Src family nonreceptor protein tyrosine kinases transduce signals that control normal cellular processes such as cell proliferation, adhesion and motility. Normally, cellular Src is held in an inactive state, but in several cancer types, abnormal events lead to elevated kinase activity of the protein and cause pleiotropic cellular responses inducing transformation and metastasis. A prerequisite of the ability of a cancer cell to undergo metastasis into distant tissues is to penetrate surrounding extracellular matrices. These processes are facilitated by the integrin family of cell adhesion molecules. As is the case with Src, altered integrin activity or substrate affinity can contribute to the neoplastic phenotype. Therefore, understanding the interplay between Src and integrin function has been of intense interest over the past few years. This review focuses on the role of Src and integrin signaling in normal cells and how this is deregulated in human cancer. We will identify the key players in the integrin-mediated signaling pathways involved in cell motility and apoptosis, such as FAK, paxillin and p130 CAS , and discuss how Src signaling affects the formation of focal adhesions and the extracellular matrix.

BackgroundGlycA is a novel spectroscopic marker of systemic inflammation with low intra-individual variability and other attributes favoring its clinical use in patients with chronic inflammatory and autoimmune diseases. GlycA is unique in its composite nature, reflecting both increased glycan complexity and circulating acute phase protein levels during local and systemic inflammation. Recent studies of GlycA from cross-sectional, observational and interventional studies have been highly informative, demonstrating that GlycA is elevated in acute and chronic inflammation, predicts death in healthy individuals and is associated with disease severity in patients with chronic inflammatory diseases such as rheumatoid arthritis, psoriasis and lupus. Moreover, following treatment with biological therapy in psoriasis, reduction in skin disease severity was accompanied by a decrease in GlycA levels and improvement in vascular inflammation.ConclusionsCollectively, these findings suggest GlycA is a marker that tracks systemic inflammation and subclinical vascular inflammation. However, larger prospective studies and randomized trials are necessary in order to assess the impact of novel therapies on GlycA in patients with chronic inflammatory conditions, which may be concomitant with cardiovascular benefits.

The insulin-like growth factor (IGF) type 1 receptor is required for growth, transformation, and protection from apoptosis. IGFs can enhance cell migration, which is known to be influenced via regulation of the E-cadherin͞␤-catenin complex. We sought to investigate whether IGF-1 modulated the interaction between E-cadherin and ␤-catenin in human colorectal cancer cells. We used the C10 cell line, which we established and have previously shown to lack adenomatous polyposis coli, E-cadherin, or ␤-catenin mutations. We found that IGF-1 stimulation enhanced tyrosine phosphorylation of two proteins, ␤-catenin and insulin-receptor substrate 1, which formed a complex with E-cadherin. Tyrosine phosphorylation of ␤-catenin was accompanied by rapid (<1 min) dissociation from E-cadherin at the plasma membrane, followed by relocation to the cellular cytoplasm. IGF-1 also enhanced the stability of ␤-catenin protein. Despite this, we observed no enhancement of transcriptional activity in complex with T-cell factor 4 (Tcf-4) in human embryonic kidney 293 cells treated with IGF-1 or insulin alone. IGF-1 did, however, enhance transcriptional activity in combination with lithium chloride, an inhibitor of glycogen synthase kinase 3␤, which also stabilizes ␤-catenin. In conclusion, we have shown that IGF-1 causes tyrosine phosphorylation and stabilization of ␤-catenin. These effects may contribute to transformation, cell migration, and a propensity for metastasis in vivo.

Objective To understand whether directly-measured psoriasis severity is associated with vascular inflammation assessed by 18F-fluorodeoxyglucose positron emission tomography computed tomography (FDG PET/CT). Approach In depth cardiovascular and metabolic phenotyping was performed in adult psoriasis patients (n=60) and controls (n=20). Psoriasis severity was measured using psoriasis area severity index (PASI). Vascular inflammation was measured using average aortic target-to-background ratio using FDG PET/CT. Results Both the psoriasis patients (28 men, 32 women, mean age 47 years) and controls (13 men, 7 women, mean age 41 years) were young with low cardiovascular risk. PASI scores (Median 5.4; IQR 2.8-8.3) were consistent with mild to moderate skin disease severity. Increasing PASI score was associated with an increase in aortic TBR (β=0.41, p=0.001), an association that changed little after adjustment for age, sex and Framingham risk score. We observed evidence of increased neutrophil frequency (mean psoriasis: 3.7±1.2; vs 2.9±1.2; p=0.02) and activation by lower neutrophil surface CD16 and CD62L in blood. Serum levels of S100A8/A9 (745.1±53.3 vs 195.4±157.8 ng/mL; p<0.01) and neutrophil elastase-1 (43.0±2.4 vs 30.8±6.7 ng/mL; p<0.001) were elevated in psoriasis. Finally, S100A8/A9 protein related to both psoriasis skin disease severity (β=0.53; p=0.02) and vascular inflammation (β=0.48; p=0.02). Conclusions Psoriasis severity is associated with vascular inflammation beyond cardiovascular risk factors. Psoriasis increased neutrophil activation and neutrophil markers, and S100A8/A9 related to both skin disease severity and vascular inflammation.