Mini-reviewThe Wnt signaling pathway in solid childhood tumors
Introduction
Childhood cancer in many aspects is distinct from cancer in adults. Malignant tumors in children are rare and they typically arise from germinal tissues, as opposed to the epithelial origin of most cancers in adults. Childhood tumors have a relatively fast growth rate and upon diagnosis they frequently present as large tumor masses and with considerable potential for metastatic spread. Local therapy alone is rarely successful and nearly all children with tumors require systemic therapy to be cured. Fortunately enough, pediatric tumors display a high sensitivity to chemotherapy and radiation.
Important information about the molecular pathogenesis of childhood cancer has been derived from the study of normal embryonic development. The similarities between the growth and differentiation of cells and tissues and the dysregulation of these events in oncogenesis are evident at multiple phenotypic levels. Massive cell proliferation, migration into neighboring compartments, and cellular differentiation are features common to both normal embryonic and cancer development. At the molecular level, this relationship has become substantial with the discovery that many proto-oncogenes encode components of signal transduction pathways, which direct normal development. One such pathway, the Wnt signaling (WS) pathway, plays a well-established role during normal embryonic development. More recently, the Wnt-signal transduction pathway has been implicated in the development of different solid childhood tumors, among them hepatoblastomas (HBs), nephroblastomas (NBs), medulloblastomas (MBs), and pancreatoblastomas (PBs).
It is the aim of this review to summarize these findings and to discuss their potential implications for the current view on how these tumors arise. To achieve this, we will first describe the functionality of the Wnt signaling pathway. Thereafter, the four solid childhood tumors, hepatoblastoma, nephroblastoma, medulloblastoma, and pancreatoblastoma, with known genetic lesions in genes encoding Wnt signaling members, will be compared concerning their molecular genetics, their respective embryonic stem cell of origin and their particular histopathological appearance.
Section snippets
The Wnt-signal transduction pathway
Wnt signaling is involved in different developmental processes such as cellular proliferation, differentiation, and epithelial–mesenchymal interactions and it does so in a wide range of tissues. At the very earliest stages of embryogenesis it is a Wnt-signal that controls formation of the main body axis [1], later on, WS is required for development of many organs, including the brain [1], [2] kidney [3], [4], mammary gland [5], [6], [7], [8], reproductive tract [9], [10], vasculature [11],
Background
Hepatoblastoma is a rare malignant tumor of the liver with a world-wide incidence of 1.5 cases per million children. It accounts for 60–80% of all hepatic tumors in children and therefore it represents the most common type of pediatric liver tumor.
HBs originate from bipotential liver precursor cells, hepatoblasts, that are induced to form through specific molecular interactions between the cardiac mesenchyme and gut endoderm during early liver development [41]. The hepatoblasts proliferate and
Background
Wilms tumor, or nephroblastoma, is the most common pediatric cancer of the kidney, affecting 1 in 10,000 children. Most cases occur before the age of 5 yrs; the incidence of bilateral involvement is about 5–10% [79].
Wilms tumors are thought to arise from metanephric blastemal cells that during normal kidney development are induced by the outgrowing ureteric bud to proliferate and differentiate into renal tubular epithelial cells and glomeruli, the functional components of the mature nephron [80]
Background
Medulloblastoma is a malignant embryonal tumor of the cerebellum and the most common malignant brain tumor in children. The peak incidence is between 5 and 10 yrs of age with boys being slightly more frequently affected than girls [108]. MB belongs to the group of primitive neuroectodermal tumors (PNET).
Medulloblastomas are most likely derived from pluripotential neuronal stem cells present in the external granular layer (EGL) of the developing cerebellum [109] which before they differentiate
Background
Pancreatoblastoma, although the most common pancreatic neoplasm in childhood, is exceedingly rare with only about 60 reported cases world-wide. Pancreatoblastoma, like all other blastomas of childhood, affects children in the early years of life. Most patients are younger than 8 yr and boys are slightly more frequently affected than girls [136].
Pancreatoblastomas arise from pluripotential pancreatic stem cells capable of differentiating along all major pathways found in the pancreas juxtaposing
Summary
When reviewing the available data it becomes apparent that solid childhood tumors arising in the liver, the kidney, the brain, and the pancreas, although originating from entirely different precursor cells, have some important features in common (Table 1).
