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?2ARs stimulation in osteoblasts promotes breast cancer cell adhesion to bone marrow endothelial cells in an IL-1? 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 ?AR 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 ?AR 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-1?) 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-1?, but not IL-6, reduced this effect. Direct IL-1? 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 ?AR 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.

SUBMITTER: Clement-Demange L

PROVIDER: S-EPMC6146568 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Clément-Demange Lise L Mulcrone Patrick L PL Tabarestani Troy Q TQ Sterling Julie A JA Elefteriou Florent F

Journal of bone oncology 20180908

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 β ...[more]

PMID: 30245970

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Project description:Lung cancer is a severe disease threatening human health worldwide. Distant hematogenous metastasis results in poor prognosis and death of lung cancer patients. In the present study, we investigated the effect of circulatory platelets (PLTs) on hematogenous metastasis of non-small cell lung carcinoma (NSCLC). Laser scanning confocal microscopy was employed to assay the expression of P-selectin in lung cancer tissue, paracancerous tissue and distant tissue, respectively. Meanwhile, fluorescence-activated cell sorting (FACS) was used to determine P-selectin activation in peripheral blood. Purified PLTs were co-cultured with A549 cells and human vascular endothelial cells (HuvECs). Subsequently, the formation of PLT-lung cancer cell complexes and their effects on rolling and adhesion of A549 on the surface of vascular endothelium were assayed. Integrin ?3, ?5, ?1, ICAM-1 and VCAM-1 mRNAs and proteins were measured by reverse RT-PCR and western blot analysis, respectively. The expression of P-selectin in lung adenocarcinoma tissue was significantly stronger compared to that in paracancerous and distant tissues. P-selectin activation in peripheral blood in lung adenocarcinoma was markedly enhanced. The rolling rate of A549 on HuvECs was significantly slowed down after co-culture of activated PLTs and A549 cells. The mRNA and protein levels of integrin ?3, ?5, ?1, ICAM-1 and VCAM-1 were significantly increased after the co-culture. In conclusion, the PLT-lung cancer cell complexes protected the lung cancer cells from mechanical injury under blood flow. Furthermore, up-regulated integrin ?3, ?5, ?1 and endothelial cell adhesion molecules ICAM-1 and VCAM-1 promoted the adhesion of A549 on vascular endothelial cells, which may be responsible for hematogenous metastasis of lung cancer.

Dataset Information

?2ARs stimulation in osteoblasts promotes breast cancer cell adhesion to bone marrow endothelial cells in an IL-1? and selectin-dependent manner.

Publications

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

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