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Evaluating the Angiogenetic Properties of Ovarian Cancer Stem-Like Cells using the Three-Dimensional Co-Culture System, NICO-1
Published on: December 5, 2020
Targeting the platelet-derived growth factor receptor in antivascular therapy for human ovarian carcinoma
Sachin M Apte1, Dominic Fan, Jerald J Killion
1Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Purpose:
We sought to determine whether blockade of platelet-derived growth factor receptor (PDGF-R) activation by oral administration of a PDGF-R tyrosine kinase inhibitor (STI571) alone or in combination with i.p. paclitaxel can inhibit the progression of tumors caused by human ovarian carcinoma cells growing in the peritoneal cavity of female nude mice.
Experimental Design:
In several different experiments, paclitaxel-sensitive and paclitaxel-resistant metastatic human ovarian carcinoma cells were injected into the peritoneal cavity of nude mice. Seven days later, groups (n = 10) of mice began receiving a control treatment, STI571 alone, paclitaxel alone, or a combination of STI571 and paclitaxel. The mice were necropsied after 45 days of treatment.
Results:
Treatment with combination therapy significantly reduced tumor weight (relative to control or single-agent therapy) in all three human ovarian cancer cell lines. Immunohistochemical analyses revealed that PDGF-R activation was blocked by STI571 administered alone or in combination with paclitaxel. Tumor-associated endothelial cells expressed both PDGF-R and phosphorylated PDGF-R. In mice receiving combination therapy, tumor-associated endothelial cells underwent apoptosis, leading to decreases in microvessel density and tumor cell proliferation relative to control and single-agent therapy.
Conclusions:
These results show that administration of a PDGF-R tyrosine kinase inhibitor in combination with paclitaxel impairs the progression of ovarian cancer in the peritoneal cavity of nude mice, in part, by blockade of PDGF, an endothelial cell survival factor, which results in the increased apoptosis of tumor-associated endothelial cells.
Insights
Combining a platelet-derived growth factor receptor (PDGF-R) inhibitor with paclitaxel significantly reduced ovarian cancer progression in mice. This therapy blocked PDGF-R signaling, leading to apoptosis of tumor-associated endothelial cells and decreased tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Ovarian carcinoma is a significant cause of cancer-related mortality.
- Tumor growth and metastasis are dependent on angiogenesis and endothelial cell survival.
- Platelet-derived growth factor receptor (PDGF-R) signaling plays a crucial role in endothelial cell function and tumor progression.
Purpose of the Study:
- To evaluate the efficacy of blocking PDGF-R activation with STI571, alone or combined with paclitaxel, in inhibiting ovarian cancer progression.
- To assess the impact of this combination therapy on tumor growth, angiogenesis, and endothelial cell apoptosis in a preclinical model.
Main Methods:
- Human ovarian carcinoma cells (paclitaxel-sensitive and resistant) were implanted intraperitoneally in nude mice.
- Mice received control treatment, STI571 alone, paclitaxel alone, or combination therapy for 45 days.
- Tumor weight, PDGF-R activation, microvessel density, and cell proliferation were analyzed.
Main Results:
- Combination therapy significantly reduced tumor weight across all tested ovarian cancer cell lines compared to single-agent or control treatments.
- STI571 effectively blocked PDGF-R activation in tumor-associated endothelial cells.
- Combination therapy induced apoptosis in tumor-associated endothelial cells, decreasing microvessel density and tumor cell proliferation.
Conclusions:
- PDGF-R tyrosine kinase inhibitor combined with paclitaxel effectively impairs ovarian cancer progression in a murine model.
- The combination therapy functions by blocking PDGF signaling, a key endothelial cell survival factor, leading to increased endothelial cell apoptosis.
- This approach offers a potential therapeutic strategy for ovarian cancer by targeting tumor angiogenesis and endothelial cell survival.
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