Abstract
IntroductionIn a cancer-free environment in the adult, the skeleton continuously undergoes remodeling. Bone-resorbing osteoclasts excavate erosion cavities, and bone-depositing osteoblasts synthesize osteoid matrix that forms new bone, with no net bone gain or loss. When metastatic breast cancer cells invade the bone, this balance is disrupted. Patients with bone metastatic breast cancer frequently suffer from osteolytic bone lesions that elicit severe bone pain and fractures. Bisphosphonate treatments are not curative. Under ideal circumstances, osteoblasts would synthesize new matrix to fill in erosion cavities caused by osteoclasts, but this is not what occurs. Our prior evidence demonstrated that osteoblasts are diverted from laying down bone matrix to producing cytokines that facilitate breast cancer cell maintenance in late-stage disease. Here, we have new evidence to suggest that there are subpopulations of osteoblasts in the tumor niche as evidenced by their protein marker expression that have distinct roles in tumor progression in the bone.MethodsTumor-bearing tibia of mice was interrogated by immunofluorescent staining for the presence of osteoblasts and alterations in niche protein expression. De-identified tissue from patients with bone metastatic breast cancer was analyzed for osteoblast subpopulations via multi-plex immunofluorescent staining. Effects of breast cancer cells on osteoblasts were recapitulated in vitro by osteoblast exposure to breast cancer-conditioned medium. Triple-negative and estrogen receptor-positive breast cancer proliferation, cell cycle, and p21 expression were assessed upon contact with āeducatedā osteoblasts.ResultsA subpopulation of osteoblasts was identified in the bone tumor microenvironment in vivo of both humans and mice with bone metastatic breast cancer that express RUNX2/OCN/OPN but is negative for IL-6 and alpha-smooth muscle actin. These tumor āeducatedā osteoblasts (EOs) have altered properties compared to āuneducatedā osteoblasts and suppress both triple-negative and estrogen receptor-positive breast cancer cell proliferation and increase cancer cell p21 expression. EO effects on breast cancer proliferation were mediated by NOV and decorin. Importantly, the presence of EO cells in the tibia of mice bearing tumors led to increased amounts of alkaline phosphatase and suppressed the expression of inflammatory cytokines in vivo.ConclusionsOur work reveals that there is a subpopulation of osteoblasts in the bone tumor microenvironment that demonstrate a functional role in retarding breast cancer cell growth.
Highlights
In a cancer-free environment in the adult, the skeleton continuously undergoes remodeling
Our work reveals that there is a subpopulation of osteoblasts in the bone tumor microenvironment that demonstrate a functional role in retarding breast cancer cell growth
Using an intratibial model of bone metastasis, we showed that the inflammatory cytokine IL-6 as well as matrix remodeling factors Matrix metalloproteinase 3 (MMP3) and type I collagen were reduced in the endosteal and hematopoietic niches of the tibia with tumors composed of an admix of Educated osteoblast (EO) plus triple-negative breast cancer cells, as compared to admixes of āuneducatedā osteoblasts plus triple-negative breast cancer cells, or triple-negative breast cancer cells injected alone
Summary
In a cancer-free environment in the adult, the skeleton continuously undergoes remodeling. Boneresorbing osteoclasts excavate erosion cavities, and bone-depositing osteoblasts synthesize osteoid matrix that forms new bone, with no net bone gain or loss. Bone-resorbing osteoclasts excavate erosion cavities and bone-depositing osteoblasts synthesize matrix to form new bone, with no net bone loss or gain. Exceptions to these circumstances include (1) bone loss as a result of aging and osteoporosis [2, 3], (2) bone loss as a result of lack of physical activity or exercise [4,5,6], and (3) perturbation of normal bone remodeling by cancer bone metastases [7,8,9,10]. One study identified the bone-specific transcriptional regulator RUNX2 as a key factor in events associated with osteoblastic lesions [16]
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