphology (Lazarevich, unpublished data).

Thus, the profound changes in the differentiation state and cell proliferation in this model of tumor progression are at least partially defined by HNF4α1 suppression. The restoration of HNF4α1 function can promote the reversion of invasive HCC toward a less aggressive phenotype by inducing hepatic re-differentiation.

The central role of HNF4α1 in the control of morphological, proliferative, and functional properties that define hepatic differentiation was confirmed in other models. Studies of gene expression profiles on the collection of chemically induced mouse HCCs of independent origin revealed a strict correlation between HNF4α1 transcription and tumor differentiation status. Downregulation of HNF4α1 transcription in the fast-growing poorly differentiated tumors coincided with the extinction of transcription factors that previously proved to be HNF4-inducible (HNF1α, HNF4α7, and HNF3γ). We also detected downregulation of HNF4α1 expression in the majority of human HCCs not associated with hepatitis infection (Fleishman and Lazarevich, in preparation). Moreover, a high incidence of dysfunction of HNF4α1 and its transcriptional target HNF1α was revealed in human renal cell carcinomas (Sel et al., 1996; Anastasiadis et al., 1999).

Thus, these factors can be considered as potential tumor suppressor genes at least in the kidney and liver, where HNF4α1/HNF1α regulatory pathway clearly defines the lineage-specific differentiation. These data support the hypothesis that dysfunction of tissue-specific transcription factors essential for definite tissue specification can be a critical step in the dedifferentiation and progression of the corresponding epithelial tumors.

This point can be illustrated by dissecting the role of C/EBP factors in epithelial carcinogenesis. Recently, reduced expression of C/EBPα was described in breast (Gery et al., 2005), lung (Halmos et al., 2002), and skin (Shim et al., 2005) tumors. In lung cancers, the decrease of C/EBPα expression correlates with the histological subtype and tumor grade (Halmos et al., 2002). Restoration of C/EBPα expression in non-small cell lung cancer cell lines induces apoptosis, proliferation arrest, and morphological changes toward a more differentiated phenotype.

mRNA and protein levels of C/EBPα are downregulated in mouse skin squamous cell carcinomas (SCC) and cell lines with activated Ras (Shim et al., 2005). Transduction of keratinocytes with oncogenic ras diminishes the expression and DNA binding of C/EBPα indicating the involvement of activated Ras in negative regulation of C/EBPα transcription. Forced expression of C/EBPα in SCC cell lines inhibits the proliferation of SCC cells containing oncogenic Ras indicating that the antiproliferative activity of C/EBPα is dominant over the Ras effects.

In humans, the normal mammary tissue expresses only C/EBPβ activatory 1 isoform (Bundy and Sealy, 2003). The overexpression of the dominant negative isoform of C/EBPβ induces proliferation and hyperplasia of the mammary gland (Zahnow et al., 2001). In addition, the overexpression of C/EBPβ activatory isoform 2 in mammary epithelial cell line induces EMT and development of invasive phenotype characterized by the loss of E-cadherin junctional localization, acquisition of a spindle-shape morphology, actin stress fibers, and the appearance of the mesenchymal intermediate filament vimentin (Bundy and Sealy, 2003). C/EBPβ regulates the expression of cyclooxygenase 2, the key enzyme of prostaglandin biosynthesis that induces mammary tumorigenesis in transgenic mice and is frequently overexpressed in invasive breast cancers. There is increasing evidence that C/EBPβ acts as downstream effector of Ras signaling. C/EBPβ also plays an important role in Ras-mediated skin tumorigenesis. C/EBPβ -/- mice are refractory to chemically induced skin carcinogenesis (Zhu et al., 2002). All these findings support the idea that dysfunction of tissue-specific transcriptional regulators is an important event in the development of malignant phenotype of different epithelial cell types.

Certainly it is unlikely that the function of the HNF transcriptional network is implemented autonomously from the ubiquitous pathways controlling the growth, morphological, and housekeeping properties of cells. While a significant progress in understanding the impact of HNFs in epithelia differentiation and function was achieved in the last decade, the mutual influence of this tissue-specific transcriptional network and the components of the main signal transduction cascades are still underestimated. In this context, we discuss the presumable mechanisms of HNF4α influence on hepatic differentiation.

