Interleukin-3 production by basal-like breast cancer cells is associated with poor prognosis.

Breast cancer represents a collection of pathologies with different molecular subtypes, histopathology, risk factors, clinical behavior, and responses to treatment. "Basal-like" breast cancers predominantly lack the receptors for estrogen and progesterone (ER/PR), lack amplification of human epidermal growth factor receptor 2 (HER2) but account for 10-15% of all breast cancers, are largely insensitive to targeted treatment and represent a disproportionate number of metastatic cases and deaths. Analysis of interleukin (IL)-3 and the IL-3 receptor subunits (IL-3RA + CSF2RB) reveals elevated expression in predominantly the basal-like group. Further analysis suggests that IL-3 itself, but not the IL-3 receptor subunits, associates with poor patient outcome. Histology on patient-derived xenografts supports the notion that breast cancer cells are a significant source of IL-3 that may promote disease progression. Taken together, these observations suggest that IL-3 may be a useful marker in solid tumors, particularly triple negative breast cancer, and warrants further investigation into its contribution to disease pathogenesis.

Rapid histamine-induced neutrophil recruitment is sphingosine kinase-1 dependent.

Leukocyte recruitment to sites of inflammation is critical for the development of acute allergic responses. Rapid P-selectin up-regulation by endothelial cells is a key promoter of leukocyte infiltration in response to mediators such as histamine. However, the mechanisms underpinning this process are still incompletely understood. We examined the role of the sphingosine kinase/sphingosine-1-phosphate (SK/S1P) pathway and showed that in human umbilical vein endothelial cells, histamine rapidly activates SK in an extracellular signal-regulated kinase (ERK) 1/2-dependent manner, concurrent with the induction of P-selectin expression. Histamine activated both SK-1 and SK-2 isoforms; inhibition of SK-1, but not SK-2, attenuated histamine-induced P-selectin up-regulation and neutrophil rolling in vitro. S1P receptor antagonists failed to prevent histamine-induced P-selectin expression, and exogenous S1P did not increase P-selectin expression, suggesting that S1P cell surface receptors are not involved in this process. Finally, the role of both SK-1 and SK-2 in histamine-induced leukocyte rolling in vivo was assessed using pharmacological and genetic methods. Consistent with the in vitro findings, mice pretreated with either sphingosine kinase inhibitor or fingolimod (FTY720) significantly attenuated histamine-induced leukocyte rolling in the cremaster muscle. Similarly, Sphk1(-/-) but not Sphk2(-/-) mice exhibited reduced histamine-induced leukocyte rolling. These findings demonstrate a key role for SK-1 in histamine-induced rapid P-selectin up-regulation and associated leukocyte rolling, and suggest that endothelial SK-1 is an important contributor to allergic inflammation.

The Expression Profile and Textural Characteristics of C595-Reactive MUC1 in Pancreatic Ductal Adenocarcinoma for Targeted Radionuclide Therapy.

Improvements in the prognosis of pancreatic ductal adenocarcinoma (PDAC) rely on the development of effective treatments to target advanced disease. Mucin 1 (MUC1) is a transmembrane glycoprotein which is involved in the metastatic progression of PDAC and is a receptor-of-interest for targeted radionuclide therapy. The aim of this study was to determine the feasibility of MUC1-based targeted radionuclide therapy for PDAC, by evaluating the expression profile of MUC1 in different pancreatic cells and tissues using the C595 antibody. MUC1 expression was evaluated in four PDAC cell lines (PANC-1, BxPC-3, CAPAN-1 and AsPC-1) using flow cytometry and immunocytochemistry. Immunohistochemistry was performed on primary and metastatic PDAC, pancreatitis, pancreatic intra-epithelial neoplasia and normal pancreatic tissue samples to identify potential changes in C595-reactive MUC1 expression across different disease groups. C595-reactive MUC1 expression was found to varying degrees in the cell lines (11.5-93.1%). A pixel analysis of the immunohistochemical staining demonstrated highest MUC1 expression in primary PDAC tissue (mean pixel value of 205.4), followed by other pancreatic cancer types (204.9), pancreatic intra-epithelial neoplasia (203.8), metastatic PDAC (201.5), chronic pancreatitis (198.1) and normal pancreatic tissue (191.4). The increased expression in malignant tissues and reduced expression in benign tissues indicate that C595-reactive MUC1 is a potential target for targeted radionuclide therapy of PDAC.