The transcription factors STAT1 and STAT3 appear to play opposite roles in tumorigenesis. While STAT3 promotes cell survival/proliferation, motility and immune tolerance and is considered as an oncogene, STAT1 enhances inflammation and innate and adaptive immunity, triggering in most instances anti-proliferative and pro-apoptotic responses in tumor cells. Despite being activated downstream of common cytokine and growth factor receptors, their activation is reciprocally regulated and perturbation in their balanced expression or phosphorylation levels may redirect cytokine/growth factor signals from proliferative to apoptotic, or from inflammatory to anti-inflammatory. Here we review the functional canonical and non canonical effects of STAT1 and STAT3 activation in tumorigenesis and their potential cross-regulation mechanisms and discuss the hypothesis that perturbation of their expression and/or activation levels may provide novel cancer therapeutic strategies.

Differential STAT1 and STAT3 Activation by Cytokines and Growth Factor Receptors

Activation of Signal transducer and activator of transcription (STAT ) transcriptional regulators by cytokine and growth factor receptors is typically fast but transient, due to specific negative feedback mechanisms. Abnormal activation, due for example to unbalanced signaling or to altered levels of either specific STATs or their negative regulators, often lead to pathological conditions such as chronic inflammation, defective immune responses or cancer. There is an intriguing convergence of distinct cytokine and growth factor receptors signaling on overlapping sets of STAT factors, particularly on STAT1 and STAT3. Indeed, both of these factors are targets for activation by distinct signals, particularly Interferons (IFNs) and cytokines belonging to the gp130 family such as interleukin (IL)-6, leukemia inhibitory factor (LIF) and Oncostatin M (OSM). Despite their activation of common STATs , these soluble mediators exert distinct and often opposing effects on target cells, correlating with specific patterns and duration of STATs activation. In addition, the final outcome of cytokines/growth factors stimulation is distinct in different contexts, partly reflecting how specific cell types can integrate and interpret the complex and often contrasting signals they receive.^{1 - 4}

STAT1 is a central mediator of both Type I (alpha and beta) and type II (gamma) IFNs, a family of multifunctional secreted proteins involved in cell growth regulation and antiviral and immune defense. Type I and II IFN receptor chains (IFNR) can recruit different Janus kinase (JAK) members to activate common and distinct STAT factors and induce a set of interferon-inducible genes through specific type I or II IFN promoter responsive elements.⁵ IFN-gamma (IFNγ), through JAK1 and JAK2, mainly triggers prolonged STAT1 activation that induces gene expression by binding to gamma-activated sequences (GAS). In contrast, type I IFNs recruit JAK1 and TYK2 and activate both STAT1 and STAT2 triggering the formation of ISGF3, a distinct transcriptional complex that also includes p48/IRF-9. Both IFN types can in addition activate STAT3, albeit to a lesser extent/more transiently.^{6 , 7}

The IL-6 family of cytokines acts instead through homo-or hetero-dimerization of a common signal transduction subunit, gp130, with other specific receptors such as the LIFR. gp130-mediated signaling can trigger activation of JAK1, JAK2 or TYK2, depending on the cell system, leading in most cases to prolonged phosphorylation of STAT3 and transient phosphorylation of STAT1 (reviewed in 8). STAT1 and STAT3 can heterodimerize and bind to similar cognate sites, at least in vitro. However, in vivo functional selectivity is much more stringent and the repertoire of genes regulated by these two factors is mostly distinct.⁹ Importantly, also growth factor receptors with intrinsic tyrosine kinase activity such as platelet-derived growth factor receptor (PDGFR) and epidermal growth factor receptor (EGFR) can activate both STAT3 and STAT1, at least partly through activation of nonreceptor tyrosine kinases belonging to the Src family.¹⁰ In addition, STAT3 can be activated by a number of oncogenes such as, for example, v-Src, v-Fps, v-Sis, Met and polyoma middle T antigen.¹¹

