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Potential Role of PDGFRβ-Associated THBS4 in Colorectal Cancer Development
Min Seob Kim1, Hyun Seok Choi1, Moxin Wu1
1Department of Physiology, Digestive Disease Research Institute, and Institute of Wonkwang Medical Science, School of Medicine, Wonkwang University, Iksan 54538, Korea.
Cancers
|September 9, 2020
Summary
Colorectal cancer progression involves tumor microenvironment factors like Thrombospondin-4 (THBS4). Increased Platelet-derived growth factor receptor β (PDGFRβ) signaling, driven by TGFβ and PDGF-D, promotes THBS4 secretion and tumor cell proliferation.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Colorectal cancer (CRC) is a leading cause of cancer death, often metastasizing to distant organs.
- The tumor microenvironment (TME) significantly influences CRC growth, invasion, and metastasis.
- Extracellular matrix proteins like Thrombospondin-4 (THBS4) and signaling pathways, including transforming growth factor-β (TGFβ) and Platelet-derived growth factor receptor β (PDGFRβ), are implicated in CRC progression.
Purpose of the Study:
- To investigate the role of THBS4 and PDGFRβ in colorectal cancer progression.
- To elucidate the signaling mechanisms underlying THBS4 regulation in CRC.
- To determine the impact of THBS4 on colon myofibroblast behavior in the TME.
Main Methods:
- Analysis of PDGFRβ and THBS4 expression in colorectal tumor tissues.
- Stimulation of colon cancer cell line DLD-1 with TGFβ and PDGF-D to assess THBS4 expression and secretion.
- Inhibition studies using blockers for PDGFRβ, inositol 1,4,5-triphosphate receptor (IP3R), and stromal interaction molecule 1 (STIM1).
- Assessment of conditioned medium from PDGF-D-stimulated DLD-1 cells on colon myofibroblast (CCD-18co) adhesion, migration, and proliferation.
Main Results:
- PDGFRβ and THBS4 were overexpressed in colorectal tumor tissues.
- TGFβ and PDGF-D increased THBS4 protein levels and secretion in DLD-1 cells, without altering THBS4 mRNA levels.
- The PDGFRβ, IP3R, STIM1, and Ca2+ signaling pathway was implicated in THBS4 secretion.
- PDGF-D-stimulated conditioned medium promoted colon myofibroblast adhesion, migration, and proliferation, an effect enhanced by thrombin.
Conclusions:
- Overexpression of PDGFRβ and THBS4 is associated with colorectal cancer.
- TGFβ and PDGF-D signaling pathways contribute to THBS4 over-secretion via post-transcriptional modification.
- The PDGFRβ/THBS4 axis promotes tumor microenvironment-mediated proliferation and invasion in colorectal cancer.
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