β2ARs stimulation in osteoblasts promotes breast cancer cell adhesion to bone marrow endothelial cells in an IL-1β and selectin-dependent manner

Abstract

Progression and recurrence of breast cancer, as well as reduced survival of patients with breast cancer, are associated with chronic stress, a condition known to impact the hypothalamic-pituitary axis and the autonomic nervous system. Preclinical and clinical evidence support the involvement of the sympathetic nervous system in the control of bone remodeling and in pathologies of the skeleton, including bone metastasis. In experimental mouse models of skeletal metastasis, administration of the βAR agonist isoproterenol (ISO), used as a surrogate of norepinephrine, the main neurotransmitter of sympathetic neurons, was shown to favor bone colonization of metastatic breast cancer cells via an increase bone marrow vascularity. However, successful extravasation of cancer cells into a distant organ is known to be favored by an activated endothelium, itself stimulated by inflammatory signals. Based on the known association between high sympathetic outflow, the expression of inflammatory cytokines and bone metastasis, we thus asked whether βAR stimulation in osteoblasts may alter the vascular endothelium to favor cancer cell engraftment within the skeleton. To address this question, we used conditioned medium (CM) from PBS or ISO-treated bone marrow stromal cells (BMSCs) in adhesion assays with bone marrow endothelial cells (BMECs) or the endothelial cell line C166. We found that ISO treatment in differentiated BMSCs led to a robust induction of the pro-inflammatory cytokines interleukin-1 beta (IL-1β) and interleukin-6 (IL-6). The CM from ISO-treated BMSCs increased the expression of E- and P-selectin in BMECs and the adhesion of human MDA-MB-231 breast cancer cells to these cells in short-term static and dynamic adhesion assays, and a blocking antibody against IL-1β, but not IL-6, reduced this effect. Direct IL-1β treatment of BMECs had a similar effect, whereas the impact of IL-6 treatment on the expression of adhesion molecules by BMECs and on the adhesion of cancer cells to BMECs was negligible. Collectively, these in vitro results suggest that in the context of the multicellular and dynamic bone marrow environment, sympathetic activation and subsequent βAR stimulation in osteoblasts may profoundly remodel the density but also the activation status of bone marrow vessels to favor the skeletal engraftment of circulating breast cancer cells.

Nerves in Bone: Evolving Concepts in Pain and Anabolism

“…In the context of cancer, both progression and metastasis are associated with chronic stress, a condition that stimulates sympathetic outflow . In bone metastasis, sympathetic signaling via activation of β 2 ‐AR on osteoblasts leads directly to cancer cell recruitment and indirectly to vascular changes that promote colonization of metastatic cancer cells in the bone marrow . Last, NE uptake by bone and immune cells may also contribute to extraneuronal control of local NE homeostasis and actions on the skeleton …”

“…(120)(121)(122) In bone metastasis, sympathetic signaling via activation of β 2 -AR on osteoblasts leads directly to cancer cell recruitment and indirectly to vascular changes that promote colonization of metastatic cancer cells in the bone marrow. (121,123,124) Last, NE uptake by bone and immune cells may also contribute to extraneuronal control of local NE homeostasis and actions on the skeleton. (56,125,126) NPY NPY is the most abundant neuropeptide in the mammalian CNS and is also released from peripheral sympathetic nerves with NE.…”

Effects of VEGFR1+ hematopoietic progenitor cells on pre-metastatic niche formation and in vivo metastasis of breast cancer cells

“…Over the past decade, increasing evidence supports that circulating tumor cells from primary tumor can regulate the microenvironment of target organs and improve the seeding efficiency of incoming tumor cells via the formation of pre-metastatic niches (Clément-Demange et al 2018 ; Xu et al 2018 ). A pioneering study by Kaplan et al defined the pre-metastatic niche and explored its temporal and functional relationship to metastasis.…”

Osteocyte Vegf-a contributes to myeloma-associated angiogenesis and is regulated by Fgf23

“…An in vivo MM study in mice lacking Vegf-a strictly in Ocys could demonstrate how the absence of this Vegf-a pool affects MM growth and development, potentially through a Notch signaling mechanism that is beyond the scope of the current study. It is also known that tumor cells exhibit close interactions with endothelium via adhesion protein interactions 40,62 . It is unclear whether Ocys can alter the adhesion profile of either MM or endothelial cells to promote seeding and growth.…”