Therapeutic targeting of soluble CD146/MCAM with the M2J-1 monoclonal antibody prevents metastasis development and procoagulant activity in CD146-positive invasive tumors.
Animals
Antibodies, Monoclonal
/ pharmacology
Antineoplastic Agents, Immunological
/ pharmacology
Blood Coagulation
/ drug effects
CD146 Antigen
/ antagonists & inhibitors
Cell Line, Tumor
Epithelial-Mesenchymal Transition
/ drug effects
Female
Humans
Melanoma
/ blood
Mice
Neoplasm Invasiveness
/ prevention & control
Neoplastic Stem Cells
/ drug effects
Ovarian Neoplasms
/ blood
Signal Transduction
/ drug effects
Skin Neoplasms
/ blood
Thromboembolism
/ etiology
Xenograft Model Antitumor Assays
CD146
EMT
antibody
metastasis
procoagulant state
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
15 09 2020
15 09 2020
Historique:
received:
15
10
2019
revised:
20
12
2019
accepted:
22
01
2020
pubmed:
6
2
2020
medline:
15
4
2021
entrez:
6
2
2020
Statut:
ppublish
Résumé
Initially discovered in human melanoma, CD146/MCAM is expressed on many tumors and is correlated with cancer progression and metastasis. However, targeting CD146 remains challenging since it is also expressed on other cell types, as vessel cells, where it displays important physiological functions. We previously demonstrated that CD146 is shed as a soluble form (sCD146) that vectorizes the effects of membrane CD146 on tumor angiogenesis, growth and survival. We thus generated a novel monoclonal antibody, the M2J-1 mAb, which specifically targets sCD146, but not membrane CD146, and counteracts these effects. In our study, we analyzed the effects of sCD146 on the dissemination and the associated procoagulant phenotype in two highly invasive human CD146-positive cancer cell lines (ovarian and melanoma). Results show that sCD146 induced epithelial to mesenchymal transition, favored the generation of cancer stem cells and increased the membrane expression of tissue factor. Treatment of cancer cells with sCD146 in two experimental models (subcutaneous xenografting and intracardiac injection of cancer cells in nude mice) led to increased tumor dissemination and procoagulant activity. The M2J-1 mAb drastically reduced metastasis but also procoagulant activity, in particular by decreasing the number of circulating tumor microparticles, and blocked the relevant signaling pathways as demonstrated by RNA expression profiling experiments. Thus, our findings demonstrate that sCD146 mediates important pro-metastatic and procoagulant effects in two CD146-positive tumors. Targeting sCD146 with the newly generated M2J-1 mAb could constitute an innovative strategy for preventing dissemination and thromboembolism in many CD146-positive tumors.
Substances chimiques
Antibodies, Monoclonal
0
Antineoplastic Agents, Immunological
0
CD146 Antigen
0
MCAM protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1666-1679Informations de copyright
© 2020 UICC.
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