Effects of blocking platelet-derived growth factor-receptor signaling in a mouse model of experimental prostate cancer bone metastases
Autor: | Dominic Fan, Hisanori Uehara, Christopher J. Logothetis, Isaiah J. Fidler, Sun Jin Kim, Paul Mathew, David L. Shepherd, Takashi Karashima, Rachel Tsan, Jerald J. Killion |
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Rok vydání: | 2003 |
Předmět: |
Male
Cancer Research Pathology Platelet-derived growth factor medicine.medical_treatment Administration Oral Fluorescent Antibody Technique Apoptosis Piperazines Metastasis Prostate cancer chemistry.chemical_compound Mice PDGF Signaling Pathway Antineoplastic Combined Chemotherapy Protocols Tumor Cells Cultured Receptors Platelet-Derived Growth Factor Enzyme Inhibitors Phosphorylation Platelet-Derived Growth Factor biology Bone metastasis Protein-Tyrosine Kinases Immunohistochemistry Gene Expression Regulation Neoplastic Radiographic Image Enhancement Oncology Benzamides Imatinib Mesylate Platelet-derived growth factor receptor Cell Division Signal Transduction medicine.medical_specialty Paclitaxel Blotting Western Mice Nude Antineoplastic Agents Bone Neoplasms medicine In Situ Nick-End Labeling Animals Humans business.industry Growth factor Microcirculation Prostatic Neoplasms Neoplasms Experimental medicine.disease Antineoplastic Agents Phytogenic Disease Models Animal Imatinib mesylate Pyrimidines chemistry biology.protein business |
Zdroj: | Journal of the National Cancer Institute. 95(6) |
ISSN: | 0027-8874 |
Popis: | BACKGROUND Expression of platelet-derived growth factor (PDGF) and activation (by autophosphorylation) of its receptor (PDGF-R), a tyrosine kinase, are associated with the growth of metastatic prostate tumor cells in the bone parenchyma. The tyrosine kinase inhibitor STI571 blocks the PDGF signaling pathway by inhibiting PDGF-R autophosphorylation. We examined the effects of STI571, given alone or with paclitaxel (Taxol), on tumor growth in a mouse model of prostate cancer metastasis. METHODS Human prostate cancer PC-3MM2 cells were injected into the tibias of male nude mice. Three days later the mice (20 per group) were randomly assigned to 5 weeks of treatment with oral and injected water (control), daily oral STI571, weekly injected paclitaxel, or STI571 plus paclitaxel. Lesions in bone and the surrounding muscles were then harvested and analyzed by histology, western blotting (for PDGF-R phosphorylation), immunohistochemistry (for expression of proangiogenic molecules), and double immunofluorescence (to identify endothelial cells and apoptotic tumor cells). Growth of bone lesions was monitored by digital radiography. Bone lesions from control mice were used to establish short-term cell cultures for analysis of PDGF-R phosphorylation. All statistical tests were two-sided. RESULTS PC-3MM2 cells cultured from bone lesions and treated in vitro with STI571 had less phosphorylated PDGF-R than untreated cells. In control mice, bone lesions expressed high levels of PDGF and activated (i.e., phosphorylated) PDGF-R, whereas lesions in the adjacent musculature did not. Activated PDGF-R was present on the surface of endothelial cells within the bone lesions but not in endothelial cells of uninjected bone. Mice treated with STI571 or STI571 plus paclitaxel had a lower tumor incidence, smaller tumors, and less bone lysis and lymph node metastasis than mice treated with water or paclitaxel alone (P |
Databáze: | OpenAIRE |
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