Reciprocal Roles of STAT1 and STAT3 in Tumorigenesis

STAT1 and STAT3 are thought to play opposite roles in tumorigenesis. STAT1 exerts a complex array of functions on both tumor cells and the immune system and is usually considered as a tumor suppressor.¹² In contrast, STAT3 is considered as an oncogene and its constitutive activation is reported in nearly 70% of solid and hematological tumors.^{11 , 13 - 19} Moreover, the over-expression of its constitutively active form, STAT3C, is sufficient to transform fibroblasts and other nonmalignant cell types such as breast and prostate epithelial cells.^{20 - 22} Both STAT1 and STAT3 can exert their opposite effects on tumorigenesis either directly, through transcriptional regulation of target genes in the neoplastic cell, or indirectly, by modulating tumor angiogenesis or the anti-tumor immune response. Here, we separately review what is known about the actions of these two factors in oncogenesis and finally discuss the existence of reciprocal cross-regulation mechanisms that can exert an influence on both physiological and pathological responses

STAT1 in Tumorigenesis

STAT1 plays a critical role in tumorigenesis by controlling a complex array of activities and functions. In many types of tumors STAT1 induces anti-proliferative and pro-apoptotic genes that directly hamper tumor growth. Other STAT1-dependent antitumor effects are due to the induction of genes that block cell cycle progression or inhibit angiogenesis. In addition, STAT1 activation is pivotal for tumor immunosurveillance as it drives induction of MHC Class I molecules, required for efficient display of antigens to effector T-lymphocytes and thus to elicit anti-tumor immune responses. Despite all this, under specific conditions STAT1 can instead favour carcinogenesis and tumor survival, confirming the complexity of this biological system. This section will briefly survey what is known of STAT1 activities related to tumorigenesis, as summarized in Table 1.

Table 1

Effects of STAT1 on tumorigenesis.

STAT3 in Tumorigenesis

Among all STAT family members, STAT3 is most often correlated to tumorigenesis, and is considered as an oncogene. Indeed, this factor is the point of convergence of many signaling pathways triggered by cytokines, growth factors and oncogenes and is accordingly found to be constitutively active in a wide range of tumors and transformed cell lines. In particular, STAT3 constitutive activity has been reported in nearly 70% of solid and hematological tumors, including multiple myeloma, several lymphomas and leukemias, breast cancer, head and neck cancer, prostate cancer, ovarian carcinoma, melanoma, renal carcinoma, colorectal carcinoma and thymic epithelial tumors.¹⁹ Interfering with its activity in these tumor systems almost invariably affects tumor growth and survival, hitting STAT3-driven proliferation, angiogenesis and immune-escape, but also impairs tumor invasivity and metastatic potential. The wide variety of different tumors where STAT3 activity is essential suggests that this factor may play multiple roles in tumorigenesis, not all of which have been so far completely understood. Thus, a growing number of studies are being performed to address unanswered questions about STAT3 and its potential value as a therapeutic target to fight cancer. In this section we review what is known about the different ways of action of STAT3 in tumorigenesis, summarized in Figure 1. These can be classified into cell-autonomous functions, directly affecting specifc features of cancer cells such as proliferation and survival, and indirect effects, exerted through the regulation of tumor angiogenesis or tumor immunosurveillance.

Figure 1

Milestones defining STAT3 role in cancer. The crucial findings identifying the multiple functions of STAT3 in oncogenesis are illustrated along a timeline. ST3, STAT3; ST3C, STAT3C; FA, focal adhesions.

STAT3 and Matrix-Metalloproteinases

Among STAT3 target genes are several members of the MMP family, known to contribute to tumor invasion, angiogenesis and metastasis. Indeed, STAT3C-mediated transformation of immortalized human mammary epithelial cells requires the activity of MMP-9 and this correlates with STAT3 activation and enhanced MMP-9 levels in human breast oncogenesis.²¹ STAT3 can activate the MMP-9 promoter in breast cancer cell lines.⁹⁷ In melanoma cells, STAT3 can directly regulate the expression of another MMP family member, MMP-2, thus increasing invasive and metastatic potential.⁹⁸ Finally, STAT3 interaction with c-Jun is required for the induction of MMP-1 in bladder cancer cells in response to EGF and is crucial for EGF-induced migration, invasion and tumor formation in xenografted nude mice.⁹⁹ A correlation between STAT3 and MMP-1 in colon carcinomas was also reported.¹⁰⁰