What mechanisms define the HNF4-dependent control of hepatic function, epithelial morphology, and proliferation? This question might be addressed by identification of new transcriptional targets of tissue-specific regulatory factors. HNF4α effects on gene regulation can be realized both directly and by regulation of transcription of other HNFs. However, the inactivation of HNFs in mice (Section II.B.1) and their re-expression in dedifferentiated tumors have less dramatic consequences suggesting that the most critical regulation of cell properties is realized by HNF4α per se.

Obviously the major part of experimentally proved HNF4α targets are functional genes encoding blood coagulation factors, enzymes of lipid (Hayhurst et al., 2001), amino acid, glucose (Parviz et al., 2003), and urea (Inoue et al., 2002) metabolism. Importantly, HNF4α regulates the expression of cytochromes P450 and some other enzymes and transporters involved in drug metabolism (reviewed in Tirona and Kim, 2005). Thus, the loss of HNF4α during HCC progression can have an additional significance – HNF4-negative tumors can have altered responsiveness to therapy. In this case, re-expression of HNF4α can be considered as a possible approach to sensitization of HCCs to therapy.

The morphogenic properties of HNF4α are likely realized by transcriptional regulation of several cell adhesion and junction proteins like E-cadherin (Spath and Weiss, 1998; Parviz et al., 2003), Bgp1, gap junctional proteins Cx32 (presumably, through HNF1α regulation) (Piechocki et al., 2000) and Cx26 (Parviz et al., 2003), and tight-junction components occludin and claudins 6 and 7 (Chiba et al., 2003). There is also an evidence for the existence of HNF4-dependent posttranslational mechanisms of ZO-1 dysfunction (Parviz et al., 2003).

HNF4α putative transcriptional targets that can mediate the antiproliferative effects of this factor include p21 (Chiba et al., 2005) and Fas ligand (Osanai et al., 2002). HNF4α is also essential for the hypoxic induction of the erythropoietin gene in the kidney and liver, thus it is likely involved in the cellular oxidative stress response in normal and tumor tissues (Galson et al., 1995).

Additional candidate HNF4α target genes were recently identified using microarray hybridization (Naiki et al., 2002). Chromatin immunoprecipitation analyses combined with promoter microarrays with Hu13K human DNA chip identified about 1500 putative HNF4α target genes in human liver (Odom et al., 2004). The experimental verification of this data will help to disclose the new mechanisms defining the key role of HNF4α in hepatic differentiation.

Studies on the one-step HCC progression model allowed us to demonstrate that the regulatory region of HNF4α1 is inactive in dedifferentiated fgHCC, indicating HNF4α1 repression at the transcriptional level as oppose to mutation, DNA rearrangement, or other damage of the HNF4α1 coding or regulatory regions. This result provides a strong evidence for the existence of HNF4α upstream mechanisms responsible for tumor progression.

2. HNFs mediate microenvironmental effects on hepatic differentiation

It has been clearly demonstrated that the maintenance of epithelial morphology is an important determinant influencing hepatic differentiation. Isolation and cultivation of hepatocytes associated with disruption of normal interaction between cells and ECM leads to drastic changes in the gene expression program. Freshly isolated adult liver hepatocytes, cultivated on dried collagen substrate in the presence of growth factors, actively proliferate, express cytoskeletal components (actin, tubulin, cytokeratins, and vinculin), but exhibit low levels of liver-specific gene expression. Cultivation of hepatocytes on reconstituted ECM gel from Engelbreth-Holm-Swarm mouse sarcoma (EHS gel), primarily composed of laminin, type IV collagen, heparin sulfate proteoglycan matrix, and several growth factors, diminishes DNA synthesis, decreases the transcription of cytoskeletal components, and prevents the loss of liver-specific (albumin, transferrin, and α1-antitrypsin) gene expression (Ben-Ze'ev et al., 1988). What molecular mechanisms translate the extracellular signals into alterations of liver-specific gene expression?

