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Timed Ang2-Targeted Therapy Identifies the Angiopoietin–Tie Pathway as Key Regulator of Fatal Lymphogenous Metastasis
- Source :
- Cancer Discovery. 11:424-445
- Publication Year :
- 2021
- Publisher :
- American Association for Cancer Research (AACR), 2021.
-
Abstract
- 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. This article is highlighted in the In This Issue feature, p. 211
- Subjects :
- 0301 basic medicine
Lung Neoplasms
medicine.medical_treatment
government.form_of_government
Regulator
Mice, Transgenic
Mice, SCID
Metastasis
Targeted therapy
Angiopoietin-2
Functional networks
Angiopoietin
Mice
03 medical and health sciences
0302 clinical medicine
medicine
Animals
Humans
ddc:610
business.industry
Endothelial Cells
medicine.disease
Receptor, TIE-2
Mice, Inbred C57BL
Disease Models, Animal
Lymphatic Endothelium
030104 developmental biology
Lymphatic system
Oncology
Lymphatic Metastasis
030220 oncology & carcinogenesis
Genetically Engineered Mouse
Cancer research
government
Female
business
Signal Transduction
Subjects
Details
- ISSN :
- 21598290 and 21598274
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Cancer Discovery
- Accession number :
- edsair.doi.dedup.....de14f320028966a213ccc58b74769674
- Full Text :
- https://doi.org/10.1158/2159-8290.cd-20-0122