STAT3 and Angiogenesis

The first evidence of an involvement of STAT3 in angiogenesis was the demonstration that STAT3C could directly induce the production of VEGF if overexpressed in fibroblasts or B16 melanoma cells¹⁰¹ and in human pancreatic and cervical cancer cells.^{102 , 103} STAT3 can also indirectly regulate VEGF by inducing the expression of hypoxia-inducible factor 1α (HIF-1α), which drives VEGF transcription upon hypoxic stimulation.¹⁰⁴ This was also indirectly confirmed by STAT3 inhibition in human renal carcinoma cells.¹⁰⁵ In addition, STAT3 was also proposed to be involved in VEGF signaling.^{106 , 107}

STAT3 and Epithelial-Mesenchymal Transition

Epithelial-mesenchymal transition (EMT) has been linked to the progression of epithelial tumors.¹⁰⁸ It is a general process required for embryonic development, tissue remodelling and wound repair, during which epithelial cells lose cell-cell adherence, remodel their cytoskeleton and acquire mesenchymal properties, becoming able to migrate, invade and form metastasis. The first step of this process is thought to be the down-regulation of some epithelial surface markers, in particular E-cadherin, by transcription factors such as Snail and Twist. E-cadherin is required to form the adherence junctions characteristic of epithelial cells.

STAT3 involvement in EMT was first suggested by the work of T. Hirano and coworkers in zebrafish, reporting that STAT3 activity is required for cell movements during gastrulation.¹⁰⁹ STAT3 acts through the regulation of the breast-cancer-associated zinc transporter LIV1, which in turn is essential for the nuclear localization of Snail. These observations link STAT3 with Snail and EMT through LIV1.¹¹⁰ More recent data suggest a direct link between STAT3 and EMT. On one side, the expression of dominant negative STAT3 inhibits TGF-β-induced apoptosis and EMT in hepatocytes.¹¹¹ On the other side, EGF was shown to induce EMT in EGFR-expressing cancer cells via STAT3-mediated induction of Twist gene expression. Accordingly, STAT3 was shown to directly bind to and transactivate Twist promoter.^{112 , 113}

STAT3 and Cell Migration

Many indications suggest a role for STAT3 in regulating cell movement, mainly by contributing to cytoskeleton reorganization and controlling cell adhesion properties. The first demonstration of a central role played by STAT3 in cell migration was the observation that STAT3 conditional disruption in keratinocytes resulted in impaired wound healing due to compromised migration, both in vivo and in vitro, in response to cytokines and growth factors such as EGF, TGF-α, HGF and IL-6.¹¹⁴ STAT3 was also shown to contribute to disrupt epithelial adhesion and polarity downstream of ErbB2-Integrin β4 signaling, leading to promotion of mammary tumorigenesis.¹¹⁵ Moreover, the introduction of STAT3C in prostate epithelial cells enhances cell migration and tumor formation by inducing the expression of Integrin β6 and its ligands.²² The target genes involved in the above-described functions have not yet been identified.

STAT3-mediated regulation of cell motility might depend not only on its canonical transcriptional activity but also on recently proposed nonnuclear functions. For example, DJ. Montell and co-authors showed a correlation between STAT3 activity, cell motility and aggressiveness of ovarian carcinoma cells. Interestingly, in these cells phosphorylated STAT3 localized to focal adhesions where it directly interacted with active focal adhesion kinase and paxillin, thus potentially playing a role in their signaling.¹¹⁶ Moreover, the group of X. Cao recently showed that nonphosphorylated STAT3 in the cytoplasm interacts with the microtubule-destabilizing protein stathmin, inhibiting its microtubule depolymerizing function and resulting in enhanced microtubules polymerization and cell migration.¹¹⁷

STAT3 Immune-Mediated Effects on Tumors

STAT3 has also been recently shown to enable tumors to evade immune system control. STAT3 activity in antigen presenting cells (APC), including dendritic cells (DC) and macrophages, was shown to inhibit their maturation, thus impairing DC-mediated induction of T-cell responses.¹¹⁸ Y. Nefedova and co-authors suggested that STAT3 activity impaired APC differentiation by maintaining cells in a proliferative stage.¹¹⁹ Interestingly, inhibition of APC maturation can be indirectly triggered by the frequently detected constitutive activity of STAT3 in the tumor cells themselves, which in turn induces the production of soluble anergyzing factors such as VEGF and IL-10, while at the same time downregulating the secretion of pro-infammatory mediators.¹²⁰ In a xenograft melanoma system, even incomplete STAT3 blockade increased the production of chemoattractants inducing the migration of lymphocytes, NK cells, neutrophils and macrophages, resulting in macrophage-mediated cytostatic activity against tumor cells.¹²¹ STAT3 could also contribute to the oncogenic activity of the PAX3-Forkhead fusion protein in rhabdomyosarcoma cells by inhibiting local inflammatory and immune responses.¹²² Accordingly, inhibition of STAT3 in macrophages could induce an anti-tumor immune response in a rat model of breast cancer¹²³ and in vivo deletion of STAT3 in hematopoietic precursor cells resulted in enhanced anti-tumor activity triggered by DC, T-cell, NK cells and neutrophils, correlating with a reduction of regulatory T-cells.¹²⁴

