Imatinib mesylate inhibits proliferation and modulates cytokine expression of human cancer-associated stromal fibroblasts from colorectal metastases.
Recent data have expanded the concept that cancer-associated stromal fibroblasts (CAFs) play an important role in tumor invasion and angiogenesis. Here, we show that platelet-derived growth factor (PDGF) is a mitogen for human CAFs isolated from hepatic metastases of colorectal cancer. The tyrosine kinase inhibitor imatinib mesylate (1 microM) abrogated the PDGF-induced DNA synthesis, and furthermore counteracted an inhibitory effect of PDGF on the expression of alpha-smooth muscle actin (alpha-SMA). High-dose imatinib mesylate (10 microM) decreased the viability of CAFs in vitro independent from co-stimulation with PDGF. Interestingly, imatinib mesylate (10 microM) strikingly induced the expression of the pro-inflammatory and pro-angiogenic cytokines interleukin (IL)-6 and IL-8, and mildly stimulated the release of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Our results suggest that imatinib mesylate, due to its anti-proliferative activity, may be effective in combination with other substances for the treatment of colorectal metastasis progression.
Mueller
Lars
L
Department of Hepatobiliary Surgery and Solid Organ Transplantation, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany. l.mueller@uke.uni-hamburg.de
Goumas
Freya A
FA
Himpel
Sigrid
S
Brilloff
Silke
S
Rogiers
Xavier
X
Broering
Dieter C
DC
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D001549:Benzamides; D049109:Cell Proliferation / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000473:pathology*; D017077:Culture Media, Conditioned; D016207:Cytokines / Q000378:metabolism*; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary*; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D000970:Antineoplastic Agents; D001549:Benzamides; D017077:Culture Media, Conditioned; D016207:Cytokines; D017931:DNA Primers; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate