Adiponectin Deficiency Promotes Tumor Growth in Mice by Reducing Macrophage Infiltration

Adiponectin is an adipocyte-derived plasma protein that has been implicated in regulating angiogenesis, but the role of adiponectin in regulating this process is still controversial. In this study, in order to determine whether adiponectin affects tumor growth and tumor induced vascularization, we implanted B16F10 melanoma and Lewis Lung Carcinoma cells subcutaneously into adiponectin knockout and wild-type control mice, and found that adiponectin deficiency markedly promoted the growth of both tumors. Immunohistochemical analyses indicated that adiponectin deficiency reduced macrophage recruitment to the tumor, but did not affect cancer cell mitosis, apoptosis, or tumor-associated angiogenesis. In addition, treatment with recombinant adiponectin did not affect the proliferation of cultured B16F10 tumor cells. Importantly, the restoration of microphage infiltration at an early stage of tumorigenesis by means of co-injection of B16F10 cells and macrophages reversed the increased tumor growth in adiponectin knockout mice. Thus, we conclude that the enhanced tumor growth observed in adiponectin deficient mice is likely due to the reduction of macrophage infiltration rather than enhanced angiogenesis

Plasminogen Alleles Influence Susceptibility to Invasive Aspergillosis

Invasive aspergillosis (IA) is a common and life-threatening infection in immunocompromised individuals. A number of environmental and epidemiologic risk factors for developing IA have been identified. However, genetic factors that affect risk for developing IA have not been clearly identified. We report that host genetic differences influence outcome following establishment of pulmonary aspergillosis in an exogenously immune suppressed mouse model. Computational haplotype-based genetic analysis indicated that genetic variation within the biologically plausible positional candidate gene plasminogen (Plg; Gene ID 18855) correlated with murine outcome. There was a single nonsynonymous coding change (Gly110Ser) where the minor allele was found in all of the susceptible strains, but not in the resistant strains. A nonsynonymous single nucleotide polymorphism (Asp472Asn) was also identified in the human homolog (PLG; Gene ID 5340). An association study within a cohort of 236 allogeneic hematopoietic stem cell transplant (HSCT) recipients revealed that alleles at this SNP significantly affected the risk of developing IA after HSCT. Furthermore, we demonstrated that plasminogen directly binds to Aspergillus fumigatus. We propose that genetic variation within the plasminogen pathway influences the pathogenesis of this invasive fungal infection

Platelet GPIIb supports initial pulmonary retention but inhibits subsequent proliferation of melanoma cells during hematogenic metastasis

Platelets modulate the process of cancer metastasis. However, current knowledge on the direct interaction of platelets and tumor cells is mostly based on findings obtained in vitro. We addressed the role of the platelet fibrinogen receptor glycoprotein IIb (integrin alpha IIb) for experimental melanoma metastasis in vivo. Highly metastatic B16-D5 melanoma cells were injected intravenously into GPIIb-deficient (GPIIb(-/-)) or wildtype (WT) mice. Acute accumulation of tumor cells in the pulmonary vasculature was assessed in real-time by confocal videofluorescence microscopy. Arrest of tumor cells was dramatically reduced in GPIIb(-/-) mice as compared to WT. Importantly, we found that mainly multicellular aggregates accumulated in the pulmonary circulation of WT, instead B16-D5 aggregates were significantly smaller in GPIIb(-/-) mice. While pulmonary arrest of melanoma was clearly dependent on GPIIb in this early phase of metastasis, we also addressed tumor progression 10 days after injection. Inversely, and unexpectedly, we found that melanoma metastasis was now increased in GPIIb(-/-) mice. In contrast, GPIIb did not regulate local melanoma proliferation in a subcutaneous tumor model. Our data suggest that the platelet fibrinogen receptor has a differential role in the modulation of hematogenic melanoma metastasis. While platelets clearly support early steps in pulmonary metastasis via GPIIb-dependent formation of platelet-tumor-aggregates, at a later stage its absence is associated with an accelerated development of melanoma metastases

D005 Proteolysis of angiogenic factors associated with intraplaque hemorrhages in human atherothrombotic plaques

AbstractIncreased permeability of, and bleeding from, microvessels within the atheromatous arterial wall participate in atherothrombosis progression. The VEGF family and angiopoietin system components govern microvessel development and maturation. Serine protease activities are proportional to atherothrombosis progression and linked to intraplaque hemorrhage. Here we investigated the relationship between angiogenic factors and proteases in human hemorrhagic and non-hemorrhagic atheromatous carotid samples by immunohistochemistry, in situ hybridization and ELISA. Plaque activity of plasmin and leukocyte elastase and proteolysis of angiogenic factors by plaque extracts were determined. Smooth muscle cell migration induced by hemorrhagic and nonhemorrhagic plaques was assessed. The absence of á-actin-positive cells characterized microvessels in hemorrhagic areas in spite of similar expression of VEGF and angiopoietin system components in microvessels of hemorrhagic and non-hemorrhagic areas. However, VEGF, PlGF and angiopoietin-1 levels were signifi cantly decreased in hemorrhagic compared to non-hemorrhagic plaques, whereas angiopoietin-2 did not change and soluble Tie-2 levels increased. Consequently, smooth muscle cell migration stimulatory activity of hemorrhagic plaques was reduced. Recombinant PlGF, VEGF and angiopoietin-1 added to plaque extracts were only degraded by hemorrhagic lesions. This proteolysis was prevented by inhibitors of plasmin and elastase, whose activity was increased in hemorrhagic plaques. No degradation was observed for angiopoietin-2. Decreased angiogenic factor levels caused by proteolysis may destabilize plaque microvessels via impairment of mural cell recruitment, thus leading to a vicious circle of intraplaque hemorrhages and lesion progression