Alterations in Control Mechanisms of STAT1 and STAT3 Activation

Despite the wide range of tumors where STAT3 is constitutively active, no activating genetic mutations have so far been described in tumors, suggesting that abnormal STAT3 activity in neoplastic cells must be triggered by unbalanced upstream activating events or defective negative feedback regulation.

As already mentioned, many oncogenes and growth factor receptors known to be abnormally activated/amplified in tumors can lead to STAT3 phosphorylation (among others, EGFR, ErbB2, PDGFR, HGFR, v-Src, Ros, v-Eyk, v-Abl, Lck, TEL-JAK, Middle T antigen). In addition, unbalanced/uncontrolled production of STAT activating cytokines and growth factors can often occur in the tumor microenvironment, triggering prolonged, abnormal STAT activation.¹⁵⁰

Other components known to be involved in aberrant STAT activation in tumors are members of the JAK family of cytokine receptor-associated protein kinases. The most frequently involved is JAK2, which participates in the signaling of many cytokines and growth factors. Several JAK2-activating mutations have been described in a number of myeloproliferative neoplasms (MPNs). The best characterized is the JAK2V617F mutation, occurring in a high percentage of patients affected by polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF),^{151 , 154} as well as in acute and chronic myeloid malignancies.^{155 , 156} This mutation results in increased kinase activity and hyper-responsiveness to cytokines¹⁵¹ and mainly affects STAT5 signaling. However, enhanced STAT3 activation appears to be specifically involved in JAK2V617F-positive myelofibrosis with myeloid metaplasia and ET^{157 , 158} A number of different JAK2 and also JAK3 gain of function mutations have been described in rare cases of myeloproliferative diseases (recently reviewed in 159). Three different fusion proteins generated by chromosomal translocation and involving JAK2 are known (TEL-JAK2, BCR-JAK2 and PCM1-JAK2). These are relatively rare and give rise to different tumors, all characterized by constitutive kinase activity.¹⁶⁰ Finally, rare JAK1 mutations have been described in T-cell acute lymphoblastic leukemia patients¹⁶¹ and in uterine leiomyosarcoma.¹⁶²

Another event that can determine STATs constitutive phosphorylation is defective activity of their negative regulators, in particular the suppressors of cytokine signaling (SOCS) family of proteins. These are cytokine target genes that in turn down-regulate the same cytokine-activated JAK-STAT signaling pathway, acting as an essential physiological self-limiting mechanism for cytokine responses.¹⁶³ In particular, SOCS1 is strongly involved in the IFNγ signaling and can associate with all known JAKs directly inhibiting their catalytic activity. SOCS3 in contrast cannot directly interact with JAK kinases but needs to be recruited to phosphotyrosine residues of activated receptors, in particular gp130, leptin, growth hormone and erythropoietin receptors. In addition to specific inhibition of JAKs kinase activity, all SOCS members are thought to act as E3 ubiquitin ligases and to mediate proteasomal degradation of associated proteins.

Growing evidence suggests a tumor suppressor role for SOCS1 in both hematological and solid neoplasms. SOCS1^-/- fibroblasts display increased susceptibility to either spontaneous or oncogene-induced transformation.¹⁶⁴ Moreover, ectopic SOCS1 expression blocks in vitro proliferation of Ba/F3 cells transformed by different hematopoietic-specific oncogenes and partially hampers metastasis formation by BCR-ABL transformed cells.¹⁶⁴ Accordingly, SOCS1 activity is frequently defective in hematological tumors, either by posttranslational modifications (for example, v-Abl-induced SOCS1 phosphorylation alters its function^{165 , 166}) or, more frequently, by direct silencing of the SOCS1 locus due to hypermethylation.^166-169 Particularly sensitive to SOCS1 silencing are tumors where cytokine activation and JAK/STAT signaling play a pathogenic role. This is the case of multiple myeloma, where SOCS1 silencing favors IL-6 signaling thus promoting STAT3-dependent survival and proliferation.¹⁶⁷ SOCS1 silencing has also been reported in acute myeloid leukemia (AML) and in a small percentage of BCR-ABL negative myeloproliferative disorders (MPD).^{168 , 170} SOCS1 activity can be impaired in tumors also by genetic mutations, as in the case of MedB-1 mediastinal lymphoma cells and of Hodgkin lymphomas, where it apparently mainly interferes with the activation of STAT5.¹⁷¹

