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Updated: Sep 26, 2026
An Orthotopic Murine Model of Human Prostate Cancer Metastasis
Published on: September 18, 2013
Effects of blocking platelet-derived growth factor-receptor signaling in a mouse model of experimental prostate
Hisanori Uehara1, Sun Jin Kim, Takashi Karashima
1Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
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<.001 for all). Mice treated with STI571 or STI571 plus paclitaxel had less phosphorylated PDGF-R on tumor cells and tumor-associated endothelial cells, less tumor cell proliferation, statistically significantly more apoptotic tumor cells (all P<.001), and fewer tumor-associated endothelial cells (P<.001) than control mice.
Conclusions:
Endothelial cells appear to express phosphorylated PDGF-R when they are exposed to tumor cells that express PDGF. Using STI571 to inhibit PDGF-R phosphorylation may, especially in combination with paclitaxel, produce substantial therapeutic effects against prostate cancer bone metastasis.
Insights
Inhibiting platelet-derived growth factor receptor (PDGF-R) with STI571, especially combined with paclitaxel, significantly reduced prostate cancer bone metastasis in mice. This targeted therapy decreased tumor growth, bone lysis, and spread by affecting PDGF-R phosphorylation in tumor and endothelial cells.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Prostate cancer bone metastasis is linked to platelet-derived growth factor (PDGF) signaling.
- PDGF receptor (PDGF-R) tyrosine kinase activity drives tumor cell growth.
- STI571 is a tyrosine kinase inhibitor targeting the PDGF signaling pathway.
Purpose of the Study:
- To investigate the therapeutic effects of STI571, alone and with paclitaxel, on prostate cancer bone metastasis.
- To evaluate the impact of STI571 on PDGF-R activation in a preclinical model.
Main Methods:
- Human prostate cancer cells (PC-3MM2) were xenografted into mouse tibias.
- Mice received oral STI571, paclitaxel, combination therapy, or control treatment.
- Tumor growth, bone lesions, metastasis, and PDGF-R phosphorylation were assessed using radiography, histology, and western blotting.
Main Results:
- STI571 treatment reduced in vitro PDGF-R phosphorylation in cultured tumor cells.
- Mice treated with STI571 (alone or with paclitaxel) showed significantly lower tumor incidence, smaller tumors, and reduced bone lysis and lymph node metastasis compared to controls.
- Combination therapy led to decreased PDGF-R phosphorylation, reduced proliferation, increased apoptosis, and fewer tumor-associated endothelial cells.
Conclusions:
- PDGF-R is phosphorylated on endothelial cells in bone metastasis, suggesting a role in tumor angiogenesis.
- Inhibiting PDGF-R phosphorylation with STI571 demonstrates significant efficacy against prostate cancer bone metastasis.
- Combination therapy with paclitaxel may enhance the therapeutic benefits of STI571 for treating bone metastatic prostate cancer.
