Article ; Online: Decorin suppresses tumor lymphangiogenesis: A mechanism to curtail cancer progression.
Proceedings of the National Academy of Sciences of the United States of America
2024 Volume 121, Issue 18, Page(s) e2317760121
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 ... ...
| 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. |
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| MeSH term(s) | Decorin/metabolism ; Decorin/genetics ; Lymphangiogenesis ; Animals ; Mice ; Humans ; Female ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Breast Neoplasms/genetics ; Lymphatic Vessels/metabolism ; Lymphatic Vessels/pathology ; Cell Line, Tumor ; Disease Progression ; Vesicular Transport Proteins/metabolism ; Vesicular Transport Proteins/genetics ; Membrane Glycoproteins/metabolism ; Membrane Glycoproteins/genetics ; Gene Expression Regulation, Neoplastic |
| Chemical Substances | Decorin ; Vesicular Transport Proteins ; Membrane Glycoproteins ; Dcn protein, mouse ; DCN protein, human |
| Language | English |
| Publishing date | 2024-04-23 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural |
| ZDB-ID | 209104-5 |
| ISSN | 1091-6490 ; 0027-8424 |
| ISSN (online) | 1091-6490 |
| ISSN | 0027-8424 |
| DOI | 10.1073/pnas.2317760121 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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