SOCS1 silencing may play a role also in the onset and growth of solid tumors, as suggested by the observation that SOCS1^+/- mice are more susceptible to carcinogen-mediated hepatocellular carcinoma development.¹⁷² Indeed, hypermethylation and silencing have also been detected in cell lines from hepatocellular,¹⁷³ ovarian, pancreatic and breast carcinoma,^{174 , 175} Barrett's adenocarcinoma,¹⁷⁶ head and neck squamous cell carcinoma (HSCC),¹⁷⁷ glioblastoma multiforme¹⁷⁸ and human gastric carcinoma,¹⁷⁹ often correlating with altered STAT3 and/or STAT1 activity.

Many reports suggest that also silencing of SOCS3, which is the main negative-feedback regulator of STAT3 signaling, may be a common mechanism to constitutively activate STAT3 in tumors. Indeed, SOCS3 promoter is frequently hypermethylated in malignant melanomas, Barrett's adenocarcinomas, head and neck squamous cell carcinomas, hepatocellular and lung carcinomas.^{176 , 180 - 183} In many of these systems, SOCS3 silencing correlates with increased STAT3 activity and restoring its expression triggers a reduction of STAT3 phosphorylation correlating with apoptosis and growth suppression.^{181 , 183} In agreement with this idea, mice where SOCS3 is conditionally inactivated in the liver display increased susceptibility to chemically-induced hepatocarcinogenesis correlating with enhanced STAT3 phosphorylation¹⁸⁴ and increased expression of STAT3 target genes Bcl-XL, Bcl-2, c-Myc, cyclin D1 and VEGF.¹⁸⁵

Probably as a consequence of STAT3 constitutive activity, SOCS3 expression can also be enhanced in tumors, where it could act by regulating STAT1 activity. For example,SOCS3 was shown to determine resistance to IFNα-induced apoptosis by inhibiting STAT1 signaling in chronic myelogenous leukemia cells and in cutaneous T-cell lymphoma.

STAT1:STAT3 Cross-Regulation

As detailed above, STAT1 and STAT3 often play opposing roles in proliferation, apoptotic death, inflammatory and anti-tumor immune responses. In addition, studies on STAT-deficient cells have revealed the existence of reciprocal STAT1:STAT3 regulatory mechanisms.^{188 - 191} For example, in STAT3-deficient murine embryonic fibroblasts (MEFs) IL-6 triggers prolonged activation of STAT1 correlating with an IFNγ-like response, including up-regulation of multiple IFNγ-inducible genes, expression of Class II MHC antigens and induction of an anti-viral state. Accordingly, increased and prolonged phosphorylation of STAT1 in response to gp130 cytokines occurs in several systems upon STAT3 gene inactivation.^{192 - 194} These data suggest that in normal cells one of the functions of STAT3 in response to IL-6 is to down-regulate STAT1 activity, thus preventing IFNγ-like responses and allowing IL-6-specific signaling. To what extent this may be true also in tumor cells has not yet been investigated. Similarly, studies on STAT1-deficient bone-marrow-derived macrophages or MEFs indicate that in the absence of STAT1 IFNγ loses its pro-apoptotic activity and can even induce proliferative responses correlating with predominant activation of STAT3 and STAT3-mediated transcription.^{190 , 195 , 196} In addition, IFNα treatment can enhance rather than inhibit cell proliferation and survival in STAT1^-/- T-lymphocytes,^{189 , 191} although contrasting data attribute this effect either to skewed STAT3 activation¹⁸⁹ or to the action of other, non STAT-mediated, pathways.¹⁹¹ These observations suggest that the relative abundance of STAT3 or STAT1 may play a role in determining their relative activation levels and biological effects in response to activating stimuli. In turn, this may be relevant for the development and growth of tumors in the presence of specific tumor microenvironments, where different cytokine/ growth factor combinations can modulate the relative levels of STAT1 and STAT3, resulting in their differential activation. Indeed, the intensity and duration of inflammatory responses is known to influence the development of a favorable microenvironment for neoplastic transformation and growth.^{197 , 198} STAT1 activation, mainly mediated by IFNs, acts as a pro-infammatory factor both indirectly, by triggering cell apoptosis¹⁹⁶ and directly, by inducing pro-inflammatory genes and promoting antigen presentation. In contrast, STAT3 is the main mediator of the functions of IL-10, a major anti-inflammatory cytokine. Of note, IL-10 can directly inhibit IFN-induced gene transcription at least partly by down-regulating STAT1 activation.¹⁹⁹ The already reported ability of STAT3 to promote the escape of tumors from cell-mediated immunity correlates with STAT3-dependent induction of anti-inflammatory mediators such as IL-10 or VEGF, acting as DC inhibitors. At the same time, the production of pro-inflammatory, DC-activating, mediators is down-regulated.¹²⁰ This observation could explain the acquired ability of many tumors to secrete IL-10.²⁰⁰ Interestingly, many of the inflammatory mediators produced by cancer cells upon STAT3 inactivation are typical STAT1 targets (e.g., CXCL10, CCL5, ICAM1), suggesting that reciprocal regulation between STAT3 and STAT1 may take place also in tumor cells and that STAT1:STAT3 unbalanced expression/activation and cross-regulation could play a role in tumor biology.

