Insulin-Like Growth Factor 2 in Development and Disease: A Mini-Review

Abstract

Background: Insulin-like growth factor 2 (IGF2) is a protein hormone known to regulate cell proliferation, growth, migration, differentiation and survival. The gene is parentally imprinted in the sense that transcripts are almost exclusively derived from the paternal allele. Loss of imprinting of the IGF2 gene is a recurrent observation in growth disorders that combine overgrowth with a variety of malignant tumours. Moreover, IGF2 has been proposed to play a role in the development of a variety of seemingly unrelated cancers that play an important role in geriatric medicine, e.g. breast cancer, colon cancer and lung cancer. Finally, IGF2 has been implicated in cardiovascular disease, since, for example, IGF2 has been shown to influence the size of atherosclerotic lesions. Objective: To summarize current knowledge about IGF2, its interactions with binding proteins and receptors and connections with key diseases. Methods: The contents of this paper were based on reviews of existing literature within the field. Results: There is a substantial amount of research linking IGF2 to growth disorders, cancer and to a much lesser degree cardiovascular disease. Some of the studies on IGF2 and tumour growth have yielded conflicting results, for instance regarding its effect on apoptosis. Conclusion: Today, our knowledge on how IGF2 is composed and interacts with receptors has come a long way. However, there is comparatively little information on how IGF2 affects tumour growth and cardiovascular diseases such as atherosclerosis. Thus, further research will be needed to elucidate the impact of IGF2 on key diseases.

Growth hormone, insulin-like growth factor system and carcinogenesis

“…Growth hormone stimulates the production of IGF-I primarily by the liver, which is the major source of circulating IGF-I, IGFBPs, and, plausibly, IGF-II [9,11]. IGF-I is also produced in several other tissues in response to GH and exerts a negative feedback effect on GH secretion by stimulation of somatostatin release in the hypothalamus and inhibition of GH gene transcription in the pituitary.…”

“…Less than 1% of total IGF-1 is free. Circulating IGF-I levels rise during juvenile life and then decline after puberty, while circulating IGF-II levels are highest in the foetal circulation [11]. When the ternary complex dissociates, the binary complexes of IGFBP-IGF are removed from the circulation and cross the endothelium to reach the target tissues.…”

“…These hybrid receptors have higher binding affinity for IGF-I than for insulin, and despite the fact that their biologic significance remains mostly unknown, it is thought that they function mainly as an IGF-IR, i.e. by activating downstream targets that lead to cellular proliferation [4,5,11].…”

“…IGF-IIR does not transduce an intracellular signal, but rather acts to reduce the bioactivity of IGF-II by sequestering it away from the IGF-IR. Thus, in addition to IGFBPs, IGF-IIR provides extra control for the circulating levels of IGFs, functioning as a "sink" that controls the local bioavailability of IGF ligands for binding to the IGF-IR [4,5,11]. Figure 1 illustrates the relationship among the main components of the GH-IGF system.…”

“…Loss of imprinting (LOI), an epigenetic alteration in the IGF-II gene that results in bi-allelic expression of IGF-II, has been reported in a variety of tumours, including Ewing sarcoma, rhabdomyosarcoma, Wilms' tumour, clear cell sarcoma, renal cell carcinoma, malignant glioma, and a variety of gynaecological and testicular neoplasms [11]. Moreover, LOI of IGF-II gene has been identified as an individual risk factor for developing colorectal carcinoma and, more recently, with poor prognosis of patients with oesophageal squamous cell carcinoma [2,11,62,63].…”