Document Type
Article
Publication Date
4-30-2024
Abstract
The complex interplay between malignant cells and the cellular and molecular components of the tumor stroma is a key aspect of cancer growth and development. These tumor-host interactions are often affected by soluble bioactive molecules such as proteoglycans. Decorin, an archetypical small leucine-rich proteoglycan primarily expressed by stromal cells, affects cancer growth in its soluble form by interacting with several receptor tyrosine kinases (RTK). Overall, decorin leads to a context-dependent and protracted cessation of oncogenic RTK activity by attenuating their ability to drive a prosurvival program and to sustain a proangiogenic network. Through an unbiased transcriptomic analysis using deep RNAseq, we identified that decorin down-regulated a cluster of tumor-associated genes involved in lymphatic vessel (LV) development when systemically delivered to mice harboring breast carcinoma allografts. We found that Lyve1 and Podoplanin, two established markers of LVs, were markedly suppressed at both the mRNA and protein levels, and this suppression correlated with a significant reduction in tumor LVs. We further identified that soluble decorin, but not its homologous proteoglycan biglycan, inhibited LV sprouting in an ex vivo 3D model of lymphangiogenesis. Mechanistically, we found that decorin interacted with vascular endothelial growth factor receptor 3 (VEGFR3), the main lymphatic RTK, and its activity was required for the decorin-mediated block of lymphangiogenesis. Finally, we identified that Lyve1 was in part degraded via decorin-evoked autophagy in a nutrient- and energy-independent manner. These findings implicate decorin as a biological factor with antilymphangiogenic activity and provide a potential therapeutic agent for curtailing breast cancer growth and metastasis.
Recommended Citation
Mondal, Dipon K.; Xie, Christopher; Pascal, Gabriel J.; Buraschi, Simone; and Iozzo, Renato V., "Decorin Suppresses Tumor Lymphangiogenesis: A Mechanism to Curtail Cancer Progression" (2024). Kimmel Cancer Center Faculty Papers. Paper 123.
https://jdc.jefferson.edu/kimmelccfp/123
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
PubMed ID
38652741
Language
English
Included in
Cancer Biology Commons, Neoplasms Commons, Therapeutics Commons
Comments
This article is the author's final published version in Proceedings of the National Academy of Sciences of the United States of America, Volume 121, Issue 18, April 2024, Pages e2317760121.
The published version is available at https://doi.org/10.1073/pnas.2317760121.
Copyright © 2024 the Author(s).