TNF-alpha similarly induces IL-6 and MCP-1 in fibroblasts from colorectal liver metastases and normal liver fibroblasts.
Cancer-associated fibroblasts (CAFs) represent the predominant cell type of the neoplastic stroma of solid tumors, yet their biology and functional specificity for cancer pathogenesis remain unclear. We show here that primary CAFs from colorectal liver metastases express several inflammatory, tumor-enhancing factors, including interleukin (IL)-6 and monocyte-chemoattractant protein (MCP)-1. Both molecules were intensely induced by TNF-alpha on the transcript and protein level, whereas PDGF-BB, TGF-beta1 and EGF showed no significant effects. To verify their potential specialization for metastasis progression, CAFs were compared to fibroblasts from non-tumor liver tissue. Interestingly, these liver fibroblasts (LFs) displayed similar functions. Further analyses revealed a comparable up-regulation of intercellular adhesion molecule-1 (ICAM-1) by TNF-alpha, and of alpha-smooth muscle actin, by TGF-beta1. Moreover, the proliferation of both cell types was induced by PDGF-BB, and CAFs and LFs displayed an equivalent migration towards HT29 colon cancer cells in Boyden chamber assays. In conclusion, colorectal liver metastasis may be supported by CAFs and resident fibroblastic cells competent to generate a prometastatic microenvironment through inflammatory activation of IL-6 and MCP-1.
Mueller
Lars
L
Department of General and Thoracic Surgery, University Hospital of Schleswig-Holstein, Germany. lars.mueller@uksh-kiel.de
von Seggern
Lena
L
Schumacher
Jennifer
J
Goumas
Freya
F
Wilms
Christian
C
Braun
Felix
F
Broering
Dieter C
DC
D000077214:Becaplermin; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000235:genetics; D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000473:pathology*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D008113:Liver Neoplasms / Q000378:metabolism / Q000556:secondary*; D009362:Neoplasm Metastasis; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D016207:Cytokines; D015850:Interleukin-6; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D000077214:Becaplermin