Cultivation of hepatocytes on collagen I decreases HNF4α and C/EBPα expression, while growth on EHS gel maintains the transcriptional level of HNF4α similar to the in vivo level (Oda et al., 1995; Runge et al., 1997). Moreover, dedifferentiated hepatocytes grown on dried collagen I matrix can redifferentiate after the addition of EHS gel. This transition is accompanied by induction of C/EBPα DNA-binding activity (Runge et al., 1997) and HNF4α transcription (Runge et al., 1999). These data suggest that the key factors of hepatic maturation, HNF4α and C/EBPα, can mediate ECM-dependent regulation of liver-specific gene expression. However, the absence of C/EBPα does not prevent ECM-dependent upregulation of albumin gene in primary hepatocytes isolated from C/EBPα -/- mice (Soriano et al., 1998). It is likely that C/EBPα alone is not responsible for this effect.

HNF3 factors are essential for early liver development and activation of liver-specific genes (Lemaigre and Zaret, 2004). HNF3α expression and HNF3 DNA binding activity are upregulated by ECM in the hepatic-derived cell lines H2.35 and HepG2 (DiPersio et al., 1991). In these cell lines, the activation of HNF3 is critical for upregulation of albumin transcription induced by ECM assuming that HNF3 factors can mediate ECM-dependent differentiation. However, the dedifferentiation of primary hepatocytes in culture leads to the upregulation of HNF3α (Oda et al., 1995; Runge et al., 1998), while EHS gel-induced redifferentiation is accompanied by the reduction of HNF3 DNA binding activity (Runge et al., 1998). Thus, it is likely that HNF3 cannot provide ECM-responsive activation of the differentiation program in normal adult hepatocytes. These data are consistent with the observation that the activity of HNF3 proteins has the most profound impact on hepatic differentiation at the early stages of liver development (Sund et al., 2000).

The results supporting the key role of HNFs in ECM-mediated differentiation were obtained on the model of "small hepatocytes" differentiation in culture (Sugimoto et al, 2002). Small hepatocytes are proliferating cells with hepatic characteristics isolated from adult liver. Cultivation in EHS gel induces the changes of the cell shape typical for mature hepatocytes, formation of bile canaliculi-like structures, and production of liver-specific proteins, which correlate with the activation of HNF4α, HNF6, C/EBPα, and C/EBPβ transcription. Addition of individual growth factors, ECM components of the EHS, or collagen gel failed to induce similar alterations in cell morphology and gene expression. It is likely that hepatic differentiation depends on the formation of complex basal membrane-like structures and is modulated by cytokines signaling.

From the first steps of hepatic organogenesis, the paracrine cytokine signaling from mesodermal cells substantially determines the hepatic differentiation into functional hepatocytes (reviewed in Lemaigre and Zaret, 2004). The liver bud formation is induced by fibroblast growth factors (FGFs) and bone morphogenetic proteins (BMPs) produced by the cardiogenic mesoderm and septum transversum, respectively. Further stages of liver development are also mediated by the action of various cytokines produced by stromal cells which control both morphogenesis and proliferation of hepatocytes. Besides, tumor cells, especially those undergoing EMT, gain the ability to secrete growth factors in an autocrine fashion, thus gaining additional independence from the microenvironment (Gotzmann et al., 2002).

The complex interplay between growth factor signaling and ECM effects on the expression of HNFs can be illustrated by studies of in vitro differentiation of fetal mouse hepatocytes. Expression of mature hepatic genes and upregulation of HNF4α in fetal hepatocytes can be induced by EHS and interleukin-6 related hepatic maturation factor oncostatin M (Kamiya et al., 2003). In fetal hepatocytes, this factor directly activates K-Ras and promotes the formation of E-cadherin-based adherence junctions by the Ras-dependent mechanism (Matsui et al., 2002). Hepatic differentiation induced by oncostatin M and EHS can be suppressed by tumor necrosis factor (TNF)-α which inhibits the induction of HNF4α and several liver-specific genes (Kamiya and Gonzalez, 2004).