It is thus tempting to speculate that interfering with the activation of either factor in tumors may result in activation or re-activation of the other, which in turn would mediate some of the observed effects through the induction of specific target genes. Very little data is available on this subject. Grandis and coworkers showed that the therapeutic mechanism of STAT3 blockade by means of an oligonucleotide decoy is independent of STAT1 activation in cell lines derived from squamous cell carcinomas of the head and neck.²⁰¹ In contrast, we have observed that STAT3 blockade by RNA interference in human T-cell lymphoma cell lines enables IL-6 to reinstate STAT1 activation, normally defective, and to induce apoptosis (Regis et al, manuscript in preparation).

Until more studies are available to establish if re-activation of either STAT in response to interference with the other one is a general mechanism and to which extent this may contribute to the observed biological outcome, care should be taken to plan therapeutic intervention using compounds that could unbalance finely tuned equilibria between STAT1 and STAT3 mediated actions. At the same time, the possibility to activate a specific STAT pathway by interfering with the other may under specific conditions provide unique therapeutic opportunities. For example, normal resting and neoplastic T-lymphocytes can become resistant to IFNγ antiproliferative effects or even proliferate in response to it, often due to down-regulation of the IFNγR chains and consequent failure to activate STAT1.²⁰² Insensitivity to IFNγ, correlating with defective STAT1 activation, has also been observed in lymphoid and non-lymphoid tumor cell lines which constitutively express high levels of both receptor chains.^{24 , 203 - 206} These observations suggest the involvement of mechanisms acting both upstream and downstream from the interaction between IFNγ and its receptor.

Therefore, the balance between activated STAT1 and STAT3 may play a role in the phenomenon of IFNγ resistance downstream of the IFNγ/IFNγR interaction. In addition, the specific responses to gp130 cytokines and/or to IFNs could be redirected by manipulating STAT1:STAT3 balance, even in the presence of defective IFNγR signaling. Indeed, we have recently observed that interference with STAT3 activity in IFNγ-resistant human T-lymphoma cells enhances pro-apoptotic responses to IFNγ and makes cells sensitive to IL-6, which under these conditions triggers prolonged activation of STAT1, apoptosis and impaired in vivo growth (Regis et al, manuscript in preparation). This strategy might be as well suitable in other conditions characterized by impaired STAT1 activation.

Acknowledgements

We wish to thank Drs. F. Bazzoni for discussions inspiring this work and I. Barbieri for sharing his unpublished results. Work in the author’s laboratories was supported by the Italian Ministry of Research (MIUR PRIN) and by the Italian Association for Cancer Research (AIRC). G. Regis was the recipient of a “Young Researchers Contract” supported by FIRB (Fondo per gli Investimenti della Ricerca di Base).

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