Mechanisms of Metastasis in Colorectal Cancer and Metastatic Organotropism: Hematogenous versus Peritoneal Spread

Metastasis is the major cause of death in patients with colorectal carcinoma (CRC). The most common sites of metastasis are the liver and the peritoneum. Peritoneal carcinomatosis is often considered the end stage of the disease after the tumor has spread to the liver. However, almost half of CRC patients with peritoneal carcinomatosis do not present with liver metastasis. This brings up the question of whether peritoneal spread can still be considered as the end stage of a metastasized CRC or whether it should just be interpreted as a site of metastasis alternative to the liver. This review tries to discuss this question and summarize the current status of literature on potential characteristics in tumor biology in the primary tumor, i.e., factors (transcription factors and direct and indirect E-cadherin repressors) and pathways (WNT, TGF-beta, and RAS) modulating EMT, regulation of EMT on a posttranscriptional and posttranslational level (miRNAs), and angiogenesis. In addition to tumor-specific characteristics, factors in the tumor microenvironment, immunological markers, ways of transport of tumor cells, and adhesion molecules appear to differ between hematogenous and peritoneal spread. Factors such as integrins and exosomal integrins, cancer stem cell phenotype, and miRNA expression appear to contribute in determining the metastatic route. We went through each step of the metastasis process comparing hematogenous to peritoneal spread. We identified differences with respect to organotropism, epithelial-mesenchymal transition, angiogenesis and inflammation, and tumor microenvironment which will be further elucidated in this review. A better understanding of the underlying mechanisms and contributing factors of metastasis development in CRC has huge relevance as it is the foundation to help find specific targets for treatment of CRC

Tracing drought effects from the tree to the stand growth in temperate and Mediterranean forests: insights and consequences for forest ecology and management

How drought affects tree and stand growth is an old question, but is getting unprecedented relevance in view of climate change. Stress effects related to drought have been mostly studied at the individual tree level, mostly investigating dominant trees and using their responses as indicator for the impact at the stand level. However, findings at tree and stand level may differ, as the stand responses include interactions and feedbacks that may buffer or aggravate what is observed at the individual tree level. Here, we trace drought effects on growth and development from tree to the stand scale. Therefore, we analyse annually measured data from long-term experiments in temperate and Mediterranean forests. With this analysis, we aim to disclose how well results of dominant tree growth reflect stand-level behaviour, hypothesizing that drought resistance of dominant trees’ can strongly deviate from the overall sensitivity of the stand. First, we theoretically derive how drought responses at the stand level emerge from the tree-level behaviour, thereby considering that potential drought resistance of individual trees is modulated by acclimation and tree–tree interactions at the stand level and that the overall stress response at the stand level results from species-specific and size-dependent individual tree growth and mortality. Second, reviewing respective peer-reviewed literature (24 papers) and complementing findings by own measurements (22 experiments) from temperate and Mediterranean monospecific and mixed-species forests, we are able to reveal main causes for deviations of tree-level and stand-level findings regarding drought stress responses. Using a long-term experiment in Norway spruce (Picea abies (L.) KARST.) and European beech (Fagus sylvatica L.), we provide evidence that the species-dependent and size-dependent reactions matter and how the size–frequency distribution affects the scaling. We show by examples that tree-level derived results may overestimate growth losses by 25%. Third, we investigate the development of the growth dominance coefficient based on measurements gathered at the Bavarian forest climate stations. We show that drought changes stand biomass partitioning in favour of small trees, reduce social differentiation, and homogenize the vertical structure of forests. Finally, we discuss the drought-related consequences of the social class-specific growth reaction patterns for inventory and monitoring and highlight the importance of these findings for understanding site-specific stand dynamics, for forest modelling, and for silvicultural management

Effect of platelet inhibition with perioperative aspirin on survival in patients undergoing curative resection for pancreatic cancer: a propensity score matched analysis

BACKGROUND The importance of platelets in the pathogenesis of metastasis formation is increasingly recognized. Although evidence from epidemiologic studies suggests positive effects of aspirin on metastasis formation, there is little clinical data on the perioperative use of this drug in pancreatic cancer patients. METHODS From all patients who received curative intent surgery for pancreatic cancer between 2014 and 2016 at our institution, we identified 18 patients that took aspirin at time of admission and continued to throughout the inpatient period. Using propensity score matching, we selected a control group of 64 patients without aspirin intake from our database and assessed the effect of aspirin medication on overall, disease-free, and hematogenous metastasis-free survival intervals as endpoints. RESULTS Aspirin intake proved to be independently associated with improved mean overall survival (OS) (46.5 vs. 24.6 months, *p = 0.006), median disease-free survival (DFS) (26 vs. 10.5 months, *p = 0.001) and mean hematogenous metastasis-free survival (HMFS) (41.9 vs. 16.3 months, *p = 0.005). Three-year survival rates were 61.1% in patients with aspirin intake vs. 26.3% in patients without aspirin intake. Multivariate cox regression showed significant independent association of aspirin with all three survival endpoints with hazard ratios of 0.36 (95% CI 0.15-0.86) for OS (*p = 0.021), 0.32 (95% CI 0.16-0.63) for DFS (**p = 0.001), and 0.36 (95% CI 0.16-0.77) for HMFS (*p = 0.009). CONCLUSIONS Patients in our retrospective, propensity-score matched study showed significantly better overall survival when taking aspirin while undergoing curative surgery for pancreatic cancer. This was mainly due to a prolonged metastasis-free interval following surgery

Changes of Tree and Stand Growth: Review and Implications

AbstractIn this chapter, we review the current long-term growth trends and short-term growth reaction to single or repeated stress events on tree and stand level in Europe. Based on growth trend analyses, the chapter reveals the strong human footprint on forest ecosystems.First, we use long-term experiments and increment cores to show change in growth trends within the last centuries. Growth reactions are caused by deposition and climate change rather than by silvicultural measures. Second, we look closer on regional-specific deviations from the general trend. Climate change, drought events, acid rain and O3 are causing regional-specific growth reaction patterns. Third, we assess stress events and the resilience and resistance of monospecific and mixed stands against biotic and abiotic stress in view of the ongoing growth trends.The revealed tree and stand growth behaviours are highly relevant, as any changes of forest growth and structure have strong impacts on the provision of goods and ecosystem services. The results underline the importance of biomonitoring and suggest counteracting measures by forest planning, adaptation of silvicultural guidelines for existing forest and innovative design of future forests stands

Enhanced ozone strongly reduces carbon sink strength of adult beech (Fagus sylvatica) – Resume from the free-air fumigation study at Kranzberg Forest

Ground-level ozone (O3) has gained awareness as an agent of climate change. In this respect, key results are comprehended from a unique 8-year free-air O3-fumigation experiment, conducted on adult beech (Fagus sylvatica) at Kranzberg Forest (Germany). A novel canopy O3 exposure methodology was employed that allowed whole-tree assessment in situ under twice-ambient O3 levels. Elevated O3 significantly weakened the C sink strength of the tree–soil system as evidenced by lowered photosynthesis and 44% reduction in whole-stem growth, but increased soil respiration. Associated effects in leaves and roots at the gene, cell and organ level varied from year to year, with drought being a crucial determinant of O3 responsiveness. Regarding adult individuals of a late-successional tree species, empirical proof is provided first time in relation to recent modelling predictions that enhanced ground-level O3 can substantially mitigate the C sequestration of forests in view of climate change

Effects of growth rate, size, and light availability on tree survival across life stages: a demographic analysis accounting for missing values and small sample sizes.

The data set supporting the results of this article is available in the Dryad repository, http://dx.doi.org/10.5061/dryad.6f4qs. Moustakas, A. and Evans, M. R. (2015) Effects of growth rate, size, and light availability on tree survival across life stages: a demographic analysis accounting for missing values.Plant survival is a key factor in forest dynamics and survival probabilities often vary across life stages. Studies specifically aimed at assessing tree survival are unusual and so data initially designed for other purposes often need to be used; such data are more likely to contain errors than data collected for this specific purpose

Simulation tools for decision support to adaptive forest management in Europe

Peer reviewe

Species mixing reduces drought susceptibility of Scots pine (Pinus sylvestris L.) and oak (Quercus robur L., Quercus petraea (Matt.) Liebl.) – Site water supply and fertility modify the mixing effect

Tree species mixing has been widely promoted as a promising silvicultural tool for reducing drought stress. However, so far only a limited number of species combinations have been studied in detail, revealing inconsistent results. In this study, we analysed the effect of mixing Scots pine and oak (pedunculate oak and sessile oak) trees on their drought response along a comprehensive ecological gradient across Europe. The objective was to improve our knowledge of general drought response patterns of two fundamental European tree species in mixed versus monospecific stands. We focused on three null hypotheses: () tree drought response does not differ between Scots pine and oak, () tree drought response of Scots pine and oak is not affected by stand composition (mixture versus monoculture) and () tree drought response of Scots pine and oak in mixtures and monocultures is not modified by tree size or site conditions. To test the hypotheses, we analysed increment cores of Scots pine and oak, sampled in mixed and monospecific stands, covering a wide range of site conditions. We investigated resistance (the ability to maintain growth levels during drought), recovery (the ability to restore a level of growth after drought) and resilience (the capacity to recover to pre-drought growth levels), involving site-specific drought events that occurred between 1976 and 2015. In monocultures, oak showed a higher resistance and resilience than Scots pine, while recovery was lower. Scots pine in mixed stands exhibited a higher resistance, but also a lower recovery compared with Scots pine in monocultures. Mixing increased the resistance and resilience of oak. Ecological factors such as tree size, site water supply and site fertility were found to have significant effects on the drought response. In the case of Scots pine, resistance was increased by tree size, while recovery was lowered. Resistance of oak increased with site water supply. The observed mixing effect on the tree drought response of Scots pine and oak was in some cases modified by the site conditions studied. Positive mixing effects in terms of resistance and resilience of oak increased with site water supply, while the opposite was found regarding recovery. In contrast, site fertility lessened the positive mixing effect on the resistance of Scots pine. We hypothesise that the observed positive mixing effects under drought mainly result from water- and/or light-related species interactions that improve resource availability and uptake according to temporal and spatial variations in environmental conditions.This work was supported by the European Union as part of the ERA-Net SUMFOREST project REFORM – Mixed species forest management. Lowering risk, increasing resilience (2816ERA02S, PCIN2017-026) and the Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 778322. All contributors thank their national funding institutions for supporting the establishment, mensuration and analysis of the studied triplets. The first author wants to thank the German Federal Ministry of Food and Agriculture (BMEL) for financial support through the Federal Office for Agriculture and Food (BLE) (grant number 2816ERA02S), as well as the Bayerische Staatsforsten (BaySF) and Landesbetrieb Forst Brandenburg for providing suitable research sites. Research on the Lithuanian triplets (LT 1, LT 2) was made possible by the national funding institution Research Council of Lithuania (LMTLT) (agreement number S-SUMFOREST-17-1). The French site FR 1 belongs to the OPTMix experimental site (https://optmix.irstea.fr), which is supported annually by Ecofor, Allenvi, and the French national research infrastructure ANAEE-F. A special thank is due to Peter Biber for supporting the statistical analysis