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ANTICANCER RESEARCH 32: 3609-3618 (2012)

Review From to Cancer: Lessons from the Kidney to Uncover New Therapeutic Targets

VALÉRIAN DORMOY1, DIDIER JACQMIN2, HERVÉ LANG2 and THIERRY MASSFELDER1

1INSERM U682, Section of Renal Cancer and Renal Physiopathology, School of Medicine, University of Strasbourg, Strasbourg, France; 2Department of Urology, New Hospital of Strasbourg, Strasbourg, France

Abstract. Several genes play essential roles in human cell carcinoma (CCC) and are thought to originate from the development and alteration of their expression or regulation renal proximal tubule. RCC is resistant to radio-, hormono-, leads to various pathologies. This review examines the and chemotherapy, and immunotherapy is effective in only literature on the expression and the roles of neurogenic locus 15% of selected patients (1-3). notch homolog protein (NOTCH), sonic Hedgehog (SHH) The best known oncogenic signal in human CCC is and wingless-type (WNT) pathways, as well as the constituted by the von Hippel-Lindau (VHL) tumor suppressor nephrogenic transcription factors Wilms’ tumor 1 (WT1), gene and hypoxia-inducible factors (HIFs). Inherited and paired box 2 (PAX2) and protein lim-1 (LIM1) in sporadic forms of CCC are associated with inactivation of the clear cell renal cell carcinoma. Besides being re-expressed VHL gene (4). In hypoxic conditions or with VHL gene defects, in human tumors, the inhibition of these factors has strong as is the case in 60% of CCCs, HIF-α is stabilized, allowing for antitumor activity both in vitro and in vivo. Interestingly, the expression of a large panel of target genes involved in these pathways are also part of the molecular network growth, motility, metabolism and , such as vascular involved in the development of organs including (VEGF), tumor growth factors nephrogenesis. The identification of developmental pathways (TGFs), parathyroid -related protein (PTHrP), and involved in clear cell renal cell carcinoma growth places an glucose transporters, all shown to contribute to CCC (5, 6). additional piece into the molecular puzzle of cancer Recent advances in our understanding of the HIF mechanisms. Moreover, the evaluation of these molecules molecular network have led to several novel targeted could pave the way to innovative and safe therapies for this therapies. Drugs that modulate the downstream targets of the refractory disease. Valuable prognostic markers might also HIF pathway, including sunitinib, sorafenib, temsirolimus, be identified through these studies. Finally, the proof of everolimus, axitinib and bevacizumab, have proven beneficial concept in other types of cancer is reviewed. in treating CCC. However, drug-induced resistance observed after a few months of treatment with these compounds and Renal cell carcinoma (RCC) is the most lethal urological the lack of validated biomarkers restricts our ability to tailor tumor and the sixth leading cause of cancer deaths in specific drugs to patients and this might be considered as the Western countries. Each year, approximately 270,000 most important barrier to a better clinical response (4, 7, 8). patients are diagnosed with this malignancy, resulting in an Thus, treating RCC represents a challenge that pushes the estimated of 110,000 deaths, and its incidence is steadily scientific community to be more effective in discovering new increasing (1-3). Eighty percent of RCCs are clear cell renal therapeutic targets against this refractory disease.

A Novel Perspective to Explore

Correspondence to: Valérian Dormoy, Ph.D., School of Medicine, There are three questions that remain in the field of biological 11 rue Humann, 67085 Strasbourg, France. Tel: +33 368853456, and medical sciences: (i) How is it possible that one cell or the Fax: +33 368853459, e-mail: [email protected] recruitment of a few of them may lead to the development of a Key Words: Renal cell carcinoma, kidney, developmental markers, functional organ? (ii) How is it possible that one cell or few signaling pathways, VHL tumor suppressor, therapeutic targets, cells starting to act differently may lead to the development of review. pathologies? The third question arises directly from the first

