Published online before print October 4, 2007

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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.060661

Accepted for publication July 20, 2007.

Article

Stromal Fibroblasts in Colorectal Liver Metastases Originate From Resident Fibroblasts and Generate an Inflammatory Microenvironment

Lars Mueller^*@, Freya A. Goumas^*, Marianne Affeldt^*, Susanne Sandtner^*, Ursula M. Gehling^*, Silke Brilloff^*, Jessica Walter, Nadia Karnatz^*, Katrin Lamszus, Xavier Rogiers, and Dieter C. Broering

From the Departments of Hepatobiliary Surgery and Solid Organ Transplantation,* and Neurosurgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany; the Department of General and Thoracic Surgery, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany; and the Department of General Surgery, Gent University Hospital and Medical School, Gent, Belgium

^@ To whom correspondence should be addressed. E-mail: lars.mueller{at}uksh-kiel.de.

	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⁺, -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- (TNF-). The effect of TNF- on CAFs is inhibited by the nuclear factor-B 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- 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--induced up-regulation of IL-8 via nuclear factor-B in CAFs is an inflammatory pathway, potentially permissive for cancer invasion that may represent a novel therapeutic target.