Timed Ang2-Targeted Therapy Identifies the Angiopoietin-Tie Pathway as Key Regulator of Fatal Lymphogenous Metastasis.
Journal
Cancer discovery
ISSN: 2159-8290
Titre abrégé: Cancer Discov
Pays: United States
ID NLM: 101561693
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
30
01
2020
revised:
13
08
2020
accepted:
09
10
2020
pubmed:
28
10
2020
medline:
15
1
2022
entrez:
27
10
2020
Statut:
ppublish
Résumé
Recent clinical and preclinical advances have highlighted the existence of a previously hypothesized lymphogenous route of metastasis. However, due to a lack of suitable preclinical modeling tools, its contribution to long-term disease outcome and relevance for therapy remain controversial. Here, we established a genetically engineered mouse model (GEMM) fragment-based tumor model uniquely sustaining a functional network of intratumoral lymphatics that facilitates seeding of fatal peripheral metastases. Multiregimen survival studies and correlative patient data identified primary tumor-derived Angiopoietin-2 (Ang2) as a potent therapeutic target to restrict lymphogenous tumor cell dissemination. Mechanistically, tumor-associated lymphatic endothelial cells (EC), in contrast to blood vascular EC, were found to be critically addicted to the Angiopoietin-Tie pathway. Genetic manipulation experiments in combination with single-cell mapping revealed agonistically acting Ang2-Tie2 signaling as key regulator of lymphatic maintenance. Correspondingly, acute presurgical Ang2 neutralization was sufficient to prolong survival by regressing established intratumoral lymphatics, hence identifying a therapeutic regimen that warrants further clinical evaluation. SIGNIFICANCE: Exploiting multiple mouse tumor models including a unique GEMM-derived allograft system in combination with preclinical therapy designs closely matching the human situation, this study provides fundamental insight into the biology of tumor-associated lymphatic EC and defines an innovative presurgical therapeutic window of migrastatic Ang2 neutralization to restrict lymphogenous metastasis.
Identifiants
pubmed: 33106316
pii: 2159-8290.CD-20-0122
doi: 10.1158/2159-8290.CD-20-0122
doi:
Substances chimiques
Angiopoietin-2
0
Receptor, TIE-2
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
424-445Subventions
Organisme : European Research Council
ID : 787181
Pays : International
Informations de copyright
©2020 American Association for Cancer Research.
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