The Effect of Insulin-like Growth Factor II in the Regulation of Tumour Cell Growth In Vitro and Tumourigenesis In Vivo

Insulin-like growth factor II (IGF-II) is a protein hormone that has been shown to exert several biological functions in mammals. IGF-II is produced mainly by the liver and to be systemically released to affect both the liver, in an autocrine and paracrine manner, as well as other tissues, through endocrine signaling. Nevertheless, it is also produced locally in various other tissues acting via autocrine and paracrine signalling. Research over the last decades has suggested that IGF-II also has a stimulatory effect on tumour cell growth but there are some notable exceptions to this rule. This conflicting view may have several explanations and hence current research has focused on gaining further insight into the transcriptional regulation and the metabolic pathways of IGF-II, which is hoped will result in greater understanding of the role of IGF-II in tumour development and new cancer therapies. This article aims at reviewing some of the key findings on how IGF-II affects tumour cells in vitro, as well as in vivo. Insulin-like growth factors (IGFs) have been of scientific interest since their ability to stimulate cartilage sulfation and replace the sulfation activity of growth hormone was discovered. They were subsequently divided into two groups and named after their homology with insulin - IGF-I and IGF-II (1, 2). The IGF-II gene has since been shown to be expressed by a large variety of normal as well as neoplastic cells when cultured in vitro and IGF-II exerts many different biological activities in cultured cells (3). Its transcription is regulated partly by imprinting - the gene is expressed monoallelically from the paternal allele in almost all tissues (4, 5) - but this can also lead to disorders when the imprinting is disrupted (6). Loss of imprinting (LOI) causes biallellic expression and abnormally high IGF-II levels. This has been observed in overgrowth syndromes, such as Beckwith-Wiedemann syndrome (7), which has suggested an impact of IGF-II on growth and development in vivo. Transgenic technology has also been developed rapidly and thus has made it possible to examine knockout effects on growth factor genes in vivo which has led to further evidence for the involvement of IGF-II in growth regulation. Since its impact on normal development and growth has been confirmed and expression has been observed in neoplastic cells in vitro, it became of interest to elucidate whether or not IGF-II has an impact on tumour development and growth. Current scientific research struggles with the issue of whether IGF-II and the regulation of its transcription are of clinical significance in the growth of different tumours or not. Previous results have not been entirely consistent regarding as to whether IGF-II gives rise to tumour cell apoptosis or prevents it. Therefore, the impact of IGF-II on tumour growth in vivo remains elusive. If more detailed information about the metabolic activity associated with tumour growth could be provided (e.g. IGF-II and its regulation), as well as to why tumours arise and what changes in hormone levels they cause, this could lead to new treatment methods or new ways of determining prognosis. The aim of this review is to summarize current knowledge about and studies of the impact of IGF-II on tumour growth and development. This will include results from experiments on cells cultured in vitro and experiments in vivo.