Vitamin D Binding Protein-Macrophage Activating Factor Directly Inhibits Proliferation, Migration, and uPAR Expression of Prostate Cancer Cells

Background: Vitamin D binding protein-macrophage activating factor (DBP-maf) is a potent inhibitor of tumor growth. Its activity, however, has been attributed to indirect mechanisms such as boosting the immune response by activating macrophages and inhibiting the blood vessel growth necessary for the growth of tumors. Methods and Findings: In this study we show for the first time that DBP-maf exhibits a direct and potent effect on prostate tumor cells in the absence of macrophages. DBP-maf demonstrated inhibitory activity in proliferation studies of both LNCaP and PC3 prostate cancer cell lines as well as metastatic clones of these cells. Flow cytometry studies with annexin V and propidium iodide showed that this inhibitory activity is not due to apoptosis or cell death. DBP-maf also had the ability to inhibit migration of prostate cancer cells in vitro. Finally, DBP-maf was shown to cause a reduction in urokinase plasminogen activator receptor (uPAR) expression in prostate tumor cells. There is evidence that activation of this receptor correlates with tumor metastasis. Conclusions: These studies show strong inhibitory activity of DBP-maf on prostate tumor cells independent of it

Identification of uPAR-positive Chemoresistant Cells in Small Cell Lung Cancer

BACKGROUND: The urokinase plasminogen activator (uPA) and its receptor (uPAR/CD87) are major regulators of extracellular matrix degradation and are involved in cell migration and invasion under physiological and pathological conditions. The uPA/uPAR system has been of great interest in cancer research because it is involved in the development of most invasive cancer phenotypes and is a strong predictor of poor patient survival. However, little is known about the role of uPA/uPAR in small cell lung cancer (SCLC), the most aggressive type of lung cancer. We therefore determined whether uPA and uPAR are involved in generation of drug resistant SCLC cell phenotype. METHODS AND FINDINGS: We screened six human SCLC cell lines for surface markers for putative stem and cancer cells. We used fluorescence-activated cell sorting (FACS), fluorescence microscopy and clonogenic assays to demonstrate uPAR expression in a subpopulation of cells derived from primary and metastatic SCLC cell lines. Cytotoxic assays were used to determine the sensitivity of uPAR-positive and uPAR-negative cells to chemotherapeutic agents. The uPAR-positive cells in all SCLC lines demonstrated multi-drug resistance, high clonogenic activity and co-expression of CD44 and MDR1, putative cancer stem cell markers. CONCLUSIONS: These data suggest that uPAR-positive cells may define a functionally important population of cancer cells in SCLC, which are resistant to traditional chemotherapies, and could serve as critical targets for more effective therapeutic interventions in SCLC

FEATURES OF DIURNAL BLOOD PRESSURE PROFILE, ARTERIAL STIFFNESS AND CENTRAL AORTIC PRESSURE IN PATIENTS WITH ARTERIAL HYPERTENSION AND PREDIABETES

Aim. To assess the features of diurnal blood pressure profile, arterial stiffness and central aortic pressure in patients with arterial hypertension (AH) and prediabetes.Materials and methods. The study included 118 patients with AH, 38 without prediabetes, 80 with prediabetes, 48 of them patients with impaired fasting glucose and 32 patients with impaired glucose tolerance. Prediabetes was determined by the results of an oral glucose tolerance test. All patients underwent 24-hour blood pressure monitoring the main parameters of arterial stiffness and central aortic pressure were determined using the BPLab Vasotens complex of OOO «Petr Telegin» (Russia).Results. The obtained data showed that in patients with hypertension and prediabetes there were recorded increased levels of systolic and pulsatile blood pressure in the brachial artery and aorta, a more pronounced "pressure load" was detected compared to patients without prediabetes. At night, the level of diastolic blood pressure in the brachial artery and aorta, the diastolic pressure time index was higher than in patients with AH without prediabetes. Pathological type of the "non-dipper" curve was detected 2.5 times more often in patients with AH and prediabetes. Moreover, the pulse wave velocity, the augmentation index in the brachial artery and aorta characterizing the stiffness of the vessel wall were significantly higher in hypertensive patients with prediabetes.Conclusion. Thereby, in patients with AH in combination with prediabetes, unlike patients without prediabetes, there were more pronounced changes in the parameters of the diurnal blood pressure profile, arterial stiffness and central aortic pressure including the pulse wave velocity, the augmentation index and pulsatile pressure which are known to be sensitive indicators of target organ damage and are associated with an increased risk of developing cardiovascular and cerebrovascular complications

In vivo safety, biodistribution and antitumor effects of uPAR retargeted oncolytic measles virus in syngeneic cancer models

The urokinase receptor (uPAR) is a clinically relevant target for novel biological therapies. We have previously rescued oncolytic measles viruses fully retargeted against human (MV-h-uPA) or murine (MV-m-uPA) uPAR. Here, we investigated the in vivo effects of systemic administration of MV-m-uPA in immunocompetent cancer models. MV-m-uPA induced in vitro cytotoxicity and replicated in a receptor dependent manner in murine mammary (4T1), and colon (MC-38 and CT-26) cancer cells. Intravenous administration of MV-m-uPA to 4T1 tumor bearing mice was not associated with significant clinical or laboratory toxicity. Higher MV-N RNA copy numbers were detected in primary tumors, and viable viral particles were recovered from tumor bearing tissues only. Non-tumor bearing organs did not show histological signs of viral induced toxicity. Serum anti-MV antibodies were detected at day 14 of treatment. Immunohistochemistry and immunofluorescence studies confirmed successful tumor targeting and demonstrated enhanced MV-m-uPA induced tumor cell apoptosis in treated, compared to control mice. Significant antitumor effects and prolonged survival were observed after systemic administration of MV-m-uPA in colon (CT-26) and mammary (4T1) cancer models. The above results demonstrate safety and feasibility of uPAR targeting by an oncolytic virus, and confirm significant antitumor effects in highly aggressive syngeneic immunocompetent cancer models