Original contributionThe insulin-like growth factor type 1 receptor and colorectal neoplasia: insights into invasion☆
Introduction
The insulin-like growth factor type 1 receptor (IGF-1R) is a highly conserved transmembrane receptor tyrosine kinase that is highly expressed in embryonic stem cells but is expressed at low levels in most adult differentiated tissues [1], [2], [3]. In contrast, most cancer phenotypes including cancers of the breast [4], prostate [5], colon [6], [7], [8], pancreas [9], liver [10], ovary [11], bladder [12], and brain [13] highly express the IGF-1R. However, some recent studies have shown that some of the more advanced cancer phenotypes of the colorectum [14], breast [15], and prostate [16] that show metastases can also show comparatively lower levels of the IGF-1R. The timing of and the possible reasons for these differences in gene expression during tumor initiation or progression remain unclear and are examined in this study.
The IGF-1R has a highly regulated promoter exhibiting high intrinsic basal activity [17]. The promoter is GC-rich and TATA-less with a single initiator. Cis-elements acting via mostly Sp1 sites in the proximal 5′-flanking region in concert with inhibition from trans regulators such as WT-1, p53, and myc acting on the 5′-flank and 5′-UTR are thought to be important in determining the low transcript levels seen in most adult differentiated tissues [18], [19], [20]. Indeed, these tumor suppressors have been cited as putative mechanisms for the rebound in IGF-1R expression seen in the tumor cell. However, the mechanisms of IGF-1R promoter control during tumor initiation or progression remain entirely speculative at this stage.
The IGF-1R coregulates through multiple signaling networks diverse cell behaviors that include proliferation, differentiation, survival, and adhesion (reviewed by Le Roith [21], Mauro and Surmacz [22], and Valentinis and Baserga [23]). Components of the signaling networks that include Ras/Raf/MAPK, PI3K/Akt/Bcl-2/BAD, β-catenin/E-cadherin/APC are targeted by mutational or expressive change in most human cancers [24] and hence are thought to confer the altered cell behaviors of the tumor phenotype. Early studies showed that functionality of the IGF-1R was a prerequisite for neoplastic transformation and for survival of the transformed cell in vitro and in vivo (reviewed by Baserga [25]). More recent evidence has pointed to putative roles for the IGF-1R in cell adhesion and in cancer cell dedifferentiation [22], [26], [27]. The IGF-1R, via its signaling moiety IRS-1, is thought to translocate as a tripartite complex with E-cadherin and β-catenin to coregulate cell adhesion-dependent gene transcription in a poorly understood manner [26], [27]. Whether any of these mostly in vitro functions of the IGF-1R have any correlates with cell behaviors in human cancer tissue is unknown.
The colorectal normal crypt-ACF-polyp-cancer sequence provides a valuable model system to examine gene expression profiles during the processes of normal cellular differentiation, tumor initiation, and tumor progression. The cell compartmentalization of the normal colorectal crypt has been described in detail and consists of the basal crypt stem cell region, the mid crypt transit amplifying (or proliferating and differentiating) region, and the upper crypt terminally differentiated region [28]. Gene expression profiles can thus be examined during the process of normal differentiation in normal colorectal crypts. These can be compared to the gene expression profiles seen during tumor initiation in ACFs and during tumor progression in adenomatous and cancerous crypts.
In advanced cancers, dedifferentiation, invasion, and metastasis occur, but the morphogenesis and gene expression changes that underlie these processes are poorly understood. Cancer cell dedifferentiation has been compared with embryologic epithelial mesenchymal transformation (EMT), but this is a conceptually different process. Furthermore, there are practical difficulties in inferring the temporal and morphological sequence of events that underlie these processes in heterogeneous cancer specimens.
