Involvement of the IGF system in fetal growth and childhood cancer: an overview of potential mechanisms

Abstract

Fetal growth is determined by a complex interplay of genetic, nutritional, environmental, and hormonal factors. Greater than expected fetal growth has been positively associated with the risk of the development of some cancers in childhood, particularly acute lymphoblastic leukemia, and the biological mechanisms underlying such associations are thought to involve insulin-like growth factors (IGFs). Circulating IGF levels are highly correlated with fetal growth, and IGFs are believed to play an important role in carcinogenesis; however, these two bodies of evidence have not been well integrated and, as a result, the potential underlying biological mechanisms linking the IGF system with the development of specific childhood cancers have not been elucidated. This review aims to draw together and summarize the literature linking the IGF system, rapidity of fetal growth, and risk of some specific childhood cancers; suggest explanations for some of the inconsistencies observed in previous studies of these associations; and propose an integrated framework for the putative involvement of the IGF system in the development of at least some childhood cancers. If the challenges involved in studying the complex IGF system can be overcome, this field presents an exciting opportunity to elucidate etiological pathways to childhood malignancies.

Birth weight, sex and childhood cancer: A report from the United Kingdom Childhood Cancer Study

“…A role for insulin-like growth factors (IGFs) has been suggested [30,31], which is supported by evidence linking insulinlike growth factors (IGFs) with both fetal growth [32] and with cancer [33]. However, data have been inconsistent and have tended to focus on specific features of the IGF network as opposed to the system as a whole [34]. Other factors that could be involved include immune function, which varies with birth weight [35] and birth order [36]; and loss of imprinting which could influence growth and development [37].…”

Pathology from evolutionary conflict, with a theory of X chromosome versus autosome conflict over sexually antagonistic traits

“…An indirect link between imprinting and childhood cancer comes from the association between higher birth weight, accelerated fetal growth, and higher rates of most of the major childhood cancers (17)(18)(19)(20)(21). To the extent that perturbations to imprinting can lead to misregulated growth, this association between growth and cancer may also link misregulated imprinting to cancer.…”

Rationale for an international consortium to study inherited genetic susceptibility to childhood acute lymphoblastic leukemia

“…1 There is also consistent data supporting birth weight as a risk factor for ALL possibly operating through association with high IGF2 levels and the latter's impact on stem/progenitor cells. 28 Ethnic differences in the risk of ALL are well recognized. 29 Thus, in assessing the interplay between inherited and non-genetic risk factors, analyses using different population cohorts with different incidence rates are likely to be highly informative.…”