Angiocrine signals regulate quiescence and therapy resistance in bone metastasis
Amit Singh, Vimal Veeriah, Pengjun Xi, Rossella Labella, Junyu Chen, Sara G. Romeo, Saravana K. Ramasamy, Anjali P. Kusumbe
Amit Singh, Vimal Veeriah, Pengjun Xi, Rossella Labella, Junyu Chen, Sara G. Romeo, Saravana K. Ramasamy, Anjali P. Kusumbe
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Research Article Bone biology Vascular biology

Angiocrine signals regulate quiescence and therapy resistance in bone metastasis

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.

Authors

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

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Figure 6

Radiation and chemotherapy drive bone-specific expansion of the pericytes.

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Radiation and chemotherapy drive bone-specific expansion of the pericyte...
(A) Representative tile scan confocal images show PDGFRβ + α-SMA (green) and endomucin (Emcn; red) immunostaining on thick sections (150 μm) of young tibia exposed to radiotherapy or control mouse tibia; nuclei, TO-PRO-3 (blue). The dotted lines mark the growth plate (gp) or endosteum (es). mp, metaphysis; dp, diaphysis. Scale bars: 400 μm. (B) Confocal images with PDGFRβ (white), CD31 (green), and endomucin (red) immunostaining on thick sections from young tibia and from aged tibia either control or exposed to radiation. Scale bars: 50 μm. (C) Representative confocal 3D images with α-SMA (white), CD31 (green), and endomucin (red) immunostaining on sections of young tibia from control and irradiated mice, i.e., metaphysis or growth plate. Scale bars: 50 μm. (D) Representative 3D confocal images with α-SMA (white) and endomucin (red) immunostaining on a young tibia with bone metastasis 19 days after intracardiac injection of MDA-MB-231-GFP cells. cb, compact bone. Scale bars: 70 μm. (E) Tile scan (left panel) confocal images show α-SMA (white) and endomucin (red) immunostaining in a young, 10-week-old tibia with bone metastasis 3-weeks after intracardiac injection of MDA-MB-231-GFP cells. Arrows highlight the isolated single MDA-MB-231-GFP cells attached to an α-SMA artery. Scale bars: 400 μm (left), 100 μm (center), 50 μm (right). (F) Distribution of quiescent MDA-MB-231-GFP cells in tibial bone sections from young mice. Seventy-nine dormant cells were analyzed and quantified from 3 mice. (G) Confocal images show PDGFRβ (white), endomucin (red), and CD31 (green) immunostaining on young, 7-week-old tibiae from control, radiation-treated, and radiation + sunitinib malate–treated (SM) groups. The dotted lines mark the growth plate. Scale bars: 70 μm. (H) FACS quantification of pericytes (CD31–CD45–Ter119–PDGFRβ+) in a single-cell suspension of long bones from radiation-treated, radiation + sunitinib malate–treated, and control young mice. Data represent mean ± SD (n = 6 replicates); 1-way ANOVA with Tukey’s multiple-comparisons test. (I) FACS quantification of pericytes (CD31–CD45–Ter119–PDGFRβ+) in a single-cell suspension of tibiae from carboplatin-treated, carboplatin + sunitinib malate–treated, and control mice. Data represent mean ± SD (n = 7 replicates); 1-way ANOVA with Tukey’s multiple-comparisons test. Representative images were derived from 3 independent experiments. ***P < 0.001, ****P < 0.0001.