title: Pharmacological macrophage inhibition decreases metastasis formation in a genetic model of pancreatic cancer.
abstract: Tumour-associated macrophages play an important role in mediating tumour progression. In pancreatic cancer, infiltrating macrophages are known to mediate tumour progression and have been identified in invasive tumours and in early preinvasive pancreatic intraepithelial precursor lesions. We aimed to study the impact of pharmacological macrophage depletion by liposomal clodronate in a genetic mouse model of pancreatic cancer.
  
  
  
  KPC mice (LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre) were treated for 12 weeks with liposomal clodronate or control liposomes. Tumour and metastasis formation as well as alterations in local and circulating immune cells and cytokines were analysed.
  
  
  
  Treatment with liposomal clodronate effectively reduced CD11b-positive macrophages both in the pancreas and other organs such as liver, lung and spleen. While tumour incidence and growth were only slightly reduced, metastasis formation in the liver and lungs was significantly diminished after macrophage depletion. This antimetastatic effect was independent of the presence of an endogenous primary tumour, since reduced pulmonary colonisation was also detected in clodronate-pretreated mice after tail vein injection of syngeneic pancreatic cancer cell lines. Macrophage inhibition by liposomal clodronate was associated with significantly impaired angiogenesis, reduced circulating vascular endothelial growth factor levels and decreased circulating CD4+CD25+ T cells. These alterations could be confirmed in an independent macrophage depletion model using CD11b-diphtheria toxin receptor mice.
  
  
  
  Pharmacological depletion of macrophages in a genetic mouse model of pancreatic cancer markedly reduced metastasis formation and is associated with impaired angiogenesis and reduced CD4+CD25+ T cell levels. Pharmacological targeting of infiltrating macrophages represents a promising novel tool for antimetastatic therapeutic approaches.
authors.affiliation: Department of Internal Medicine I, Martin Luther University, Halle, Germany.|Department of Gastroenterology and Endocrinology, Philipps University, Marburg, Germany.
authors.forename: Heidi
authors.initials: H
authors.lastname: Griesmann
authors.affiliation: Department of Gastroenterology and Endocrinology, Philipps University, Marburg, Germany.
authors.forename: Christof
authors.initials: C
authors.lastname: Drexel
authors.affiliation: Department of Gastroenterology and Endocrinology, Philipps University, Marburg, Germany.
authors.forename: Nada
authors.initials: N
authors.lastname: Milosevic
authors.affiliation: Department of Pathology and Neuropathology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Bence
authors.initials: B
authors.lastname: Sipos
authors.affiliation: Department of Internal Medicine I, Martin Luther University, Halle, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Rosendahl
authors.affiliation: Department of Gastroenterology and Endocrinology, Philipps University, Marburg, Germany.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Gress
authors.affiliation: Department of Internal Medicine I, Martin Luther University, Halle, Germany.|Department of Gastroenterology and Endocrinology, Philipps University, Marburg, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Michl
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D039481:CD11b Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004002:Clodronic Acid / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008081:Liposomes; D008113:Liver Neoplasms / Q000276:immunology / Q000556:secondary; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008957:Models, Genetic; D009374:Neoplasms, Experimental; D009389:Neovascularization, Pathologic; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000473:pathology*; D013601:T-Lymphocytes / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D000970:Antineoplastic Agents; D039481:CD11b Antigen; D053645:Interleukin-2 Receptor alpha Subunit; D008081:Liposomes; D042461:Vascular Endothelial Growth Factor A; D004002:Clodronic Acid
keywords: ANGIOGENESIS; MACROPHAGES; PANCREATIC CANCER