Cancer Letters

Cancer Letters

Volume 198, Issue 2, August 2003, Pages 123-138
Cancer Letters

Mini-review
The Wnt signaling pathway in solid childhood tumors

https://doi.org/10.1016/S0304-3835(03)00367-7Get rights and content

Abstract

The Wnt signaling pathway has long been known to direct growth and patterning during embryonic development. Recent evidence also implicates this pathway in the development of childhood tumors of the liver, the kidney, the brain, and the pancreas. Here, we review the current evidence on how constitutive activation of the Wnt signaling pathway may occur in hepato-, nephro-, medullo- and pancreatoblastomas. With particular emphasis the mutational activation of CTNNB1, an emerging major oncogene in solid childhood tumors, is discussed.

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,

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