HBs, NBs, MBs, and PBs are all derived from rapidly dividing stem cells, which during embryonic development are programmed to undergo a massive but transient boost of proliferation. In tumor cells this state of high proliferation is locked,
References (154)
- et al.
The midbrain–hindbrain phenotype of Wnt-1-/Wnt-1-mice results from stepwise deletion of engrailed-expressing cells by 9.5 days postcoitum
Cell
(1992) - et al.
Developmental and hormonal regulation of Wnt gene expression in the mouse mammary gland
Differentiation
(1994) - et al.
WNT signals are required for the initiation of hair follicle development
Dev. Cell
(2002) - et al.
Signalling networks regulating dental development
Mech. Dev.
(1997) - et al.
Analysis of epithelial–mesenchymal interactions in the initial morphogenesis of the mammalian tooth
Dev. Biol.
(1998) - et al.
The Wnt/Ca2+ pathway: a new vertebrate Wnt signaling pathway takes shape
Trends Genet.
(2000) - et al.
The ballet of morphogenesis: unveiling the hidden choreographers
Cell
(2002) - et al.
Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism
Cell
(2002) - et al.
Axis determination in Xenopus involves biochemical interactions of axin, glycogen synthase kinase 3 and beta-catenin
Curr. Biol.
(1998) TCF: transcriptional activator or repressor?
Curr. Opin. Cell Biol.
(1998)
LEF-1, a nuclear factor coordinating signaling inputs from wingless and decapentaplegic
Cell
Frequent nuclear/cytoplasmic localization of beta-catenin without exon 3 mutations in malignant melanoma
Am. J. Pathol.
Lessons from hereditary colorectal cancer
Cell
Primary hepatic tumors of childhood
Hum. Pathol.
Beta-catenin antisense studies in embryonic liver cultures: role in proliferation, apoptosis, and lineage specification
Gastroenterology
Risk of cancer during the first four years of life in children from the Beckwith–Wiedemann syndrome registry
J. Pediatr.
Hepatoblastoma and polyposis coli
Lancet
Risk of hepatoblastoma in familial adenomatous polyposis
J. Pediatr.
Somatic mutations of beta-catenin play a crucial role in the tumorigenesis of sporadic hepatoblastoma
Cancer Lett.
Sequence variants of AXIN1 in hepatoblastoma
Hepatol. Res.
Maternal allele loss in Wilms' tumour
Lancet
Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus
Cell
A syndrome of pseudohermaphroditism, Wilms' tumor, hypertension, and degenerative renal disease
J. Pediatr.
Mechanisms of Wnt signaling in development
Annu. Rev. Cell Dev. Biol.
Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4
Nature
Wnt-4 is a mesenchymal signal for epithelial transformation of metanephric mesenchyme in the developing kidney
Development
A beta-catenin survival signal is required for normal lobular development in the mammary gland
J. Cell Sci.
Essential function of Wnt-4 in mammary gland development downstream of progesterone signaling
Genes Dev.
Differential regulation of the Wnt gene family during pregnancy and lactation suggests a role in postnatal development of the mammary gland
Mol. Cell Biol.
Female development in mammals is regulated by Wnt-4 signalling
Nature
Sexually dimorphic development of the mammalian reproductive tract requires Wnt-7a
Nature
Wnt signaling in the vasculature
Angiogenesis
Wnt signaling is required for thymocyte development and activates Tcf-1 mediated transcription
Eur. J. Immunol.
Epithelial–mesenchymal signaling during tooth development
Connect. Tissue Res.
Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4
Nat. Genet.
Wnt signaling in oncogenesis and embryogenesis—a look outside the nucleus
Science
Casein kinase I phosphorylates the Armadillo protein and induces its degradation in Drosophila
EMBO J.
Beta-catenin is a target for the ubiquitin-proteasome pathway
EMBO J.
Identification of c-MYC as a target of the APC pathway
Science
Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells
Nature
A beta-catenin/XTcf-3 complex binds to the siamois promoter to regulate dorsal axis specification in Xenopus
Genes Dev.
Mutations in beta-catenin are uncommon in colorectal cancer occurring in occasional replication error-positive tumors
Cancer Res.
Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC
Science
A mutated beta-catenin gene encodes a melanoma-specific antigen recognized by tumor infiltrating lymphocytes
J. Exp. Med.
Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas
Proc. Natl Acad. Sci. USA
Mutations in the beta-catenin gene (CTNNB1) in endometrioid ovarian carcinomas
Cancer Res.
Beta-catenin mutations in human prostate cancer
Cancer Res.
Beta-catenin mutation in carcinoma of the uterine endometrium
Cancer Res.
APC mutations occur early during colorectal tumorigenesis
Nature
AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1
Nat. Genet.
Cited by (44)
Crosstalk between PI3K/AKT/mTOR and WNT/β-Catenin signaling in GBM - Could combination therapy checkmate the collusion?
2022, Cellular SignallingCitation Excerpt :In this context, one of the major alterations reported to drive its aberrant activation is mutations in the APC gene in Familial Adenomatous Polyposis (FAP) and sporadic colon cancers [61]. On the other hand, involvement of WNT/β-Catenin in GBM and medulloblastoma was reflected due to the occurrence of germline mutations in WNT/β-Catenin signaling molecules [62]. However, the mechanisms of over activation of β-Catenin in GBM remain unveiled.
Hepatoblastoma
2014, Diagnostic HistopathologyCitation Excerpt :Children of familial adenomatous polyposis (FAP) families, caused by germline mutations of the adenomatous polyposis coli (APC) gene53 carry a significantly elevated relative risk for hepatoblastoma54 and other hepatocellular tumors, suggesting that APC mutations and canonical Wnt pathway activation confer liver cancer predisposition. Wnt signaling is a crucial developmental pathway55,56 necessary for liver development, hepatic zonation, and metabolism,57,58 and it is aberrantly activated in numerous types of cancers,59 including colon,60 skin,61 ovary,62 and liver tumors.63 The high incidence of hepatoblastoma in children from FAP families, occurring in 50–90% of cases reported (depending on the testing methodology), represented the first clue to the importance of the Wnt pathway in these neoplasms.
Immunohistochemical evaluation of solid pseudopapillary tumors of the pancreas: The expression pattern of CD99 is highly unique
2011, Cancer LettersCitation Excerpt :Cytoplasmic and nuclear accumulation of β-catenin protein, which is the key mediator of the Wnt signaling, has been reported in SPTs [11,12,18]. However, the expression pattern of E-cadherin/β-catenin was also seen in most of acinar cell carcinomas and several other tumors in our experiment and other studies [11,19–25]. Since nuclear expression of β-catenin is rare in PET [26], expression of this cell adhesion molecule can be used to differentiate SPT from PET as reported previously by Liu et al. [27].
Wnt4 induces nephronic tubules in metanephric mesenchyme by a non-canonical mechanism
2011, Developmental BiologyCitation Excerpt :These studies imply the existence of progenitor cells in MM rudiments with the retained capacity to produce the epithelia that comprise the various segments of the nephron (Karavanova et al., 1996; Osafune et al., 2006; Perantoni et al., 1995). Wnt/β-catenin signaling is essential for both normal development and tumorigenesis (Koesters and von Knebel Doeberitz, 2003; Logan and Nusse, 2004; Smalley and Dale, 1999). In the canonical Wnt/β-catenin signaling pathway, engagement of a Wnt receptor Frizzled leads to stabilization of β-catenin, which is then translocated into the nucleus to initiate gene expression through interaction with a member of the TCF transcription factor family.
MSX1 induces the Wnt pathway antagonist genes DKK1, DKK2, DKK3, and SFRP1 in neuroblastoma cells, but does not block Wnt3 and Wnt5A signalling to DVL3
2010, Cancer LettersCitation Excerpt :Embryonal oncogenesis is thought to occur by the disruption of the normal embryonic developmental program, thereby giving rise to aberrant cell growth and differentiation, and finally to cancer. In line with this, anomalous regulation of developmental pathways such as Delta-Notch and Wnt is involved in malignant growth in different paediatric tumours [16–18]. Both pathways play key roles in normal neural crest development and neuronal differentiation, and are interesting candidate pathways for neuroblastoma tumorigenesis [9–12,14].