Extracellular Granzyme K Modulates Angiogenesis by Regulating Soluble VEGFR1 Release From Endothelial Cells

Angiogenesis is crucial for normal development and homeostasis, but also plays a role in many diseases including cardiovascular diseases, autoimmune diseases, and cancer. Granzymes are serine proteases stored in the granules of cytotoxic cells, and have predominantly been studied for their pro-apoptotic role upon delivery in target cells. A growing body of evidence is emerging that granzymes also display extracellular functions, which largely remain unknown. In the present study, we show that extracellular granzyme K (GrK) inhibits angiogenesis and triggers endothelial cells to release soluble VEGFR1 (sVEGFR1), a decoy receptor that inhibits angiogenesis by sequestering VEGF-A. GrK does not cleave off membrane-bound VEGFR1 from the cell surface, does not release potential sVEGFR1 storage pools from endothelial cells, and does not trigger sVEGFR1 release via protease activating receptor-1 (PAR-1) activation. GrK induces de novo sVEGFR1 mRNA and protein expression and subsequent release of sVEGFR1 from endothelial cells. GrK protein is detectable in human colorectal tumor tissue and its levels positively correlate with sVEGFR1 protein levels and negatively correlate with T4 intratumoral angiogenesis and tumor size. In conclusion, extracellular GrK can inhibit angiogenesis via secretion of sVEGFR1 from endothelial cells, thereby sequestering VEGF-A and impairing VEGFR signaling. Our observation that GrK positively correlates with sVEGFR1 and negatively correlates with angiogenesis in colorectal cancer, suggest that the GrK-sVEGFR1-angiogenesis axis may be a valid target for development of novel anti-angiogenic therapies in cancer

Daily physical activities of patients with chronic pain or fatigue versus asymptomatic controls. A systematic review

Objective: To gain an insight into the daily physical activity levels of patients with chronic pain or fatigue compared with asymptomatic controls. Data sources: MEDLINE, EMBASE, PsycINFO, Picarta, Cochrane Database of Systematic Reviews, reference tracking and a manual search of relevant journals. Review methods: A systematic, computerized database search of the medical databases up to September 2006 was performed. In addition, a hand search of relevant journals was carried out. Appropriate studies reported on the daily physical activities of adult patients with chronic pain or fatigue and included an asymptomatic control group. Two reviewers independently carried out methodological quality assessment and data extraction. A qualitative analysis was performed. Results: Twelve studies were included, involving five different syndromes. Results show large heterogeneity in methods used and syndromes investigated, which limited evidence. Eleven different methods were used to assess daily physical activities resulting in 16 different outcome parameters. There seem to be differences between the different syndromes, but results are not conclusive. Eight studies reported a lower physical activity level in patients compared with controls. There seems to be a difference in results between studies using objective versus those using subjective methods. Conclusions: Results reported in the literature with respect to the activity level of patients with chronic pain or fatigue compared with controls were too heterogeneous to give sufficient evidence and were not conclusive