Angiocrine signals regulate quiescence and therapy resistance in bone metastasis.

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Title: Angiocrine signals regulate quiescence and therapy resistance in bone metastasis.
Authors: Singh, A
Veeriah, V
Xi, P
Labella, R
Chen, J
Romeo, SG
Ramasamy, SK
Kusumbe, AP
Item Type: Journal Article
Abstract: Bone provides supportive microenvironments for hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) and is a frequent site of metastasis. While incidences of bone metastases increase with age, the properties of the bone marrow microenvironment that regulate dormancy and reactivation of disseminated tumor cells (DTCs) remain poorly understood. Here, we elucidate the age-associated changes in the bone secretome that trigger proliferation of HSCs, MSCs, and DTCs in the aging bone marrow microenvironment. Remarkably, a bone-specific mechanism involving expansion of pericytes and induction of quiescence-promoting secretome rendered this proliferative microenvironment resistant to radiation and chemotherapy. This bone-specific expansion of pericytes was triggered by an increase in PDGF signaling via remodeling of specialized type H blood vessels in response to therapy. The decline in bone marrow pericytes upon aging provides an explanation for loss of quiescence and expansion of cancer cells in the aged bone marrow microenvironment. Manipulation of blood flow - specifically, reduced blood flow - inhibited pericyte expansion, regulated endothelial PDGF-B expression, and rendered bone metastatic cancer cells susceptible to radiation and chemotherapy. Thus, our study provides a framework to recognize bone marrow vascular niches in age-associated increases in metastasis and to target angiocrine signals in therapeutic strategies to manage bone metastasis.
Issue Date: 11-Jul-2019
Date of Acceptance: 24-May-2019
URI: http://hdl.handle.net/10044/1/71498
DOI: https://doi.org/10.1172/jci.insight.125679
ISSN: 2379-3708
Publisher: American Society for Clinical Investigation
Journal / Book Title: JCI Insight
Volume: 4
Issue: 13
Copyright Statement: © 2019 Singh et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Sponsor/Funder: Medical Research Council (MRC)
Wellcome Trust
Funder's Grant Number: PO#4050724483
202300/Z/16/Z
Keywords: Adult stem cells
Bone Biology
Bone marrow
Cancer
Vascular Biology
Adult stem cells
Bone Biology
Bone marrow
Cancer
Vascular Biology
Publication Status: Published online
Conference Place: United States
Open Access location: https://insight.jci.org/articles/view/125679
Online Publication Date: 2019-07-11
Appears in Collections:Clinical Sciences
Molecular Sciences



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