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Platelet-derived growth factor CC (PDGF-CC) is important during foetal development but also in pathogenesis of neurologic diseases, cancer and fibrosis. We have previously demonstrated that blocking the PDGF-CC/PDGF receptor alpha (PDGFRα) axis resulted in reduction of stroke volume and cerebrovascular permeability after experimentally induced stroke. Recently, we could translate these findings into the clinic showing that imatinib, a small tyrosine kinase inhibitor targeting PDGF receptors, can significantly improve neurological outcome after ischemic stroke in human. Herein we report preclinical toxicological analyses of our newly generated monoclonal anti-human PDGF-CC antibody 6B3 (mAb 6B3) in PDGF-CC humanized mice. Beside histological organ assessment, we also analysed serum, urine, haematological parameters and the general health status of the treated mice. We could not find any indications that mAb 6B3 is toxic or has other significant side effects neither in short, nor in long treatment regimens. Our results indicate that mAb 6B3 can be further developed for clinical use. This opens up the possibility to assess the therapeutic potential of blocking PDGF-CC in diverse pathological conditions such as neurologic diseases, cancer and fibrosis. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with unknown origins. Neurodegeneration in ALS mouse models occurs together with signs of disrupted blood-spinal cord barrier (BSCB) and regressed capillary network, but the molecular pathways contributing to these vascular pathologies remain unknown. We show that motor neurons of human sporadic ALS patients ( n = 12) have increased gene expression of PDGFC and its activator PLAT and presymptomatic activation of the PDGF-CC pathway in SOD1 mice leads to BSCB dysfunction. Decrease of Pdgfc expression in SOD1 mice restored vascular barrier properties, reduced motor neuron loss and delayed symptom onset by up to 3 weeks. Similarly, lower expression levels of PDGFC or PLAT in motor neurons of sporadic ALS patients were correlated with older age at disease onset. PDGF-CC inhibition and restoration of BSCB integrity did not prevent capillary regression at disease end stage. Lower vessel density was found in spinal cords of sporadic ALS patients and the degree of regression in SOD1 mice correlated with more aggressive progression after onset regardless of BSCB status. We conclude that PDGF-CC-induced BSCB dysfunction can contribute to timing of ALS onset, allow insight into disease origins and development of targeted novel therapies. [ABSTRACT FROM AUTHOR]

Background: Pericytes are members of the tumor stroma; however, little is known about their origin, function, or interaction with other tumor components. Emerging evidence suggest that pericytes may regulate leukocyte transmigration. Myeloid-derived suppressor cells (MDSC) are immature myeloid cells with powerful inhibitory effects on T-cell-mediated antitumor reactivity.Methods: We generated subcutaneous tumors in a genetic mouse model of pericyte deficiency (the pdgfb (ret/ret) mouse) and littermate control mice (n = 6-25). Gene expression profiles from 253 breast cancer patients (stage I-III) were evaluated for clinic-pathological parameters and survival using Cox proportional hazard ratios (HRs) and 95% confidence intervals (CIs) based on a two-sided Wald test.Results: We report that pericyte deficiency leads to increased transmigration of Gr1(+)/CD11b(+) cells in experimentally induced tumors. Pericyte deficiency produced defective tumor vasculature, resulting in a more hypoxic microenvironment promoting IL-6 upregulation in the malignant cells. Silencing IL-6 expression in tumor cells attenuated the observed differences in MDSC transmigration. Restoring the pericyte coverage in tumors abrogated the increased MDSC trafficking to pericyte-deficient tumors. MDSC accumulation in tumors led to increases in tumor growth and in circulating malignant cells. Finally, gene expression analysis from human breast cancer patients revealed increased expression of the human MDSC markers CD33 and S100A9 with concomitant decreased expression of pericyte genes and was associated with poor prognosis (HR = 1.88, 95% CI = 1.08 to 3.25, P = .03).Conclusions: Our data uncovers a novel paracrine interaction between tumor pericytes and inflammatory cells and delineates the cellular events resulting in the recruitment of MDSC to tumors. Furthermore, we propose for the first time a role for tumor pericytes in modulating the expression of immune mediators in malignant cells by promoting a hypoxic microenvironment. [ABSTRACT FROM AUTHOR]

