title: Stromal fibroblasts in colorectal liver metastases originate from resident fibroblasts and generate an inflammatory microenvironment.
abstract: Cancer-associated stromal fibroblasts (CAFs) are the main cellular constituents of reactive stroma in primary and metastatic cancer. We analyzed phenotypical characteristics of CAFs from human colorectal liver metastases (CLMs) and their role in inflammation and cancer progression. CAFs displayed a vimentin(+), alpha-smooth-muscle actin(+), and Thy-1(+) phenotype similar to resident portal-located liver fibroblasts (LFs). We demonstrated that CLMs are inflammatory sites showing stromal expression of interleukin-8 (IL-8), a chemokine related to invasion and angiogenesis. In vitro analyses revealed a striking induction of IL-8 expression in CAFs and LFs by tumor necrosis factor-alpha (TNF-alpha). The effect of TNF-alpha on CAFs is inhibited by the nuclear factor-kappaB inhibitor parthenolide. Conditioned medium of CAFs and LFs similarly stimulated the migration of DLD-1, Colo-678, HuH7 carcinoma cells, and human umbilical vein endothelial cells in vitro. Pretreatment of CAFs with TNF-alpha increased the chemotaxis of Colo-678 colon carcinoma cells by conditioned medium of CAFs; however, blockage of IL-8 activity showed no inhibitory effect. In conclusion, these data raise the possibility that the majority of CAFs in CLM originate from resident LFs. TNF-alpha-induced up-regulation of IL-8 via nuclear factor-kappaB in CAFs is an inflammatory pathway, potentially permissive for cancer invasion that may represent a novel therapeutic target.
authors.affiliation: Department of Hepatobiliary Surgery and Solid Organ Transplantation, University Hospital Hamburg-Eppendorf, Hamburg, Germany. lars.mueller@uksh-kiel.de
authors.forename: Lars
authors.initials: L
authors.lastname: Mueller
authors.forename: Freya A
authors.initials: FA
authors.lastname: Goumas
authors.forename: Marianne
authors.initials: M
authors.lastname: Affeldt
authors.forename: Susanne
authors.initials: S
authors.lastname: Sandtner
authors.forename: Ursula M
authors.initials: UM
authors.lastname: Gehling
authors.forename: Silke
authors.initials: S
authors.lastname: Brilloff
authors.forename: Jessica
authors.initials: J
authors.lastname: Walter
authors.forename: Nadia
authors.initials: N
authors.lastname: Karnatz
authors.forename: Katrin
authors.initials: K
authors.lastname: Lamszus
authors.forename: Xavier
authors.initials: X
authors.lastname: Rogiers
authors.forename: Dieter C
authors.initials: DC
authors.lastname: Broering
mesh_terms: D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002633:Chemotaxis; D015179:Colorectal Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D042783:Endothelial Cells / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000473:pathology; D016209:Interleukin-8 / Q000096:biosynthesis; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000556:secondary; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D015854:Up-Regulation
chemical_list: D016209:Interleukin-8; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha