Macrophages are an abundant inflammatory cell type in the tumor microenvironment that can contribute to tumor growth and metastasis. Macrophage recruitment into tumors is mediated by multiple cytokines, including vascular endothelial growth factor (VEGF), which is thought to function primarily through VEGF receptor (VEGFR) 1 expressed on macrophages. Macrophage infiltration is affected by VEGF inhibition. We show that selective inhibition of VEGFR2 reduced macrophage infiltration into orthotopic pancreatic tumors. Our studies show that tumor-associated macrophages express VEGFR2. Furthermore, peritoneal macrophages from tumor-bearing animals express VEGFR2, whereas peritoneal macrophages from non-tumor-bearing animals do not. To our knowledge, this is the first time that tumor-associated macrophages have been shown to express VEGFR2. Additionally, we found that the cytokine pleiotrophin is sufficient to induce VEGFR2 expression on macrophages. Pleiotrophin has previously been shown to induce expression of endothelial cell markers on macrophages and was present in the microenvironment of orthotopic pancreatic tumors. Finally, we show that VEGFR2, when expressed by macrophages, is essential for VEGF-stimulated migration of tumor-associated macrophages. In summary, tumor-associated macrophages express VEGFR2, and selective inhibition of VEGFR2 reduces recruitment of macrophages into orthotopic pancreatic tumors. Our results show an underappreciated mechanism of action that may directly contribute to the antitumor activity of angiogenesis inhibitors that block the VEGFR2 pathway. [Cancer Res 2008;68(11):4340-6]

Pancreatic cancer is the fourth leading cause of cancer-related death in the USA and little improvement has been seen over the last 20 years in the 5-year survival rate, which remains at 5% (Surveillance, Epidemiology, and End Results, SEER, http://seer.cancer.gov). Historically, studies have focused on cell-autonomous behavior or the molecular biology of cancer cells. However, focus is shifting to the interaction of cancer cells with their microenvironment. In particular, desmoplasia (or stromal response) is prominent in pancreatic adenocarcinoma (Korc, 2007). Crosstalk between malignant epithelial cells and the stromal compartment can promote extracellular matrix (ECM) remodeling, angiogenesis, immune cell recruitment and metastasis (Desmouliere et al

No abstract

Pancreatic cancer continues to have a dismal prognosis and novel therapy is needed. In this study, we evaluate a promising new target for therapy, phosphatidylserine (PS). PS is an anionic phospholipid located normally on the inner leaflet of the plasma membrane in mammalian cells. In the tumor microenvironment, PS becomes externalized on vascular endothelium. The monoclonal antibody 3G4 binds PS and promotes an inflammatory response against tumor blood vessels, resulting in reduction of tumor growth. Mice with orthotopic pancreatic tumors were treated with 3G4, gemcitabine or a combination of both drugs. Tumor burden including pancreas weight and metastatic lesions (liver, lymph node and peritoneal) were reduced 3-to 5-fold by the combination therapy as compared with 1.5-to 2-fold with 3G4 and gemcitabine alone, respectively. Treatment of tumor-bearing animals with the combination therapy increased macrophage infiltration into the tumor mass 10-fold and reduced microvessel density in the tumor by 2.5-fold compared with tumors from untreated animals. Gemcitabine alone and 3G4 alone were less effective than the combination of the 2 agents together. The additive therapeutic effect of both agents appears to be because chemotherapy increases PS exposure on tumor vascular endothelium and amplifies the target for attack by 3G4. In conclusion, 3G4 enhanced the anti-tumor and anti-metastatic activity of gemcitabine without contributing to toxicity. ' 2005 Wiley-Liss, Inc.

No abstract

Background: Pancreatic cancer continues to have a 5-year survival of less than 5%. Therefore, more effective therapies are necessary to improve prognosis in this disease. Angiogenesis is required for tumor growth, and subsequently, mediators of angiogenesis are attractive targets for therapy. Vascular endothelial growth factor (VEGF) is a well-characterized mediator of tumor angiogenesis that functions primarily by binding and activating VEGF receptor 2 (VEGFR2). In this study, we evaluate the use of CT-322, a novel biologic (Adnectin). This small protein is based on a human fibronectin domain and has beneficial properties in that it is fully human, stable, and is produced in bacteria. CT-322 binds to and inhibits activation of VEGFR2.

This study examined relationships between cognitive and emotional processing with changes in pain and depression among intimate partner violence survivors. Twenty-five women who wrote about their most traumatic experiences completed measures of pain and depressive symptoms before the first writing session and again 4 months following the last writing session. Reduced pain was significantly associated with less use of positive and negative emotion words. Relationships between cognitive and emotional aspects of writing with changes in depressive symptoms fell short of statistical significance. The results suggest that emotional processing in narrative writing predicts changes in pain in intimate partner violence survivors.

Background: Prior studies have shown racial differences in concussion awareness and outcome. Objective: To assess if racial or ethnic differences exist in Emergency Department (ED) utilization and diagnosis for children with sports-related head injuries. Methods: We performed a retrospective, cross-sectional analysis of ED visits from 2008 to 2017 using National Electronic Injury Surveillance System (NEISS) data. Population-weighted ED visits for children age 7–18 years with a sport-related injury were included. We compared the probability of an ED visit being for an injury to the head or diagnosed as a concussion between children of different races/ethnicities. Analyses were adjusted for age, gender, sport, year, and location where the injury occurred. Results: We identified 11,529,994 population-weighted ED visits for pediatric sports-related injuries, of which 1,497,717 (13.0%) were injuries to the head and 619,714 (5.4%) received a diagnosis of concussion. Black children were significantly less likely than non-Hispanic white children to have their ED visit be for an injury to the head [Odds Ratio (OR) 0.72, 95%CI 0.65–0.79] or concussion (OR 0.58, 95%CI 0.50–0.68). Black children presenting to the ED with an injury to their head were less likely than non-Hispanic white children to be diagnosed with a concussion (OR = 0.71, 95%CI 0.59–0.85). Conclusions: Racial differences exist in both ED utilization for pediatric sports-related head injuries and in the diagnosis of concussion. Further work is needed to understand these differences to ensure all brain injured athletes receive optimal care, regardless of race.