ROLE OF THE ANG-TIE2 PATHWAY IN THE INVASIVE RECURRENCE OF GBM FOLLOWING ANTI-VEGF THERAPY

Strong pre-clinical and clinical data supporting the effectiveness of bevacizumab, a humanized monoclonal anti-VEGF antibody, for the treatment of gliomas led to its accelerated approval for the treatment of patients with recurrent glioma. However, despite strong anti-tumor effects, upon treatment with bevacizumab, patients will invariably recur with a tumor characterized by enhanced invasiveness and resistance to therapy. This study aims to elucidate the mechanisms leading to this enhanced malignancy with the hope of uncovering new potential therapeutic targets for combined treatment. Using tissue sections from U87-derived glioma bearing mice treated with or without aflibercept (another anti-VEGF antibody) we have gathered evidence of a significant increase in the number of Tie2 expressing monocytes (TEMs) within the tumor after treatment, particularly around areas of invasion. TEMs are a pro-angiogenic subset of circulating monocytes that express the Tie2 receptor. Our data demonstrates that TEMs have higher expression and activity of pro-invasive molecules, such as MMP2 and MMP9, than their Tie2 negative counterparts and are able to increase glioma cell invasion in vitro, suggesting an active role of these cells in the invasive process observed after treatment. Furthermore, we have shown that expression of angiopoietin 2 (Ang2), a Tie2 ligand, is dramatically increased in the periphery of the tumor after aflibercept treatment. Interestingly, our data provides evidence that Ang2 is chemoattractant to TEMs, both in vitro and in vivo suggesting a potential mechanism of recruitment of these cells to the tumor. These data suggests an active role of the Ang-Tie2 pathway, and in particular Ang2, in the invasive recurrence of GBM following anti-VEGF therapy and that targeting it in combination with anti-VEGF therapy could lead to improved outcomes. Supporting this idea, we were able to observe a dramatic decrease in the invasive phenotype after anti-VEGF treatment when we inhibited the Ang-Tie2 pathway in combination with an anti-VEGFR antibody. These results have important implications for patients with GBM since a decrease in the invasive pattern upon recurrence after anti-angiogenesis therapy could potentially render the tumors amenable to surgical excision upon recurrence. This in turn can lead to improved patient survival

TIE2-mediated tyrosine phosphorylation of H4 regulates DNA damage response by recruiting ABL1

DNA repair pathways enable cancer cells to survive DNA damage induced after genotoxic therapies. Tyrosine kinase receptors (TKRs) have been reported as regulators of the DNA repair machinery. TIE2 is a TKR overexpressed in human gliomas at levels that correlate with the degree of increasing malignancy. Following ionizing radiation, TIE2 translocates to the nucleus, conferring cells with an enhanced nonhomologous end-joining mechanism of DNA repair that results in a radioresistant phenotype. Nuclear TIE2 binds to key components of DNA repair and phosphorylates H4 at tyrosine 51, which, in turn, is recognized by the proto-oncogene ABL1, indicating a role for nuclear TIE2 as a sensor for genotoxic stress by action as a histone modifier. H4Y51 constitutes the first tyrosine phosphorylation of core histones recognized by ABL1, defining this histone modification as a direct signal to couple genotoxic stress with the DNA repair machinery

Macrophage Ablation Reduces M2-Like Populations and Jeopardizes Tumor Growth in a MAFIA-Based Glioma Model

