Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting
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Summary
This summary is machine-generated.Targeting cancer-associated fibroblasts in cervical cancer stroma with imatinib slowed tumor progression and reduced angiogenesis. This approach may complement conventional therapies for cervical carcinoma and other solid tumors.
Area Of Science
- Oncology
- Cancer Biology
- Tumor Microenvironment
Background
- Tumor stroma contains various cell types that support tumor growth, angiogenesis, and invasion.
- Cancer-associated fibroblasts (CAFs) are increasingly recognized as key functional participants within the tumor stroma.
- The prominent stroma in cervical carcinoma suggests altered, tumor-promoting functions.
Purpose Of The Study
- To investigate the therapeutic potential of targeting stromal support functions, specifically those of CAFs, in cervical cancer.
- To assess the role of platelet-derived growth factor (PDGF) receptor signaling in CAFs and pericytes within a pre-clinical cervical cancer model.
Main Methods
- Utilized a genetically engineered mouse model of cervical carcinogenesis.
- Investigated PDGF receptor signaling in CAFs and pericytes.
- Administered imatinib, a clinically approved kinase inhibitor, to block PDGF receptor signaling.
- Used neutralizing antibodies to PDGF receptors and a ligand trap for fibroblast growth factors (FGFs).
Main Results
- Pharmacological blockade of PDGF receptor signaling with imatinib slowed premalignant cervical lesion progression and impaired invasive carcinoma growth.
- Inhibition of stromal PDGF receptors reduced proliferation and angiogenesis by suppressing FGF-2 and FGF-7 expression in CAFs.
- Targeting PDGF or FGF signaling pathways demonstrated similar anti-tumor and anti-angiogenic effects.
Conclusions
- Mechanism-based targeting of the tumor stroma, particularly CAFs, demonstrated therapeutic benefits in a mouse model of human cervical cancer.
- Stromal targeting drugs may complement conventional cancer treatments for various solid tumors, including cervical carcinoma.
- This highlights a multicellular signaling network where epithelial-derived PDGF ligands stimulate stromal PDGFRs to up-regulate FGFs, promoting tumor growth and angiogenesis.