0250-7005/2012 $2.00+.40 3609 ANTICANCER RESEARCH 32: 3609-3618 (2012) two: (iii) What are the molecular and cellular mechanisms family (20). LIM1 is expressed throughout involved in these profound modifications? Recent findings in the urinary tract during development (16). Although most oncology point to a new perspective for exploration, by Lim1–/– mice embryos died at the embryonic stage E10 combining the first two questions with the third: Are the because of a disability in the forming placenta, the few developmental pathways involved in the genesis and the growth surviving newborns had no kidney (21). of an organ responsible for the development and the growth of An important actor of nephrogenesis for the regulation of a tumor, as might be the case for human CCC? mesenchymal-to-epithelial transition and the development and As the formation of the kidney is very well-documented maturation of podocytes is the zinc finger protein WT1, also in literature, it is not surprising that this organ serves as an identified as a tumor suppressor protein. While the protein is example to uncover the links between organogenesis and barely detectable in newborns, the pattern of expression pathologies from a mechanistic point of view. Additional during the early steps of the development of the organs and oncogenic events are required for CCC formation, and this its interactions with the WNT proteins and PAX2 suggests a concept has been clearly proven recently by molecular and crucial role for this protein during kidney development. In genetic approaches (9-11). The emerging idea is that tumors accordance with this statement, it is important to notice that hijack signaling pathways involved in normal development Wt1-null mutant mice fail to develop kidneys (22, 23). for their own growth. Two categories of actors have been It has been proven that WNT proteins are involved in the revealed so far: the first includes transcription factors and the induction of the kidney mesenchyme. Patterning along the second is represented by complex signaling pathways. proximal-distal axis, as the nephron develops, mostly Regarding the kidney, this is at least the case for paired box involves NOTCH signaling along with additional markers 2 (PAX2), homeobox protein lim-1 (LIM1) and Wilms’ (24). This is particularly interesting since CCC develops tumor 1 (WT1) transcription factors, and the Sonic from proximal tubular epithelial cells, as mentioned above. Hedgehog (SHH), neurogenic locus notch homolog protein Interestingly, LIM1 transcription factor controls the activity (NOTCH) and wingless-type (WNT) signaling pathways. of the NOTCH signaling pathway during tubule patterning. Keeping in mind that it is not only the presence but also the In addition to the NOTCH signaling pathway, which is level of expression/activation of the proteins that allow them critical for cell–cell communication and the regulation of a to regulate mechanisms, here we aim to review their role in broad spectrum of cell fate specifications (25), the involvement kidney tumorigenesis in the light of their involvement in of the phosphoinositide-3-kinase (PI3K)/ alpha normal developmental processes (Figure 1 and Table I). (AKT), nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB), mitogen-activated protein kinase (MAPK), Developmental Pathways and bone morphogenetic proteins (BMPs) and Jun kinase pathways Markers during Nephrogenesis in the different steps of kidney development has been well- documented (26-28). The SHH-glioma-associated The study of the development of the mammalian kidney has homolog (GLI) signaling pathway, discovered in 1993, carries- helped elucidate the general concepts of mesenchymal- out essential roles in cell differentiation and proliferation epithelial interactions, epithelial cell polarization and during embryogenesis (29). The SHH-GLI pathway mainly branching (12-15). The early molecular controls the expression of three classes of genes in normal events occurring in the developing kidney are becoming kidney development: the genes responsible for the spatial increasingly clear through the use of genetically engineered organization and the PAX2 and sal-like protein 1 mouse models, experimentations on frog and chick embryos, (SALL1); the modulators of the cell cycle (cyclin D1 and as well as through the identification of human genes N-); and the effectors of the SHH pathway itself: GLI1 responsible for renal disease. and GLI2. It is noteworthy that the SHH-GLI pathway plays Early patterning of the kidney region depends on interactions an orchestral role in the activation of several signaling between PAX/eye absent homolog (EYA)/sine oculis pathways (29) mentioned above. homeobox homolog (SIX) transcription factors, with essential With the advance of various expression arrays, roles for LIM1 and odd-skipped related 1 (ODD1) transcription nephrogenesis is becoming one of the best characterized factors (15-18). The proto-oncogene c-Ret (RET)/ glial-derived organ systems in , despite the kidney’s neurotrophic factor (GDNF) (/) pathway, which architectural complexity. is subject to ‘on and off’ regulations by a broad range of developmental factors and signaling pathways, controls bud PAX2 and the Proof of Concept outgrowth and branching morphogenesis (15, 19). One of the most important factors during nephrogenesis is LIM1 (also Human CCC remains a challenge for clinicians and scientists known as LHX1). This gene was described for the first time in working in this field. Indeed, as presented above, CCC is not . It belongs to the class LIM-hd in the homeobox gene only characterized by a high intrinsic resistance but also by

3610 Dormoy et al: New Targets in Renal Cell Carcinoma (Review)

Figure 1. From development to cancer, actors involved in nephrogenesis and cancerogenesis. The known level of expression of the indicated actors is depicted during the main steps of kidney development, in adult functional kidney, in renal cell carcinoma and in metastasis. Blank, no expression; shaded tones, from the lowest expression to the highest expression described in the literature. PAX2: Paired box 2; WT1: Wilms’ tumor 1; LIM1: homeobox protein lim-1; NOTCH: neurogenic locus notch homolog protein; GLI: glioma-associated oncogene homolog; WNT: wingless-type.

