The prenatal origins of cancer

Abstract

The concept that some childhood malignancies arise from postnatally persistent embryonal cells has a long history. Recent research has strengthened the links between driver mutations and embryonal and early postnatal development. This evidence, coupled with much greater detail on the cell of origin and the initial steps in embryonal cancer initiation, has identified important therapeutic targets and provided renewed interest in strategies for the early detection and prevention of childhood cancer.

Figure 1. Neural crest development and neuroblastoma

Neuroblast progenitors migrate from the neural crest (nc), around the neural tube (nt) and somites (so) to a region immediately lateral to the notochord (no) and the dorsal aorta (da) under the influence of MYCN and bone morphogenetic proteins (BMPs). At this site the cells undergo specification as the primary sympathetic ganglia (psg) before divergence into neural cells of the mature sympathetic ganglia (sg) or chromaffin cells of the adrenal medulla (am). MYCN is a first hit by virtue of the observations from the tyrosine hydroxylase (Th)-MYCN transgenic mouse model, whereas mutations/alterations in anaplastic lymphoma kinase (ALK) and paired-like homeobox 2 (PHOX2B) are inherited human susceptibility genes. Local access to nerve growth factor (NGF) determines whether the normal sg matures into a terminal ganglion cell or undergoes apoptotic cell death. A relatively common pathologic state is postnatal survival of neuroblast rest disease which requires the cell destined to become malignant to be resistant to trophic factor withdrawal before these persistent rest cells undergo a third change to induce transformation, which presents as a clinical malignancy in early childhood. MASH1, murine achaete-scute homolog 1; HAND2, heart and neural crest derivatives expressed 2; NF-M, neurofilament medium polypeptide.

Figure 2. TMD and ML-DS

Children with Down Syndrome (DS) can develop Transient Myeloproliferative Disease (TMD) at birth which can later transform to Myeloid Leukaemia (ML-DS). The production of megakaryocyte-erythroid progenitors (MEPs) is enhanced in the foetal liver of children with DS and trisomy 21 as a first hit. Some megakaryocyte precursor cells develop a second hit mutation in GATA1 resulting in a mutant, truncated protein, GATA1s. All children with TMD and ML-DS exhibit GATA1s and more than two copies of chromosome 21. TMD resolves clinically in almost all patients to later present as ML-DS in 25% of TMD cases. Thus, some TMD cells at birth must survive through unique death resistance mechanisms and may undergo further changes which lead to genomic instability and clinical presentation as ML-DS.

Figure 3. The development of B-ALL

The presence of specific prenatal oncogenic fusion proteins in haematopoietic stem cells (HSCs) or B progenitor cells combines with aberrant expression of transcription factors necessary for normal B cell development and maturation during the genesis of acute lymphoblastic leukaemia (B-ALL). Foetal haematopoiesis begins in the haemogenic endothelium formed from the yolk sac and aorto-gonadal-mesonephros (AGM), then localizes to the foetal liver, to finally reside in the bone marrow from the perinatal period. Several fusion genes (ETV6-RUNX1, MLL-ENL, BCR-ABL) present as clonal chromosome rearrangements at the point of diagnosis of B-ALL, represent the first hit as they have also been identified in blood samples at birth in children who later develop B-ALL. Since the incidence of the ETV6-RUNX1 fusion gene is higher than the clinical incidence of B-ALL, some B-ALL rest cells must survive the perinatal period to undergo a third hit that leads to clinical presentation.

Figure 4. Cerebellar development and embryonal origin of medulloblastoma

The upper (anterior) rhombic lip (URL) is a germinal zone of proliferating granule cell precursors (GCPs) that migrate rostrally to form the external granular layer (EGL). A second germinal centre is the ventricular zone (VZ), which gives rise to Purkinje cells and several other types of cerebellar interneurons. Sonic hedgehog (SHH) tumours may arise from persistent cells of the EGL that have not migrated to the internal granular layer (IGL), while Wnt tumours may originate from persistent cells of the ventricular zone in the brainstem (BS). Group 3 and 4 medulloblastomas likely arise from neural stem cells of the hindbrain.

Figure 5. A model of embryonal tumorigenesis

We propose that each of the four embryonal malignancies with evidence of a prenatal origin (neuroblastoma, ML-DS, B-ALL, medulloblastoma) share common features: (i) a prenatal proliferative excess in the tissue of origin; (ii) a cell intrinsic mechanism for surviving the hostile early postnatal environment; (iii) an accelerated pathway toward genomic instability.