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Tissues in different anatomical sites can sculpt and vary the tumor microenvironment to affect responses to therapy.

ABSTRACT: The tumor microenvironment can promote tumor growth and reduce treatment efficacy. Tumors can occur in many sites in the body, but how surrounding normal tissues at different anatomical sites affect tumor microenvironments and their subsequent response to therapy is not known.We demonstrated that tumors from renal, colon, or prostate cell lines in orthotopic locations responded to immunotherapy consisting of three agonist antibodies, termed Tri-mAb, to a much lesser extent than the same tumor type located subcutaneously. A tissue-specific response to Tri-mAb was confirmed by ex vivo separation of subcutaneous (SC) or orthotopic tumor cells from stromal cells, followed by reinjection of tumor cells into the opposite site. Compared with SC tumors, orthotopic tumors had a microenvironment associated with a type 2 immune response, related to immunosuppression, and an involvement of alternatively activated macrophages in the kidney model. Orthotopic kidney tumors were more highly vascularized than SC tumors. Neutralizing the macrophage- and Th2-associated molecules chemokine (C-C motif) ligand 2 or interleukin-13 led to a significantly improved therapeutic effect. This study highlights the importance of the tissue of implantation in sculpting the tumor microenvironment. These are important fundamental issues in tumor biology and crucial factors to consider in the design of experimental models and treatment strategies.

SUBMITTER: Devaud C

PROVIDER: S-EPMC3978809 | biostudies-other | 2014 Jan

REPOSITORIES: biostudies-other

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Tissues in different anatomical sites can sculpt and vary the tumor microenvironment to affect responses to therapy.

Devaud Christel C Westwood Jennifer A JA John Liza B LB Flynn Jacqueline K JK Paquet-Fifield Sophie S Duong Connie P M CP Yong Carmen S M CS Pegram Hollie J HJ Stacker Steven A SA Achen Marc G MG Stewart Trina J TJ Snyder Linda A LA Teng Michele W L MW Smyth Mark J MJ Darcy Phillip K PK Kershaw Michael H MH

Molecular therapy : the journal of the American Society of Gene Therapy 20130919 1

The tumor microenvironment can promote tumor growth and reduce treatment efficacy. Tumors can occur in many sites in the body, but how surrounding normal tissues at different anatomical sites affect tumor microenvironments and their subsequent response to therapy is not known.We demonstrated that tumors from renal, colon, or prostate cell lines in orthotopic locations responded to immunotherapy consisting of three agonist antibodies, termed Tri-mAb, to a much lesser extent than the same tumor ty ...[more]

PMID: 24048441

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Project description:European beech (Fagus sylvatica L.) adapts to local growing conditions to enhance its performance. In response to variations in climatic conditions, beech trees adjust leaf phenology, cambial phenology, and wood formation patterns, which result in different tree-ring widths (TRWs) and wood anatomy. Chronologies of tree ring width and vessel features [i.e., mean vessel area (MVA), vessel density (VD), and relative conductive area (RCTA)] were produced for the 1960-2016 period for three sites that differ in climatic regimes and spring leaf phenology (two early- and one late-flushing populations). These data were used to investigate long-term relationships between climatic conditions and anatomical features of four quarters of tree-rings at annual and intra-annual scales. In addition, we investigated how TRW and vessel features adjust in response to extreme weather events (i.e., summer drought). We found significant differences in TRW, VD, and RCTA among the selected sites. Precipitation and maximum temperature before and during the growing season were the most important climatic factors affecting TRW and vessel characteristics. We confirmed differences in climate-growth relationships between the selected sites, late flushing beech population at Idrija showing the least pronounced response to climate. MVA was the only vessel trait that showed no relationship with TRW or other vessel features. The relationship between MVA and climatic factors evaluated at intra-annual scale indicated that vessel area in the first quarter of tree-ring were mainly influenced by climatic conditions in the previous growing season, while vessel area in the second to fourth quarters of tree ring width was mainly influenced by maximum temperature and precipitation in the current growing season. When comparing wet and dry years, beech from all sites showed a similar response, with reduced TRW and changes in intra-annual variation in vessel area. Our findings suggest that changes in temperature and precipitation regimes as predicted by most climate change scenarios will affect tree-ring increments and wood structure in beech, yet the response between sites or populations may differ.

Project description:IntroductionAnimal models for the study of sepsis are being increasingly scrutinized, despite their essential role for early translational research. In particular, recent studies have suggested that at the level of the leukocyte transcriptome, murine models of burns, trauma and endotoxemia markedly differ from their human equivalents, and are only weakly similar amongst themselves. We compared the plasma cytokine and leukocyte transcriptome responses between two different low-lethality murine models of polymicrobial intra-abdominal sepsis.MethodsSix to ten week male C57BL/6j mice underwent either the 'gold standard' cecal ligation and puncture (CLP) model of intra-abdominal sepsis or administration of a cecal slurry (CS), where cecal contents are injected intraperitoneally. Surviving mice were euthanized at two hours, one or three days after sepsis.ResultsThe murine leukocyte transcriptomic response to the CLP and CS models of sepsis was surprisingly dissimilar at two hours, one, and three days after sepsis. The Pearson correlation coefficient for the maximum change in expression for the entire leukocyte transcriptome that changed significantly over time (n = 19,071) was R = 0.54 (R2 = 0.297). The CS model resulted in greater magnitude of early inflammatory gene expression changes in response to sepsis with associated increased production of inflammatory chemokines and cytokines. Two hours after sepsis, CLP had more significant expression of genes associated with IL-10 signaling pathways, whereas CS had greater expression of genes related to CD28, apoptosis, IL-1 and T-cell receptor signaling. By three days, the changes in gene expression in both sepsis models were returning to baseline in surviving animals.ConclusionThese analyses reveal that the murine blood leukocyte response to sepsis is highly dependent on which model of intra-abdominal sepsis is employed, despite their similar lethality. It may be difficult to extrapolate findings from one murine model to another, let alone to human sepsis.

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Tissues in different anatomical sites can sculpt and vary the tumor microenvironment to affect responses to therapy.

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Tissues in different anatomical sites can sculpt and vary the tumor microenvironment to affect responses to therapy.

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