Journal
CELLULAR AND MOLECULAR LIFE SCIENCES
Volume 79, Issue 6, Pages -Publisher
SPRINGER BASEL AG
DOI: 10.1007/s00018-022-04262-w
Keywords
Pre-metastatic; Metastatic; Cervical cancer; Lymph node; Periostin
Categories
Funding
- Fonds de la Recherche Scientifique-FNRS (F.R.S.-FNRS, Belgium)
- Fondation Contre le Cancer (foundation of public interest, Belgium)
- Fonds Speciaux de la Recherche (University of Liege)
- Fondation Hospital Universitaire Leon Fredericq (FHULF, University of Liege)
- Walloon Region through the FRFS-WELBIO strategic research program
- Walinnov Immucan [1610119]
- Wallonia-Brussels Federation [A.R.C. 19/23-21]
- F. R.S.FNRS-Televie Grant
- Walloon Region grant Walinnov Immucan [1610119]
- FRFS-WELBIO
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This study revealed an association between POSTN deposition and lymphangiogenesis in lymph nodes of cervical cancer patients, highlighting the key role of POSTN in promoting lymphatic vessel formation and the seeding of metastatic cells.
Although lymph node (LN) metastasis is an important prognostic parameter in cervical cancer, the tissue remodeling at a pre-metastatic state is poorly documented in LNs. We here identified periostin (POSTN) as a component of non-metastatic LNs by applying proteomic analyses and computerized image quantifications on LNs of patients with cervical cancer. We provide evidence for remarkable modifications of POSTN and lymphatic vessel distributions and densities in non-metastatic sentinel and metastatic human LNs, when compared to distant non-metastatic LNs. POSTN deposition at a pre-metastatic stage was demonstrated in a pre-clinical murine model (the ear sponge assay). Its expression by fibroblastic LN cells was assessed by in situ hybridization and in vitro cultures. In vitro, POSTN promoted lymphatic endothelial cell functions and tumor cell proliferation. Accordingly, the in vivo injection of recombinant POSTN together with VEGF-C boosted the lymphangiogenic response, while the metastatic potential of tumor cells was drastically reduced using a POSTN blocking antibody. This translational study also supports the existence of an unprecedented dialog in cascade, between the primary tumor and the first pelvic nodal relay in early cervical cancer, and subsequently from pelvic LN to para-aortic LNs in locally advanced cervical cancers. Collectively, this work highlights the association of POSTN deposition with lymphangiogenesis in LNs, and provides evidence for a key contribution of POSTN in promoting VEGF-C driven lymphangiogenesis and the seeding of metastatic cells.
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