Figure 2. Similar actors under different regulations determine cell fate. PAX2: Paired box 2; WT1: Wilms’ tumor 1; LIM1: homeobox protein lim-1; NOTCH: neurogenic locus notch homolog protein; SHH: sonic hedgehog; GLI: glioma-associated oncogene homolog; WNT: wingless-type.

therapy-induced resistance; the mechanisms accounting for lead to innovative and efficient therapies for human CCC, such characteristics have not received much attention yet, either alone or in combination. and remain largely unknown. The developmental signaling Following the findings that PAX2 is re-expressed in nearly pathways/markers described above may constitute the keys 80% of CCCs (30, 31), the best example of such a concept to uncovering the mechanisms of tumor resistance, and thus has been described by Hueber and colleagues (32). Indeed, in

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Table I. Regulatory molecules involved in nephrogenesis and in RCC and their cellular effects during the processes.

Regulatory molecule Roles in kidney development Roles in carcinogenesis References

PAX2 Epithelial differentiation of the metanephric Involvement in RCC resistance Reidy and Rosenblum (15) mesenchyme; cell proliferation; cell adhesion to chemotherapy Hueber et al. (32) Hueber et al. (36) WT1 Epithelial differentiation of the metanephric Promotes cell survival and Kreidberg et al. (51) mesenchyme; ureteric bud ingrowth in the cell proliferation Md Zin et al. (23) metanephric blastema; repressor of myogenic Kawakami et al. (44) cell fates; podocyte and epithelial differentiation Sitaram et al. (50) LIM1 Growth of the ureteric bud; formation of the Promotes cell proliferation; Reidy and Rosenblum (15) collecting system inhibits cell ; stimulates cell Kobayashi et al. (16) migration/invasion Varis et al. (58) Dormoy et al. (59) SHH/Gli Spatial organisation and segmentation; Promotes cell proliferation Gill and Rosenblum (29) modulation of the cell cycle; control on the and cell survival Katoh et al. (55) GLI effectors themselves Stanton and Peng (56) Dormoy et al. (57) NOTCH Cell-cell communication; regulation of apoptosis; Defect of control in cell fate in Pulkkinen et al. (24) regulation of proliferation; regulation of migration the absence of Notch signaling McCright et al. (25) Sun et al. (52) Aparicio et al. (53) WNT Cell proliferation; epithelial conversion of Promotes tumor growth and metastasis Pulkkinen et al. (24) mesenchymal cells; inducer of tubulogenesis Kawakami et al. (44) in the mesenchyme; epithelial differentiation Banumathy and Cairns (45) of the renal mesenchyme

PAX2: Paired box 2; WT1: Wilms’ tumor 1; LIM1: homeobox protein lim-1; NOTCH: neurogenic locus notch homolog protein; SHH: sonic hedgehog; GLI: glioma-associated oncogene homolog; WNT: wingless-type.

