title: Endothelin-1 stimulates colon cancer adjacent fibroblasts.
abstract: Endothelin-1 (ET-1) is produced by and stimulates colorectal cancer cells. Fibroblasts produce tumour stroma required for cancer development. We investigated whether ET-1 stimulated processes involved in tumour stroma production by colonic fibroblasts. Primary human fibroblasts, isolated from normal tissues adjacent to colon cancers, were cultured with or without ET-1 and its antagonists. Cellular proliferation, migration and contraction were measured. Expression of enzymes involved in tumour stroma development and alterations in gene transcription were determined by Western blotting and genome microarrays. ET-1 stimulated proliferation, contraction and migration (p < 0.01 v control) and the expression of matrix degrading enzymes TIMP-1 and MMP-2, but not MMP-3. ET-1 upregulated genes for profibrotic growth factors and receptors, signalling molecules, actin modulators and extracellular matrix components. ET-1 stimulated colonic fibroblast cellular processes in vitro that are involved in developing tumour stroma. Upregulated genes were consistent with these processes. By acting as a strong stimulus for tumour stroma creation, ET-1 is proposed as a target for adjuvant cancer therapy.
authors: Department of Surgery, UCL Division of Surgery and Interventional Science, London, United Kingdom.
authors: Jonathan P
authors: JP
authors: Knowles
authors: Xu
authors: X
authors: Shi-Wen
authors: Samer-ul
authors: SU
authors: Haque
authors: Ashish
authors: A
authors: Bhalla
authors: Michael R
authors: MR
authors: Dashwood
authors: Shiyu
authors: S
authors: Yang
authors: Irving
authors: I
authors: Taylor
authors: Marc C
authors: MC
authors: Winslet
authors: David J
authors: DJ
authors: Abraham
authors: Marilena
authors: M
authors: Loizidou
mesh_terms: D000199:Actins / Q000378:metabolism; D048708:Cell Growth Processes / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000235:genetics / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000235:genetics / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000235:genetics
chemical_list: D000199:Actins; D019332:Endothelin-1; D036341:Intercellular Signaling Peptides and Proteins; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017978:Receptors, Growth Factor; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D020778:Matrix Metalloproteinase 2