Monocytes/macrophages are an influential component of the glioma microenvironment. However, understanding their diversity and plasticity constitute one of the most challenging areas of research due to the paucity of models to study these cells' inherent complexity. Herein, we analyzed the role of monocytes/macrophages in glioma growth by using a transgenic model that allows for conditional ablation of this cell population. We modeled glioma using intracranial GL261-bearing CSF-1R–GFP+ macrophage Fas-induced apoptosis (MAFIA) transgenic mice. Conditional macrophage ablation was achieved by exposure to the dimerizer AP20187. Double immunofluorescence was used to characterize M1- and M2-like monocytes/macrophages during tumor growth and after conditional ablation. During glioma growth, the monocyte/macrophage population consisted predominantly of M2 macrophages. Conditional temporal depletion of macrophages reduced the number of GFP+ cells, targeting mainly the repopulation of M2-polarized cells, and altered the appearance of M1-like monocytes/macrophages, which suggested a shift in the M1/M2 macrophage balance. Of interest, compared with control-treated mice, macrophage-depleted mice had a lower tumor mitotic index, microvascular density, and reduced tumor growth. These results demonstrated the possibility of studying in vivo the role and phenotype of macrophages in gliomas and suggested that transitory depletion of CSF-1R+ population influences the reconstitutive phenotypic pool of these cells, ultimately suppressing tumor growth. The MAFIA model provides a much needed advance in defining the role of macrophages in gliomas

Endoscopic ultrasound-guided diagnosis of Helicobacter pylori-associated gastric Burkitt's lymphoma in an adolescent patient: a rare case

Primary gastric Burkitt's lymphoma (BL) is rare in the pediatric population. Furthermore, the association of Burkitt's lymphoma with Helicobacter pylori is not well defined. We report a case of primary gastric Burkitt's lymphoma associated with Helicobacter pylori diagnosed in a pediatric patient. This diagnosis was made with the aid of endoscopic ultrasound (EUS)-guided fine-needle biopsy (FNB). This is one of the first pediatric cases of EUS-guided FNB for the diagnosis of H. pylori-associated gastric BL

The 2022 Banff Meeting Lung Report

International audienceThe Lung Session of the 2022 16th Banff Foundation for Allograft Pathology Conference-held in Banff, Alberta-focused on non-rejection lung allograft pathology and novel technologies for the detection of allograft injury. A multidisciplinary panel reviewed the state-of-the-art of current histopathologic entities, serologic studies, and molecular practices, as well as novel applications of digital pathology with artificial intelligence, gene expression analysis, and quantitative image analysis of chest computerized tomography. Current states of need as well as prospective integration of the aforementioned tools and technologies for complete assessment of allograft injury and its impact on lung transplant outcomes were discussed. Key conclusions from the discussion were: (1) recognition of limitations in current standard of care assessment of lung allograft dysfunction; (2) agreement on the need for a consensus regarding the standardized approach to the collection and assessment of pathologic data, inclusive of all lesions associated with graft outcome (eg, non-rejection pathology); and (3) optimism regarding promising novel diagnostic modalities, especially minimally invasive, which should be integrated into large, prospective multicenter studies to further evaluate their utility in clinical practice for directing personalized therapies to improve graft outcome

The 2022 Banff Meeting Lung Report

Abstract: The Lung Session of the 2022 16th Banff Foundation for Allograft Pathology Conference-held in Banff, Alberta-focused on non-rejection lung allograft pathology and novel technologies for the detection of allograft injury. A multidisciplinary panel reviewed the state-of-the-art of current histopathologic entities, serologic studies, and molecular practices, as well as novel applications of digital pathology with artificial intelligence, gene expression analysis, and quantitative image analysis of chest computerized tomography. Current states of need as well as prospective integration of the aforementioned tools and technologies for complete assessment of allograft injury and its impact on lung transplant outcomes were discussed. Key conclusions from the discussion were: specialIntscript recognition of limitations in current standard of care assessment of lung allograft dysfunction; specialIntscript agreement on the need for a consensus regarding the standardized approach to the collection and assessment of pathologic data, inclusive of all lesions associated with graft outcome (eg, non-rejection pathology); and specialIntscript optimism regarding promising novel diag- nostic modalities, especially minimally invasive, which should be integrated into large, prospective multicenter studies to further evaluate their utility in clinical practice for directing personalized therapies to improve graft outcomes