this study, PAX2 was shown to confer resistance to cisplatin- very useful histological marker to differentiate between induced apoptosis in non-transformed kidney cells and fetal various forms or stages of renal cancer (37-43). kidney explants, and its overexpression in CCC cells also contributed to cisplatin resistance. Thus, from a therapeutic CCC: From Kidney Development to Cancer point of view, a strategy of inactivating PAX2 expression/activity might enhance the efficacy of cytotoxic While the example of PAX2 may seem isolated at first drugs against CCC. To explain the antitumor activity induced glance, there is numerous compelling evidence showing that by the targeting of PAX2, several targets have been unveiled, proteins involved in developmental processes are re- such as metalloproteases (disintegrin and metalloproteinase expressed or deregulated after development, thus explaining domain-containing protein 10 (ADAM10), phosphatase and at least partially, the physiopathology of a particular organ. tensin homolog (PTEN) and the PI3K-AKT pathway (33, 34). Thus, an overview of literature concerning the WNT It should be stressed-out that the regulation of PAX2 pathways reveals their implication in development (including expression in CCC is at least under the control of the kidney) and their role in tumor growth and metastasis (24, VHL/HIF system and hypoxia, although no induction was 44, 45). In brief, WNT antagonists induce apoptosis and obtained despite the presence of six hypoxia response element inhibit proliferation in RCC (46-48). (HRE) motifs in the promoter of PAX2 (35, 36). In addition, It has been known for a long time that WT1 is re- the PAX2 repressor WT1 and hypo/hypermethylation were expressed in CCC (49), but only recently has it been shown not important for transcriptional regulation of PAX2. that WT1, through its multiple targets, may act as an Nevertheless, this latter study suggested that VHL loss and oncogene in human CCC (50, 51). In particular, WT1 hypoxia might be part of the cellular machinery leading to the modifies telomerase activity to induce resistance of cancer re-expression/reactivation of developmental markers and cells to avoid programmed cell death. clearly of developmental signaling pathways through effects, Among the four NOTCH receptors responsible for NOTCH for example, on growth factor receptors. In addition, further signaling, it has been shown very recently that CCC is investigations on PAX2 concluded that this actor of the characterized by a significant decrease of and kidney development described recently as an oncogene, is a receptor expression (52). This is important because

3612 Dormoy et al: New Targets in Renal Cell Carcinoma (Review) the proteins responsible for the loss of their expression might Targeting the Developemental Pathways constitute a target to treat CCC. Of note, their evaluation as to Trigger Anticancer Mechanisms pathological markers is currently under investigation (53). It should be stressed-out that in another study, NOTCH 1 and We demonstrated that players in the various steps of kidney the NOTCH ligand Jagged-1 were shown to be expressed at development may later be re-expressed or de-regulated and significantly higher levels in CCC than in normal human renal contribute to cancerogenesis. In addition, these proteins may tissue, and that the growth of primary CCC cells was reduced constitute an extremely useful strategy to target cancer cells upon inhibition of NOTCH signaling, both in vitro and in vivo efficiently and may define precious markers for the diagnosis in a xenografted nude mouse model (54). Although no clear of or staging of kidney cancer. Is it possible to use the same explanation yet accounts for such an apparent discrepancy, it analysis for other types of cancer? could be due to the difference in the experimental approach To emphasize that our discussion not only concerns the used to measure NOTCH and NOTCH ligand expressions, i.e. renal system, we started with the example of PAX2 and it immunohistochemistry vs. western blotting. should be stressed-out that PAX2 and the Paired-box genes In cancer, it has been shown that the blockade of the SHH- have been described as essential actors of cancer initiation GLI signaling pathway induces death of cancer cells. In and progression (61). PAX2 is overexpressed in prostatic addition, recent evidence suggests that an SHH paracrine cancer (62) and its inhibition triggers cell death of prostatic mechanism, mediating tumor mesenchymal interactions, may cancer cells (63, 64). In breast cancer, PAX2 confers a low contribute to the metastatic capacity of cancer cells. invasive after estradiol activation (65) and Complete regression of tumor growth in xenografted nude modulates fate switching through progesterone modulation mice treated with inhibitors of the SHH pathway has been (66). It has been described that PAX2 regulates ADAM10 reported (55). Targeting the SHH-GLI pathway has shown and its silencing reduced the migratory and invasive promising results in vivo for gastric, pancreatic, prostatic, capacity of melanoma cells (67). In addition, the down- breast cancer, and (56). Recently, our regulation of PAX2 abrogated chemoresistance of laboratory demonstrated that this pathway is specifically re- melanoma cells to cisplatin, indicating its role in survival expressed in human CCC and that its targeting might be and melanoma progression. Finally, PAX2 expression particularly efficient against this disease, not only through allows for distinction between various grades of ovarian inhibition of tumor growth but also by impeding tumor carcinomas (68, 69). vascularization (57). As demonstrated during development, Even if LIM1 has not been well-studied, it has been these studies also revealed that the SHH-GLI signaling recently shown that this transcription factor is re-activated in pathway interacts with various oncogenic, but also with nephroblastomas and an overview of the literature indicates developmental pathways including the PI3K/AKT, NF-κB, that LIM domain kinases play a critical role in tumor cell and MAPK pathways, and the developmental NOTCH invasion (60, 70). pathway. Interestingly, these pathways have been shown to Overexpression of WT1 is characterized in leukemia and be critical for development of human CCC. solid tumors, and several studies showed its role in cell In addition, we identified various SHH-GLI targets, some growth and differentiation (71, 72). In addition, WT1 is used never previously described, such as the Smoothened receptor as a marker in acute and chronic leukemia, as well as for and the transcription factor LIM1, an important player in minimal residual disease detection and quantification in kidney development, as reported above (57). It has been myeloid leukemia and myelodysplastic syndrome (71, 73, reported that LIM1 is overexpressed in gastric cancer (58), 74). Recently, WT1 immunotherapy has made progress and and aberrant methylation of this gene is implicated in clinical trials of WT1 peptide vaccination for cancer patients tumorigenesis, growth of pancreatic cancer, and in chronic were started (72, 75, 76). leukemia (59). Very recently, our group demonstrated that the Considering the NOTCH receptors, the WNT pathway and LIM1 transcription factor acts as an oncogene in CCC and the SHH-GLI pathway, describing only few types of cancer that it reproduces the main effects observed with the SHH- where their implications have been shown would be GLI pathway, including the regulation of various oncogenic extremely restrictive, as their role in the progression, survival pathways and receptors. In addition, LIM1 or the metastasis of nearly every kind of cancer has been blockade induces substantial inhibition of cell movement, at characterized. For an overview of the literature, we propose the basis of metastatic invasion (59). Finally, it has been a selection of articles in the references (77-90). shown that deficiency in LIM1 contributes to the While the number of clinical trials involving the proteins pathogenesis of nephroblastoma (60). Altogether, these data implicated in normal renal development described in this suggest that LIM1 regulation may represent a new target for review is still limited, we may expect to see an augmentation refractory diseases of the kidney, such as CCC and in the near future, as the studies describing their relation with nephroblastoma. cancer are constantly increasing.

