Angiocrine signals regulate quiescence and therapy resistance in bone metastasis.

Amit Singh,Rossella Labella,Anjali P Kusumbe,Pengjun Xi,Saravana K Ramasamy,Junyu Chen,Vimal Veeriah,Sara G Romeo

doi:10.1172/jci.insight.125679

Amit Singh, Rossella Labella + Show 6 more

Open Access

https://doi.org/10.1172/jci.insight.125679

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Journal: JCI insight	Publication Date: Jul 11, 2019
Citations: 59	License type: CC BY 4.0

Affiliation: University of Oxford

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.

Highlights

In addition to supplying oxygen and nutrients, the vasculature provides a number of inductive factors and signals, so-called angiocrine signals, to regulate tissue functions
In line with the previous reports, we found that the CD150+CD48–Lin–Sca-1+c-Kit+ Hematopoietic stem cells (HSCs) fraction increased in aged mice as compared with their young counterparts
We found that age-dependent changes in cell-extrinsic factors, secretory factors, promote disseminated tumor cells (DTCs) proliferation while inhibiting the quiescence of stem and cancer cells in bone

Summary

Introduction

In addition to supplying oxygen and nutrients, the vasculature provides a number of inductive factors and signals, so-called angiocrine signals, to regulate tissue functions. Blood vessels play a central role in the maintenance of microenvironment required for regulating osteogenesis and hematopoiesis [1,2,3,4,5,6,7]. Blood vessels regulate aging of the hematopoietic and skeletal systems. Skeletal aging is associated with the decline in tissue homeostasis, decreased osteogenesis, and altered hematopoiesis [8,9,10]. Hematopoietic stem cells (HSCs) exhibit age-associated structural and functional alterations that involve skewing toward myeloid lineage and loss of reconstitution potential [11,12,13]. Bone marrow (BM) mesenchymal stem cells (MSCs) are thought to undergo age-related changes and exhibit a bias toward an adipogenic lineage [14, 15]. The contribution of cell-extrinsic signals and the impact of the BM microenvironment toward stem cell aging and quiescence remain poorly understood [18,19,20]

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