Colonic epithelial cell hyperproliferation and hyperplasia induced in mice fed a Western-style diet can be reversed by the addition of calcium to the diet. We propose that calcium in the intestinal lumen can mediate its growth-regulatory and cancer-preventing properties not only by binding and eliminating harmful bile acids but also by a direct effect on colonocytes. Therefore we investigated its concentration-dependent action on proliferating cell nuclear antigen (PCNA) expression by immunohistochemistry and on expression of CYP27B1 (25cholecalciferol-1α-hydroxylase) and of estrogen receptors alpha and beta (ER-α, ER-β) by real-time reverse-transcription polymerase chain reaction. Mice were fed a modified AIN-76 diet containing 20% lactose and 0.9%, 0.1%, or 0.04% calcium. We measured the calcium content of the feces, which decreased depending on the calcium concentration of the diet (53.4, 9.7, and 2.4 mg/g feces, respectively). When we evaluated PCNA expression, we found that only 0.1% calcium (compared with 0.9% calcium) had a consistently promitotic effect on crypts. Crypts of mice fed the diet containing 0.04% calcium displayed almost no positive reaction for PCNA, both in proximal and distal colon. CYP27B1 expression in ascending colon was higher than in descending colon. Low-calcium diets significantly reduced CYP27B1 mRNA expression in both segments of the colon. ER-α gene expression was elevated both in colon ascendens and descendens in mice fed the 0.1% calcium-containing diet but not in mice fed 0.04% calcium. There are much higher levels of ER-β in colon descendens than in colon ascendens regardless of the calcium concentration. In the distal colon, feeding 0.04% calcium also results in considerable induction of ER-β. We conclude that colonic synthesis of 1,25-dihydroxycholecalciferol is, in contrast to 1α-hydroxylation in the kidney, down-regulated by low calcium. Low dietary calcium levels increased proliferation of colonocytes. This high proliferation rate correlated with up-regulated ER-α and, at least in the distal colon, also with upregulation of ER-β. [Supported by the Austrian National Bank. [ABSTRACT FROM AUTHOR]

Cerebrovascular injuries leading to edema and hemorrhage after ischemic stroke are common. The mechanisms underlying these events and how they are connected to known risk factors for poor outcome, like obesity and diabetes, is relatively unknown. Herein we demonstrate that increased adipose tissue lipolysis is a dominating risk factor for the development of a compromised cerebrovasculature in ischemic stroke. Reducing adipose lipolysis by VEGF-B antagonism improved vascular integrity by reducing ectopic cerebrovascular lipid deposition. Thrombolytic therapy in ischemic stroke using tissue plasminogen activator (tPA) leads to increased risk of hemorrhagic complications, substantially limiting the use of thrombolytic therapy. We provide evidence that thrombolysis with tPA promotes adipose tissue lipolysis, leading to a rise in plasma fatty acids and lipid accumulation in the ischemic cerebrovasculature after stroke. VEGF-B blockade improved the efficacy and safety of thrombolysis suggesting the potential use of anti-VEGF-B therapy to extend the therapeutic window for stroke management., Competing Interests: Declaration of interest I.N., E.J.S, D.A.L. and U.E. hold patents on the method of reducing the effect of stroke using a VEGF-B inhibitor, and of treating stroke by inhibition of VEGF-B signaling in combination with a thrombolytic agent. I.N., L.F., C.M., M.Z., L.M. and U.E. are shareholders in a company within the diabetes field. P.D.S. is an employee of, and shareholder in CSL Limited, a biopharmaceutical company. U.E. is a member of a scientific advisory board of a hedge fund in the biotech sector. No other authors have declared competing interest.

Central nervous system (CNS) disorders such as ischemic stroke, multiple sclerosis (MS) or Alzheimers disease are characterized by the loss of blood-brain barrier (BBB) integrity. Here we demonstrate that the small tyrosine kinase inhibitor imatinib enhances BBB integrity in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS). Treatment was accompanied by decreased CNS inflammation and demyelination and especially reduced T-cell recruitment. This was supported by downregulation of the chemokine receptor (CCR) 2 in CNS and lymph nodes, and by modulation of the peripheral immune response towards an anti-inflammatory phenotype. Interestingly, imatinib ameliorated neuroinflammation, even when the treatment was initiated after the clinical manifestation of the disease. We have previously shown that imatinib reduces BBB disruption and stroke volume after experimentally induced ischemic stroke by targeting platelet-derived growth factor receptor -α (PDGFR-α) signaling. Here we demonstrate that PDGFR-α signaling is a central regulator of BBB integrity during neuroinflammation and therefore imatinib should be considered as a potentially effective treatment for MS.