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Conclusion Acknowledgements

The data presented in this review suggest crucial roles for This study was sponsored by the Institut National de la Santé Et de developmental markers and signaling pathways, not only in la Recherche Médicale and the University of Strasbourg (recipient kidney tumorigenesis but also in intrinsic and therapy-induced Thierry Massfelder). We thank Dr. A. Donai for helpful suggestions and R.A. Hanna for text correction. CCC resistance. Focusing on the kidney, this review shows that similar molecular actors may orchestrate both the development of an organ and its pathological transformation References (Figure 2). Thus, understanding in detail the development and the physiology of an organ may lead to a better understanding 1 McDermott DF: Immunotherapy of metastatic renal cell carcinoma. 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82 Takebe N, Harris PJ, Warren RQ and Ivy SP. Targeting cancer 88 Gould A and Missailidis S: Targeting the hedgehog pathway: the stem cells by inhibiting Wnt, Notch, and Hedgehog pathways. development of cyclopamine and the development of anticancer Nat Rev Clin Oncol 8: 97-106, 2010. drugs targeting the hedgehog pathway. Mini Rev Med Chem 11: 83 Curtin JC and Lorenzi MV: Drug discovery approaches to target 200-213, 2011. WNT signaling in cancer stem cells. Oncotarget 1: 563-577, 89 Barakat MT, Humke EW and Scott MP: Learning from Jekyll to 2011. control Hyde: Hedgehog signaling in development and cancer. 84 de Sousa EM, Vermeulen L, Richel D and Medema JP: Targeting Trends Mol Med 16: 337-348, 2010. WNT signaling in colon cancer stem cells. Clin Cancer Res 17: 90 Nehme R and Mus-Veteau I: Proteins of the hedgehog signaling 647-653, 2010. pathway as therapeutic targets against cancer. Expert Rev 85 Lucero OM, Dawson DW, Moon RT and Chien AJ: A re- Proteomics 7: 601-612, 2010. evaluation of the ‘oncogenic’ nature of WNT/beta-catenin signaling in melanoma and other cancers. Curr Oncol Rep 12: 314-318, 2010. 86 Marini KD, Payne BJ, Watkins DN and Martelotto LG: Mechanisms of hedgehog signalling in cancer. Growth Factors 29: 221-234, 2011. 87 Onishi H and Katano M: Hedgehog signaling pathway as a Received April 23, 2012 therapeutic target in various types of cancer. Cancer Sci 102: Revised July 16, 2012 1756-1760, 2011. Accepted July 17, 2012

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