There is growing evidence that the activity of TGF-β signaling pathway can modulate HNF4α-dependent regulation of hepatic differentiation. HNF4α was shown to physically interact and functionally cooperate with Smad 3 and 4 transcription factors which mediate TGF-β signaling (Chou et al., 2003).

In primary rat hepatocytes, TGF-β was shown to repress HNF4α transcription through activation of WilmTs tumor suppressor WT1, transcription factor referred to as dedifferentiation marker in hepatocytes (Berasain et al., 2003). De Lucas et al. (2004) reported the decrease of HNF4α DNA-binding activity in human hepatoma HepG2 treated with TGF-β and proposed that TGF-β induces HNF4α degradation in the proteasome.

Downregulation of HNF4α expression was also revealed during TGF-β induced EMT in cultured fetal hepatocytes (Sanchez et al., 1999; Valdes et al., 2002) and immortalized hepatocytes transformed with oncogenic Ha-Ras (Gotzmann et al., 2002). These findings suggest that the loss of HNF4α can at least partially mediate the alterations of the functional and morphological properties of hepatocytes during this process.

C/EBP proteins, important mediators of both proliferation and differentiation, are regulated by injury-related cytokines such as TNF-α and interleukin-6 (Diehl, 1998). Suzuki and coworkers (2003) showed that a gradual differentiation of hepatic stem cells to albumin-producing hepatoblasts and finally to mature hepatocytes induced by HGF and oncostatin M is mediated by C/EBPα activation. Lack of C/EBP proteins inhibits hepatic differentiation of stem cells. In this model, several ECM components also induce differentiation by C/EBP expression control, although this effect was less pronounced. Modulation of C/EBP signaling can not only directly influence liver-specific gene expression, but also modify the production of proteins directly involved in the maintenance of epithelial cell morphology. Functional C/EBP sites are identified in the promoters of genes coding ECM proteins, MMPs and protease inhibitors (Doyle et al., 1997; Greenwel et al., 2000; Boffa et al., 2002).

We illustrated the role of ECM in tissue-specific gene regulation on various models of hepatic differentiation; however, it seems suitable for other epithelial tissues. For example, ECM dependent regulation of tissue-specific αs1- and β-casein genes in mammary cells is mediated by alterations in activity of C/EBP proteins, which are critical regulators of mammary gland differentiation (Myers et al., 1998; Jolivet et al., 2005).

Thus, it is likely that tissue-specific transcription factors essential for the specification of definite cell lineages mediate the interaction of epithelial cells with the microenvironment. ECM remodeling, which can regulate signal transduction pathways through interactions with integrins or by releasing growth factors bound to the matrix, together with paracrine signaling from stroma cells can modulate expression or activity of transcription factors. On the other hand, alteration of the transcription factors activity can regulate various genes essential for the maintenance of epithelial morphology. Interrelations between HNF signaling and microenvironment are highly complex and need further investigations, while the importance of tissue-specific transcriptional regulators for the transmission of extracellular signals into alterations of cell transcriptional program is already clear. Consequently, the impairment of tissue-specific transcriptional network seems a very probable cause of epithelial dedifferentiation and carcinoma progression.

IV. Concluding remarks and further perspective

A. Different ways of progression in carcinomas and hemoblastoses

In conclusion, we would like to stress some not trivial features of progression in relation to differentiation in tumors. These features become most clear when epithelial tumors are compared with hemoblastoses. The first and the most crucial difference lies in interrelations between the mechanisms of normal differentiation and development of malignant phenotype in both types of neoplasia. Transformation itself is most probably similar in both systems. It includes constitutive activation of protooncogene or inactivation of tumor suppressor gene and immortalization, i.e. events leading to autonomous and infinite cell proliferation. These processes take place both in hemopoietic and epithelial tissues through the similar mechanisms: protooncogene mutations, activation of protooncogene by its translocation next to functional transcription regulatory elements, or formation of fused genes, driven by the promoters, active in target tissue (see Barr, 1998).

