IRS-1 and SOCS2 are key regulators of insulin-like growth factor signaling in intestinal cancer

The growth hormone/insulin-like growth factor (GH/IGF) axis has been implicated at various stages of tumor progression in colon cancer. Insulin receptor substrate-1 (IRS-1) is a major downstream signaling molecule of insulin, IGF-I, and IGF-II and is constitutively active in various tumor types, including breast. Its role in colon cancer has not been studied in vivo to date. Conversely, Suppressor of Cytokine Signaling-2 (SOCS2) has been shown to limit this pathway and could thereby limit tumorigenesis in intestine. IRS-1 and SOCS2 deficient mice were crossbred with the ApcMin/+ model of intestinal polyposis to test whether IRS-1 or SOCS2 play a role in tumor formation in intestine. SOCS2 deficient mice were crossbred with GH-transgenic mice to test the hypothesis that SOCS2 normally limits GH-mediated trophic and tumorigenic actions. In mice with partial and absolute IRS-1 deficiency, intestinal crypt apoptosis levels were significantly increased, most notably in the putative stem cell region. Partial and absolute IRS-1 deficiency also lead to decreased tumor formation and decreased expression of a putative stem cell marker and [beta]-catenin transcriptional target, Sox9, in intestine of ApcMin/+ mice. Partial SOCS2 deficiency in GH-transgenic mice lead to greater intestinal growth. SOCS2 deficiency lead to greater tumorigenesis in intestine of GH-transgenic and ApcMin/+ mice, but not using the AOM/DSS model of inflammation-associated colon cancer. Overall, these studies suggest that IRS-1 plays a significant role in intestinal tumorigenesis and SOCS2 may serve as a crucial tumor suppressor by limiting the actions of the GH/IGF-I and IRS-1 pathway. Future studies will be aimed at determining if IRS-1, Sox9, and SOCS2 levels in human intestine can serve as useful biomarkers of colon cancer or adenoma risk

Biochromoendoscopy: molecular imaging with capsule endoscopy for detection of adenomas of the GI tract

Current capsule endoscopy (CE) provides minimally invasive technology for gastrointestinal imaging, but has limited ability to discriminate different polyp types. Near Infrared Fluorescent (NIRF) probes activated by biomarkers upregulated in adenomas (e.g., cathepsin B) are potentially powerful tools to distinguish premalignant or malignant lesions from benign or inflammatory lesions

Suppressor of Cytokine Signaling-2 Gene Disruption Promotes ApcMin/+ Tumorigenesis and Activator Protein-1 Activation

Epigenetic in vitro and in vivo studies suggest that suppressor of cytokine signaling-2 (SOCS2) may normally limit tumorigenesis in the intestine; however, this theory has not been directly tested. We hypothesized that SOCS2 deficiency promotes spontaneous intestinal tumorigenesis in ApcMin/+ mice. Therefore, we quantified tumor number, size, and load in the small intestine and colon using SOCS2+/+/ApcMin/+, SOCS2+/−/ApcMin/+, and SOCS2−/−/ApcMin/+ mice and assayed hematocrit as an indirect marker of disease severity. Biochemical and histological assays were used to assess mechanisms. Heterozygous and homozygous disruption of SOCS2 alleles promoted 166 and 441% increases in tumor load in the small intestine, respectively, accelerated development of colon tumors, and caused severe anemia. SOCS2 deletion promoted significant increases in intestinal insulin-like growth factor-I mRNA but did not affect plasma insulin-like growth factor-I. Western blots and immunohistochemical analysis demonstrated that tumor and nontumor intestinal tissue of SOCS2−/−/ApcMin/+ mice had increased serine 727 phosphorylation of signal transducer and activator of transcription 3 compared with SOCS2+/+/ApcMin/+ mice. Moreover, electromobility shift assays showed that SOCS2 deletion did not alter signal transducer and activator of transcription 3 DNA binding. However, tumors and small intestine from SOCS2−/−/ApcMin/+ showed dramatic increases in activator protein-1 (AP-1) DNA binding, and SOCS2 overexpression in vitro reduced levels of AP-1. These studies indicate that SOCS2 deletion promotes the spontaneous development of intestinal tumors driven by mutations in the adenomatous polyposis coli/β-catenin pathway and activates AP-1. Therefore, reduced expression or epigenetic silencing of SOCS2 may serve as a useful biomarker for colorectal cancer risk

Quantifying the Effects of 16p11.2 Copy Number Variants on Brain Structure: A Multisite Genetic-First Study

International audienceBackground: 16p11.2 breakpoint 4 to 5 copy number variants (CNVs) increase the risk for developing autism spectrum disorder, schizophrenia, and language and cognitive impairment. In this multisite study, we aimed to quantify the effect of 16p11.2 CNVs on brain structure.Methods: Using voxel- and surface-based brain morphometric methods, we analyzed structural magnetic resonance imaging collected at seven sites from 78 individuals with a deletion, 71 individuals with a duplication, and 212 individuals without a CNV.Results: Beyond the 16p11.2-related mirror effect on global brain morphometry, we observe regional mirror differences in the insula (deletion > control > duplication). Other regions are preferentially affected by either the deletion or the duplication: the calcarine cortex and transverse temporal gyrus (deletion > control; Cohen's d > 1), the superior and middle temporal gyri (deletion duplication; -0.5 > Cohen's d > -1). Measures of cognition, language, and social responsiveness and the presence of psychiatric diagnoses do not influence these results.Conclusions: The global and regional effects on brain morphometry due to 16p11.2 CNVs generalize across site, computational method, age, and sex. Effect sizes on neuroimaging and cognitive traits are comparable. Findings partially overlap with results of meta-analyses performed across psychiatric disorders. However, the lack of correlation between morphometric and clinical measures suggests that CNV-associated brain changes contribute to clinical manifestations but require additional factors for the development of the disorder. These findings highlight the power of genetic risk factors as a complement to studying groups defined by behavioral criteria