title: Oncogenic properties of apoptotic tumor cells in aggressive B cell lymphoma.
abstract: BACKGROUND
  Cells undergoing apoptosis are known to modulate their tissue microenvironments. By acting on phagocytes, notably macrophages, apoptotic cells inhibit immunological and inflammatory responses and promote trophic signaling pathways. Paradoxically, because of their potential to cause death of tumor cells and thereby militate against malignant disease progression, both apoptosis and tumor-associated macrophages (TAMs) are often associated with poor prognosis in cancer. We hypothesized that, in progression of malignant disease, constitutive loss of a fraction of the tumor cell population through apoptosis could yield tumor-promoting effects.
  
  
  RESULTS
  Here, we demonstrate that apoptotic tumor cells promote coordinated tumor growth, angiogenesis, and accumulation of TAMs in aggressive B cell lymphomas. Through unbiased "in situ transcriptomics" analysis-gene expression profiling of laser-captured TAMs to establish their activation signature in situ-we show that these cells are activated to signal via multiple tumor-promoting reparatory, trophic, angiogenic, tissue remodeling, and anti-inflammatory pathways. Our results also suggest that apoptotic lymphoma cells help drive this signature. Furthermore, we demonstrate that, upon induction of apoptosis, lymphoma cells not only activate expression of the tumor-promoting matrix metalloproteinases MMP2 and MMP12 in macrophages but also express and process these MMPs directly. Finally, using a model of malignant melanoma, we show that the oncogenic potential of apoptotic tumor cells extends beyond lymphoma.
  
  
  CONCLUSIONS
  In addition to its profound tumor-suppressive role, apoptosis can potentiate cancer progression. These results have important implications for understanding the fundamental biology of cell death, its roles in malignant disease, and the broader consequences of apoptosis-inducing anti-cancer therapy.
authors.affiliation: Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Catriona A
authors.initials: CA
authors.lastname: Ford
authors.affiliation: Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Sofia
authors.initials: S
authors.lastname: Petrova
authors.affiliation: Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: John D
authors.initials: JD
authors.lastname: Pound
authors.affiliation: Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Jorine J L P
authors.initials: JJ
authors.lastname: Voss
authors.affiliation: Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Lynsey
authors.initials: L
authors.lastname: Melville
authors.affiliation: Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Margaret
authors.initials: M
authors.lastname: Paterson
authors.affiliation: Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Farnworth
authors.affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Awen M
authors.initials: AM
authors.lastname: Gallimore
authors.affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Simone
authors.initials: S
authors.lastname: Cuff
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Gartnavel General Hospital, Glasgow G12 0XB, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Wheadon
authors.affiliation: University of Edinburgh Departments of Haematology and Pathology, Western General Hospital, Edinburgh EH4 2XU, UK.
authors.forename: Edwina
authors.initials: E
authors.lastname: Dobbin
authors.affiliation: Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Carol Anne
authors.initials: CA
authors.lastname: Ogden
authors.affiliation: Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Dumitriu
authors.affiliation: Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK; Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Donald R
authors.initials: DR
authors.lastname: Dunbar
authors.affiliation: Cancer Research United Kingdom (CRUK) Institute for Cancer Studies, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Murray
authors.affiliation: Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh EH9 3FL, UK.
authors.forename: Dominik
authors.initials: D
authors.lastname: Ruckerl
authors.affiliation: Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh EH9 3FL, UK.
authors.forename: Judith E
authors.initials: JE
authors.lastname: Allen
authors.affiliation: The Roslin Institute, R(D)SVS, University of Edinburgh, Easter Bush EH25 9RG, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Hume
authors.affiliation: Department of Molecular and Cell Biology, Free University Medical Centre, P.O. Box 7057, 1007 MB Amsterdam, the Netherlands.
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.affiliation: University of Edinburgh Departments of Haematology and Pathology, Western General Hospital, Edinburgh EH4 2XU, UK.
authors.forename: John R
authors.initials: JR
authors.lastname: Goodlad
authors.affiliation: The Roslin Institute, R(D)SVS, University of Edinburgh, Easter Bush EH25 9RG, UK.
authors.forename: Tom C
authors.initials: TC
authors.lastname: Freeman
authors.affiliation: Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK. Electronic address: chris.gregory@ed.ac.uk.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Gregory
mesh_terms: D000704:Analysis of Variance; D017209:Apoptosis / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology; D005453:Fluorescence; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006652:Histological Techniques; D006801:Humans; D053208:Kaplan-Meier Estimate; D016393:Lymphoma, B-Cell / Q000503:physiopathology*; D008264:Macrophages / Q000502:physiology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008546:Melanoma, Experimental / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D010586:Phagocytes / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D059016:Tumor Microenvironment / Q000502:physiology*
chemical_list: D020782:Matrix Metalloproteinases