The primary aim of this study was to examine the expression profile of the IGF-1R in the colorectal normal crypt-ACF-polyp-cancer sequence to discern the timing and nature of any change in IGF-1R expression during this sequence. In addition, the expression profile of the IGF-1R was examined in relation to the expressions of the WT-1 and c-myc regulators as well as in relation to cell morphologies in normal and tumoral crypts. The study's secondary aim was therefore to discern possible reasons for expression change in the IGF-1R during tumor initiation and progression along with the possible reasons for the low levels of IGF-1R expression seen in advanced cancers in some previous studies.
Section snippets
Tissue samples and demographics
Tissue samples were sourced from patients undergoing elective and emergency colorectal resection for benign and malignant conditions at the Colorectal Unit, Western General Hospital, Edinburgh, UK. A total of 8 fresh and 69 archival resection specimens were examined by means of Northern blotting, immunohistochemistry, or Western blotting. Patient demographics showed a male/female ratio of 1.1:1.0 and a mean age of 72.0. There were 6 well-differentiated, 7 moderately differentiated, and 8 poorly
Northern blots
Matched normal and tumoral specimens were initially analyzed by total RNA Northern blots for expression of IGF-1R, c-myc, and WT-1. Colorectal tumors (polyps and cancers) showed high levels of IGF-1R RNA expression when compared to the normal mucosal part of the specimen (blot optical densitometry, 2.94 ± 2.08 versus 1.0 ± 0.28, respectively; 95% confidence interval) (Fig. 2 and Table 1). Normal mucosal specimens showed relatively little variation in IGF-1R expression when normalized to β
Discussion
The study's first finding is that of high levels of IGF-1R expression in the basal crypt stem cell region of the normal colorectal crypt. When these cells undergo programmed differentiation and migrate to the mid crypt, they appear to concomitantly and irreversibly reduce their IGF-1R expression. Although not previously documented by means of immunohistochemistry, the normal crypt axis has been previously examined by means of IGF-1 radioligand binding to show a similar pattern of high receptor
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2017, Digestive and Liver DiseaseCitation Excerpt :IGF1 is a differentiation factor. Thus, the decrease in expression might be due to the dedifferentiation process to which cancer cells are exposed [27]. We have also found low IR expression levels in EAC patients compared to BE and IEN-BE patients.
Circulating levels of IGF-1, IGFBP-3, and IGF-1/IGFBP-3 molar ratio and colorectal adenomas: A meta-analysis
2015, Cancer EpidemiologyCitation Excerpt :However, our result by advancement of CRA indicated that IGF-1 might be involved in progression from non-advanced adenoma to advanced adenoma, though this result was based on only three studies. An experimental study comparing expression of IGF1R for different stages of colorectal carcinogenesis showed that IGF-1R immunoexpression occurred at high levels during tumor progression in colorectal adenomatous and cancerous crypts [29]. However, we cannot draw a definitive conclusion, given the study designs included in this meta-analysis, i.e., a cross-sectional analysis of prevalent adenomas.
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2014, Archives of Medical ResearchCitation Excerpt :Local expression of IGF-1 messenger RNA (mRNA) in the CRC had been significantly positively associated with proliferation (14). High-level IGF-1R expression in colorectal cancer tissue is initiated by an abnormality of stem cell programmed differentiation in the aberrant crypt focus (ACF) (15). ACFs of the colon are possible precursors of colon adenoma and cancer (16).
Body size, IGF and growth hormone polymorphisms, and colorectal adenomas and hyperplastic polyps
2010, Growth Hormone and IGF ResearchAn alternate insulin-like growth factor I receptor signaling pathway for the progression of endothelial-mesenchymal transition
2008, Bioscience HypothesesCitation Excerpt :However, previous reports have proposed that IGFIR activation may also occur in a ligand-independent way during malignant transformation [25] and during neointimal formation in vein graft induced by mechanical stretch [18]. From these and other studies, it is clear that activation of the IGFI signaling pathways is at least critical for cancer development and progression [27,29,31,35]. Less is known regarding the activation of IGFII signaling pathways.
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We gratefully acknowledge the support of the Melville Trust for the Care and Cure of Cancer.