Decorin suppresses tumor lymphangiogenesis: A mechanism to curtail cancer progression

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Tumor growth involves complex interactions between cancer cells and the tumor stroma.
• Soluble bioactive molecules like proteoglycans modulate these tumor-host interactions.
• Decorin, a small leucine-rich proteoglycan, influences cancer progression by interacting with receptor tyrosine kinases (RTKs).

Purpose of the Study:

• To investigate the effect of systemically delivered decorin on tumor-associated gene expression, specifically focusing on lymphatic vessel development.
• To elucidate the mechanism by which decorin affects lymphangiogenesis and its potential as a therapeutic agent for breast cancer.

Main Methods:

• Deep RNA sequencing (RNAseq) was used for unbiased transcriptomic analysis in mice with breast carcinoma allografts.
• In vitro studies utilized a 3D model of lymphangiogenesis to assess decorin's effect on lymphatic vessel sprouting.
• Mechanistic studies involved investigating decorin's interaction with vascular endothelial growth factor receptor 3 (VEGFR3) and decorin-evoked autophagy.

Main Results:

• Decorin down-regulated genes involved in lymphatic vessel (LV) development, suppressing key markers like Lyve1 and Podoplanin at mRNA and protein levels.
• Systemic decorin administration significantly reduced tumor lymphatic vessel density.
• Soluble decorin inhibited LV sprouting ex vivo and this effect was dependent on its interaction with VEGFR3.
• Decorin induced the degradation of Lyve1 via autophagy.

Conclusions:

• Decorin exhibits significant antilymphangiogenic activity.
• Decorin's interaction with VEGFR3 is crucial for blocking lymphangiogenesis.
• Decorin presents a potential therapeutic strategy for inhibiting breast cancer growth and metastasis by targeting lymphatic vessel formation.