Format:
22
ISSN:
2159-8290
Content:
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
Note:
Gesehen am 03.05.2021
,
Published online first October 26, 2020
In:
Cancer discovery, Philadelphia, Pa. : [Verlag nicht ermittelbar], 2011, 11(2021), 2, Seite 424-445, 2159-8290
In:
volume:11
In:
year:2021
In:
number:2
In:
pages:424-445
In:
extent:22
Language:
English
DOI:
10.1158/2159-8290.CD-20-0122
URL:
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