In vivo hemin conditioning targets the vascular and immunologic compartments and restrains prostate tumor development

Purpose: Conditioning strategies constitute a relatively unexplored and exciting opportunity to shape tumor fate by targeting the tumor microenvironment. In this study, we assessed how hemin, a pharmacologic inducer of heme oxygenase-1 (HO-1), has an impact on prostate cancer development in an in vivo conditioning model. Experimental Design: The stroma of C57BL/6 mice was conditioned by subcutaneous administration of hemin prior to TRAMP-C1 tumor challenge. Complementary in vitro and in vivo assays were performed to evaluate hemin effect on both angiogenesis and the immune response. To gain clinical insight, we used prostate cancer patient-derived samples in our studies to assess the expression of HO-1 and other relevant genes. Results: Conditioning resulted in increased tumor latency and decreased initial growth rate. Histologic analysis of tumors grown in conditioned mice revealed impaired vascularization. Hemin-treated human umbilical vein endothelial cells (HUVEC) exhibited decreased tubulogenesis in vitro only in the presence of TRAMP-C1-conditioned media. Subcutaneous hemin conditioning hindered tumor-associated neovascularization in an in vivo Matrigel plug assay. In addition, hemin boosted CD8+ T-cell proliferation and degranulation in vitro and antigen-specific cytotoxicity in vivo. A significant systemic increase in CD8+ T-cell frequency was observed in preconditioned tumor-bearing mice. Tumors from hemin-conditioned mice showed reduced expression of galectin-1 (Gal-1), key modulator of tumor angiogenesis and immunity, evidencing persistent remodeling of the microenvironment. We also found a subset of prostate cancer patient-derived xenografts and prostate cancer patient samples with mild HO-1 and low Gal-1 expression levels. Conclusions: These results highlight a novel function of a human-used drug as a means of boosting the antitumor response

European beech stem diameter grows better in mixed than in mono-specific stands at the edge of its distribution in mountain forests

Recent studies show that several tree species are spreading to higher latitudes and elevations due to climate change. European beech, presently dominating from the colline to the subalpine vegetation belt, is already present in upper montane subalpine forests and has a high potential to further advance to higher elevations in European mountain forests, where the temperature is predicted to further increase in the near future. Although essential for adaptive silviculture, it remains unknown whether the upward shift of beech could be assisted when it is mixed with Norway spruce or silver fir compared with mono-specific stands, as the species interactions under such conditions are hardly known. In this study, we posed the general hypotheses that the growth depending on age of European beech in mountain forests was similar in mono-specific and mixed-species stands and remained stable over time and space in the last two centuries. The scrutiny of these hypotheses was based on increment coring of 1240 dominant beech trees in 45 plots in mono-specific stands of beech and in 46 mixed mountain forests. We found that (i) on average, mean tree diameter increased linearly with age. The age trend was linear in both forest types, but the slope of the age–growth relationship was higher in mono-specific than in mixed mountain forests. (ii) Beech growth in mono-specific stands was stronger reduced with increasing elevation than that in mixed-species stands. (iii) Beech growth in mono-specific stands was on average higher than beech growth in mixed stands. However, at elevations > 1200 m, growth of beech in mixed stands was higher than that in mono-specific stands. Differences in the growth patterns among elevation zones are less pronounced now than in the past, in both mono-specific and mixed stands. As the higher and longer persisting growth rates extend the flexibility of suitable ages or size for tree harvest and removal, the longer-lasting growth may be of special relevance for multi-aged silviculture concepts. On top of their function for structure and habitat improvement, the remaining old trees may grow more in mass and value than assumed so far.The authors would like to acknowledge networking support by the COST (European Cooperation in Science and Technology) Action CLIMO (Climate-Smart Forestry in Mountain Regions—CA15226) financially supported by the EU Framework Programme for Research and Innovation HORIZON 2020. This publication is part of a project that has received funding from the European Union’s HORIZON 2020 research and innovation programme under the Marie Skłodowska-Curie Grant Agreement No 778322. Thanks are also due to the European Union for funding the project ‘Mixed species forest management. Lowering risk, increasing resilience (REFORM)’ (# 2816ERA02S under the framework of Sumforest ERA-Net). Further, we would like to thank the Bayerische Staatsforsten (BaySF) for providing the observational plots and to the Bavarian State Ministry of Food, Agriculture, and Forestry for permanent support of the Project W 07 ‘Long-term experimental plots for forest growth and yield research’ (#7831-26625-2017). We also thank the Forest Research Institute, ERTI Sárvár, Hungary, for assistance and for providing observational plots. Furthermore, our work was partially supported by the SRDA via Project No. APVV-16-0325 and APVV-15-0265, the Ministry of Science and Higher Education of the Republic of Poland, the Project “EVA4.0” No. CZ.02.1.01/0.0/0.0/16_019/0000803 funded by OP RDE and the Project J4-1765 funded by the Slovenian Research Agency and also by the Bulgarian National Science Fund (BNSF) and the Project No. DCOST 01/3/19.10.2018