Cell cycle control by the insulin-like growth factor signal: at the crossroad between cell growth and mitotic regulation

Abstract

In proliferating cells and tissues a number of checkpoints (G1/S and G2/M) preceding cell division (M-phase) require the signal provided by growth factors present in serum. IGFs (I and II) have been demonstrated to constitute key intrinsic components of the peptidic active fraction of mammalian serum. In vivo genetic ablation studies have shown that the cellular signal triggered by the IGFs through their cellular receptors represents a non-replaceable requirement for cell growth and cell cycle progression. Retroactive and current evaluation of published literature sheds light on the intracellular circuitry activated by these factors providing us with a better picture of the pleiotropic mechanistic actions by which IGFs regulate both cell size and mitogenesis under developmental growth as well as in malignant proliferation. The present work aims to summarize the cumulative knowledge learned from the IGF ligands/receptors and their intracellular signaling transducers towards control of cell size and cell-cycle with particular focus to their actionable circuits in human cancer. Furthermore, we bring novel perspectives on key functional discriminants of the IGF growth-mitogenic pathway allowing re-evaluation on some of its signal components based upon established evidences.

Autocrine IGF-II-Associated Cancers: From a Rare Paraneoplastic Event to a Hallmark in Malignancy

“…Consistent with the concept of a differential effect of IGFs in cancer, increased IGF-II bioavailability in the tumor microenvironment is also provided by reduced expression of its high affinity scavenger receptor SpI2-6 [12], formerly referred as IGF2 receptor, secondary to its loss of heterozygosity [51][52][53]. Indeed, SpI2-6/IGF2R tumor suppressor functions have been widely demonstrated to be linked to its ability to sequestrate and degrade IGF-II through direct cell internalization [10,54], while this does not apply to IGF-I, which displays negligible binding to SpI2-6/IGF2R at physiological concentrations [55,56].…”

“…Under such circumstances, cancer cells and tissues will display a variable amount of homogeneous receptors (individual IR and IGF1R) along with an increasing amount of hybrid IGF1R-IR receptors (HRs) directly depending on the increase in the expressed IGF1R (the higher the IGF-IR expression, the higher the amount of HRs) [25]. (B) With the only exception of pancreatic beta-cell benign tumors (insulinomas), which produce an excess of insulin, the vast majority of solid malignancies express IGF-II in higher molecular variants (O-Glycosylated pro-hormone peptides with MW spanning between 15 and 27 KDa [7,74]) which are resistant to extracellular binding and sequestration by physiological IGF binding/scavenging factors, namely IGFBP3 and SpI2-6 [12], improperly referred as IGF-II "receptor" (IGF2R). IGF-II production/secretion has also been shown to be provided by cancer-associated fibroblasts [68], although there is still no evidence that this type of IGF-II belongs to an high-molecular-weight variant.…”

“…Specifically, cancer-secreted IGF-II corresponds to the IGF-II pro-hormone retaining its E domain, allowing its O-Glycosylation [6,8,9]. This processing defect increases the life-span and bioavailability of the IGF-II variants, both in the tumor microenvironment and in the systemic circulation, by reducing binding to IGFBP-3 and the IGF-II scavenger protein SpI2-6 (deceivingly known as the IGF-II "receptor" but actually causing IGF-II sequestration and degradation) [10][11][12]. The timeline of key discoveries connecting IGF-II to paraneoplastic hypoglycemia and proving its unique biological features are conveyed in Figure 1.…”

Human IGF2 Gene Epigenetic and Transcriptional Regulation: At the Core of Developmental Growth and Tumorigenic Behavior

“…This discovery has provided a rationale for the inverse relationship demonstrated in cancer between IGF2 expression and TP53 status [ 78 ], reinforcing the role of IGF-II as a bona fide oncogenic factor in a variety of tumors [ 17 , 79 ]. The role of the TP53/ IGF2 axis towards IGF-mediated effects in cancer have been discussed elsewhere [ 80 ].…”

Nerve Growth Factor and the Role of Inflammation in Tumor Development

“…NGF level evaluation may be useful to predict hepatic dysfunction after irradiation and has been studied as a possible biomarker for liver cancer. [80,[122][123][124][125][126][127][128][129][130][131][132][133] Table 1. Cont.…”