Cyclooxygenase-2 is a target of KRASD12, which facilitates the outgrowth of murine C26 colorectal liver metastases
| Autor: | Niels, Smakman, Onno, Kranenburg, Jan M, Vogten, Alexander L A, Bloemendaal, Paul, van Diest, Inne H M, Borel Rinkes |
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| Rok vydání: | 2005 |
| Předmět: |
Male
Time Factors Apoptosis Dinoprostone Proto-Oncogene Proteins p21(ras) Mice Cell Line Tumor Image Processing Computer-Assisted Animals Cyclooxygenase Inhibitors Neoplasm Metastasis Cell Proliferation Mice Inbred BALB C Cyclooxygenase 2 Inhibitors Microcirculation Liver Neoplasms Isoxazoles Immunohistochemistry Disease Models Animal Genes ras Ki-67 Antigen Liver Cyclooxygenase 2 Prostaglandin-Endoperoxide Synthases Mutation RNA Interference Colorectal Neoplasms Neoplasm Transplantation |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 11(1) |
| ISSN: | 1078-0432 |
| Popis: | Mutational activation of the KRAS oncogene and overexpression of cyclooxygenase-2 (COX-2) contribute to colorectal carcinoma (CRC) development, but the relationship between these two events is unclear. This study was designed to clarify that relationship and to assess the contribution of KRAS-dependent COX-2 to the seeding of CRC cells in the liver and to their outgrowth as liver metastases in an experimental mouse model.The effect of RNA interference-mediated KRAS knockdown on COX-2 expression and activity was tested in murine C26 CRC cells. The contribution of KRAS-dependent COX-2 to early metastatic tumor cell seeding (by intravital microscopy) and outgrowth of metastases in the liver (by bioluminescence imaging) was studied by using parecoxib, a novel and highly selective liver-activated COX-2 inhibitor. Intratumoral cell proliferation, apoptosis, and tumor-associated angiogenesis were assessed by immunohistochemistry on liver tissue sections.Stable knockdown of mutant KRAS(D12) in murine C26 CRC cells by RNA interference lead to a dramatic reduction of COX-2 synthesis and prostaglandin E2 production. Inhibition of host or tumor cell COX-2 activity had no effect on early metastatic cell seeding in the liver but greatly reduced intrahepatic tumor cell proliferation and the rate of liver metastasis outgrowth. COX-2 inhibition had no effect on early tumor vascularization or on tumor cell apoptosis.The high levels of COX-2 enzyme and prostaglandin production in C26 CRC cells are primarily caused by the presence of endogenous mutant KRAS(D12). Furthermore, COX-2 inhibition affects the tumoral rather than the vascular compartment during the early stages of C26 liver metastasis outgrowth. |
| Databáze: | OpenAIRE |
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