Selectins as mediators of lung metastasis

Lung metastasis remains the major cause of cancer related mortality in patients with breast, gastrointestinal, sarcoma, melanoma and kidney cancer. Here we characterize the expression of selectins during metastatic lung colonization and analyzed their function in the formation of pulmonary metastasis. E-selectin, together with VCAM-1, were detected 6h after the microvascular arrest of tumor cells indicating an inflammatory activation of the local endothelial cells. No E-selectin expression was detected in pre-metastatic lungs of mice carrying primary tumors. P- and L-selectin were present during initiating steps of lung colonization and correlated with the recruitment of platelets and leukocytes to metastatic tumor cells. Experimental metastasis was significantly reduced in the absence of P- or L-selectin while no attenuation of metastasis was observed in E-selectin-deficient mice. Collectively, selectins are upregulated within the metastatic microenvironment of tumor cells and the formation of a permissive metastatic microenvironment is facilitated by P- and L-selectin mediated interactions between tumor cells and blood components. E-selectin does not affect metastatic initiation in the lung tissue and its expression rather indicates a local activation of lung microvascular endothelial cell

12PLECTIN GALACTOSIDE-BINDING SOLUBLE 3 BINDING PROTEIN (LGALS3BP) IS A CANCER-ASSOCIATED LIGAND FOR INHIBITORY SIGLECS

Tumor cells subvert the control of the immune system by downregulation of their antigenicity and production of an immunosuppressive microenvironment including the upregulation and engagement of inhibitory receptors on immune cells. Therapeutic strategies have demonstrated that the immune system can be reactivated and control established cancers by blocking inhibitory receptors on immune cells such CTLA-4 and PD1. While such activation of the immune system is successful in some patients, many patients still show cancer progression after some time. Thus, the definition of new targetable immunomodulatory pathways is needed to improve the outcome in those patients. Recent evidence suggests that sialic acid dependent ligands on tumor cells can engage inhibitory sialic acid binding immunoglobulin-like lectins (Siglecs) on NK cells and cells of the myelomonocytic lineage and thereby facilitate evasion of immune-mediated killing. Moreover, the presence of a natural variant of Siglec-9 with reduced binding capacity to sialic acid dependent ligands in patients with non-small cell lung cancer improved the two year survival in a retrospective multivariate analysis. Here we identify a novel cancer-associated ligand for immuno-inhibitory Siglecs by affinity chromatography and subsequent proteomic analysis. LectinGalactoside-Binding Soluble 3 Binding Protein (LGALS3BP) bound to various inhibitory Siglecs including Siglec-5, Siglec-9 and Siglec-10 with high affinity. LGALS3BP was previously found to be upregulated in various carcinomas such as breast, colorectal, prostate and lung cancer and linked to advanced stage and poor prognosis. The exact function during cancer progression, however, was not yet defined. Our findings provide a novel insight into how LGALS3BP could promote immune evasion by inhibiting immune cell activation through engagement of Siglecs and defines LGALS3BP-Siglec interactions as potential novel target to interfere with cancer progression and reactivate the immune system against carcinomas. Disclosure: All authors have declared no conflicts of interes

Heparins attenuate cancer metastasis: are selectins the link?

Heparin is often used to prevent or treat thromboembolism in cancer patients. Clinical and experimental evidence suggest that heparin also has anti-cancer activities. Experimental evidence consistently supports the ability of heparin to attenuate metastasis. The potential anti-metastatic effects of heparin include the inhibition of cell-cell interactions or heparanase and modulation of growth factors and anticoagulant activity. Heparin inhibits selectin-mediated interactions of tumor cells with leukocytes, platelets and endothelial cells, which are likely to mediate the initial steps of hematogenous metastasis. Prospective clinical trials can be designed based on the insights obtained from experimental studies

Urinary methanol and formic acid as indicators of occupational exposure to methyl formate.

OBJECTIVE: To evaluate the validity of methanol (MeOH) and formic acid (FA) in urine as biological indicators of methyl formate (MF) exposure in experimental and field situations. METHODS: The subjects were 28 foundrymen and two groups of volunteers (20 control and 20 exposed). Exposure assessment of the workers was performed by personal air and biological monitoring. Methyl formate vapour collected on charcoal tube was analysed by gas chromatography. The concentration of MF in the exposure chamber (volunteer-study) was monitored by two independent methods [flame ionisation detection (FID) and Fourier transformation infra-red detection (FTIR)]. Urinary metabolites (MeOH and FA) were analysed separately by headspace gas chromatography. RESULTS: The volunteers exposed to 100 ppm MF vapour at rest for 8 h excreted 3.62 +/- 1.13 mg MeOH/l (mean +/- SD) at the end of the exposure. This was statistically different (P < 0.001) from pre-exposure MeOH excretion (2.15 +/- 0.80 mg/1), or from that of controls (1.69 +/- 0.48 mg/l). The urinary FA excretion was 32.2 +/- 11.3 mg/g creatinine after the exposure, which was statistically different (P < 0.001) from pre-exposure excretion (18.0 +/- 9.3 mg/g creatinine) or that of controls (13.8 +/- 7.9 mg/g creatinine). In foundrymen, the urinary FA excretion after the 8 h workshift exposure to a time weighted average (TWA) concentration of 2 to 156 ppm MF showed a dose-dependent increase best modelled by a polynomial function. The highest urinary FA concentration was 129 mg/g creatinine. The pre-shift urinary FA of the foundrymen (18.3 +/- 5.6 mg/g creatinine) did not differ from that of controls (13.8 +/- 7.9 mg/g creatinine). The urinary MeOH excretion of the foundrymen after the shift, varied from < 1 to 15.4 mg/l, while the correlation with the preceding MF exposure was poor. The foundrymen excreted more (P = 0.01) FA (2.12 +/- 3.56 mg/g creatinine) after the workshift than experimentally, once-exposed volunteers (0.32 +/- 0.11 mg/g creatinine) at a similar inhaled MF level of 1 ppm). CONCLUSIONS: In spite of its high background level in non-exposed subjects, urinary FA seems to be a useful biomarker of methyl formate exposure. The question remains as to what is the reason for the differences in chronic and acute exposure respectively

Isopropanol and methylformate exposure in a foundry: exposure data and neurobehavioural measurements.

OBJECTIVES: The aim of this study was to determine the dose-effect relationship between solvent exposure and acute neurobehavioural effects at the worksite. METHODS: In a balanced design, ten workers in a Swiss foundry were monitored for 15 days at ten different times during work. Urine samples were taken in the morning and at the time of examination, and personal exposure to isopropanol and methylformate was measured with active samplers. Neurobehavioural tests such as postural balance (bipedal, bipedal blind, monopedal), simple reaction time and digit span of the Neurobehavioural Evaluation System (NES2) and a combined memory and reaction-time test, the combi-test, were performed. A rating of well-being, and the last consumption of alcohol, caffeine, nicotine and medication were reported. RESULTS: Average environmental concentrations of isopropanol were at 44 ppm ( +/- 16 ppm), and at 36 ppm (+/-21 ppm) for methylformate. Maximum values of personal exposure to isopropanol reached barely the maximal allowable concentration (MAC) value (400 ppm); the methylformate personal exposure of three workers exceeded the MAC value (100 ppm). Urine concentrations of methanol were high (3.1 +/- 2.3 mg/l in the morning, 7.8 +/- 4.9 mg/l after exposure) compared with the results of other studies; concentrations of isopropanol were rather low (0.88 +/- 0.73 mg/l after exposure). CONCLUSIONS: Nevertheless, between personal exposure and biomonitoring, linear correlation was found. Methylformate exposure correlated with methanol and formic acid concentration in the urine, and isopropanol exposure with its concentration in the urine. With the neurobehavioural tests used, no solvent effect in relation to the dose could be determined