Principal differences appear at the next steps of tumor evolution – in tumor progression – in selection of the most autonomous variants from a genetically unstable population. In epithelial tumors it leads to invasion and metastases, i.e. to ultimate independence on homologous microenvironment permitting the tissue growth in heterologous territories. Dedifferentiation is associated with either process. Thus, partial or complete loss of tissue-specific proteins and antigens is a natural consequence of epithelial tumor evolution.

On the contrary, progression of hemoblastoses tends to maintain the ability of hemopoietic cells of invading normal tissue (diapedesis) and to expand their ability of forming extramedullar islands of clonal growth. Both properties are inherent in the normal hemopoietic tissue. The fatal feature of progression in this system is overproduction of leukemic cells, their accumulation in the bone marrow and blood, extramedullar hemopoesis, and suppression of normal hemopoeisis. However, autonomous leukemic progenitor cells unlike the normal progenitors do not sense the excess of blood cells in leukemia, while normal progenitors are suppressed by this excess.

It should be kept in mind that after differentiation of hemopoietic cells, which takes place in bone marrow microenvironment, committed or mature cells no more require specific microenvironment for maintaining their differentiation state. This is the principal difference between hemopoietic and epithelial tumors, especially in their progression. Progression of hemoblastoses is not only compatible with the normal properties of hemopoietic cells, but is based on their normal physiological functions, thus keeping differentiation antigens unchanged. Rare cases of "promiscuous" hemopoietic line markers expression are due, most probably, to the existence of corresponding transitional stages in development of certain blood cells (Greaves et al. 1986).

B. Future investigations

We are trying to formulate several questions, which remain unresolved on the way of development of a unifying concept, binding microenvironment to epitheliocyte differentiation, and its dedifferentiation in the process of tumor progression due to disruption of microenvironment.

The first problem includes clarification of the microenvironment function in induction versus maintenance of epithelial differentiation. The known elements of this process include obligatory participation of heterologous tissue, most typically mesenchymal tissue, in the specification of epithelial organs, such as liver, pancreas, kidney, mammary gland, skin epidermis, etc. This problem raises the underlying one as to: how tissue interactions induce (and maintain?) a network of tissue-specific transcription factors determining epithelial tissue differentiation. It is obviously a key point of the whole concept, including disruption of these mechanisms in tumor progression. The investigations of Kenneth Zaret and his colleagues as well as George MichalopoulosT team on the regulation of tissue-specific HNFs by ECM gel opened a way in this direction.

The most enigmatic but clearly formulated problem is why and how 3D ECM induces a specific set of transcription factors operating in tissue-specific differentiation? Undoubtedly, this is a key problem relating ECM structure and epitheliocytes differentiation. Its solution is in the air, but the way to solve it is not yet found. Only few publications to our knowledge showed that the nuclear shape and organization of nuclear matrix associated with gene expression depend on ECM structure (Lelievre et al., 1998; Maniotis et al., 1997).

Another very important problem is identification of tissue-specific transcription factors essential for epithelial differentiation. Does epitheliocytes interaction with ECM lead to independent mosaic-like induction of individual transcription factors, or implements through a single crucial step, which determines the further chain of events resulting in the formation of a specific transcriptional network? Evidence of the critical role of HNF4α in hepatocyte differentiation favors the latter possibility (Lazarevich et al., 2004).

How should EMT be regarded: as a regular change in epitheliocytes development, including remodeling of epitheliocytes and natural evolution of tissue structure, or as a result of pathological development of epithelial-mesenchymal interrelations?

And finally, to what extent can tumor progression be reversed? Is the normalization of malignant phenotype limited to some intermediate stages, or can the whole process be turned back? In this respect the identification of definitive events of tumor reversion is extremely important (Mintz and Illmensee, 1975; Kenny and Bissell, 2003).

ACKNOWLEDGMENTS

We would like to acknowledge Prof. Sergey Vassetzky and Dr. Nikita Vassetzky for editing the manuscript. We thank Mrs. Olga Salnikova, Drs. Tatyana Eraiser and Maria Goncharskaya for the help in manuscript preparation.

This work was supported by the program "Leading Russian Scientific Schools", and Russian Foundation for Basic Research, project No 04-04-49189.

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