title: Colon Cancer Growth and Dissemination Relies upon Thrombin, Stromal PAR-1, and Fibrinogen.
abstract: Thrombin-mediated proteolysis is a major determinant of metastasis, but is not universally important for primary tumor growth. Here, we report that colorectal adenocarcinoma represents one important exception whereby thrombin-mediated functions support both primary tumor growth and metastasis. In contrast with studies of multiple nongastrointestinal cancers, we found that the growth of primary tumors formed by murine and human colon cancer cells was reduced in mice by genetic or pharmacologic reduction of circulating prothrombin. Reduced prothrombin expression was associated with lower mitotic indices and invasion of surrounding tissue. Mechanistic investigations revealed that thrombin-driven colonic adenocarcinoma growth relied upon at least two targets of thrombin-mediated proteolysis, protease-activated receptor-1 (PAR-1) expressed by stromal cells and the extracellular matrix protein, fibrinogen. Colonic adenocarcinoma growth was reduced in PAR-1-deficient mice, implicating stromal cell-associated PAR-1 as one thrombin target important for tumor outgrowth. Furthermore, tumor growth was dramatically impeded in fibrinogen-deficient mice, offering the first direct evidence of a critical functional role for fibrinogen in malignant tumor growth. Tumors harvested from fibrinogen-deficient mice displayed a relative reduction in cell proliferative indices, as well as increased tumor necrosis and decreased tumor vascular density. Collectively, our findings established a functional role for thrombin and its targets PAR-1 and fibrinogen in the pathogenesis of colonic adenocarcinoma, supporting tumor growth as well as local invasion and metastasis.
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Adams
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Leah
authors.initials: L
authors.lastname: Rosenfeldt
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Malinda
authors.initials: M
authors.lastname: Frederick
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Whitney
authors.initials: W
authors.lastname: Miller
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Dusty
authors.initials: D
authors.lastname: Waltz
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Keith
authors.initials: K
authors.lastname: Kombrinck
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: McElhinney
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Flick
authors.affiliation: Department of Antisense Drug Discovery, ISIS Pharmaceuticals, Inc., Carlsbad, California.
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
authors.affiliation: Department of Antisense Drug Discovery, ISIS Pharmaceuticals, Inc., Carlsbad, California.
authors.forename: Alexey S
authors.initials: AS
authors.lastname: Revenko
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Joe.Palumbo@cchmc.org.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Palumbo
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D000347:Afibrinogenemia / Q000150:complications / Q000235:genetics; D000818:Animals; D002455:Cell Division; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D005340:Fibrinogen / Q000502:physiology*; D045325:HCT116 Cells / Q000637:transplantation; D064593:Heterografts; D006801:Humans; D008297:Male; D008546:Melanoma, Experimental / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D011516:Prothrombin / Q000032:analysis; D044463:Receptor, PAR-1 / Q000172:deficiency / Q000502:physiology*; D017154:Stromal Cells / Q000378:metabolism; D013917:Thrombin / Q000172:deficiency / Q000502:physiology*; D047368:Tumor Burden; D059016:Tumor Microenvironment
chemical_list: D044463:Receptor, PAR-1; D011516:Prothrombin; D005340:Fibrinogen; D013917:Thrombin