期刊
CELL REPORTS
卷 13, 期 12, 页码 2687-2698出版社
CELL PRESS
DOI: 10.1016/j.celrep.2015.12.004
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资金
- National Health and Medical Research Foundation (NHMRC) of Australia [APP1042446, APP1006636, 634304, APP1058073]
- Cancer Council of Western Australia
- Royal Perth Hospital Medical Research Foundation
- National Health and Medical Research Council of Australia [634304] Funding Source: NHMRC
Normalization of the tumor vasculature is an emerging concept shown to improve anti-cancer therapy. However, there are currently no clinical interventions that effect long-lasting normalization. Here, we have developed a strategy for normalization by specific intratumoral delivery of LIGHT/TNFSF14. Importantly, normalization occurs by induced expression of contractile markers in intratumoral pericytes, which in turn re-establishes tight pericyte-vessel alignment. Restoring vessel integrity improves tumor perfusion and acts as adjuvant to chemo-and immunotherapy. Mechanistically, intratumoral LIGHT induces pericyte differentiation and normalization via Rho kinase signaling. Minute amounts of LIGHT act in a paracrine fashion to trigger an amplifying cascade involving transforming growth factor beta (TGF-beta) from peri-vascular macrophages. That these effects can be reproduced by adoptive transfer of LIGHT-stimulated macrophages alone demonstrates their central role in regulating pericyte differentiation. Our findings highlight a crucial role of pericyte contractile properties in vascular normalization, effected by macrophage signaling, thus providing so far unexplored anti-cancer opportunities.
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