Overexpression of Lrp5 enhanced the anti-breast cancer effects of osteocytes in bone
Open Access
- 6 July 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Bone Research
- Vol. 9 (1), 1-13
- https://doi.org/10.1038/s41413-021-00152-2
Abstract
Osteocytes are the most abundant cells in bone, which is a frequent site of breast cancer metastasis. Here, we focused on Wnt signaling and evaluated tumor-osteocyte interactions. In animal experiments, mammary tumor cells were inoculated into the mammary fat pad and tibia. The role of Lrp5-mediated Wnt signaling was examined by overexpressing and silencing Lrp5 in osteocytes and establishing a conditional knockout mouse model. The results revealed that administration of osteocytes or their conditioned medium (CM) inhibited tumor progression and osteolysis. Osteocytes overexpressing Lrp5 or β-catenin displayed strikingly elevated tumor-suppressive activity, accompanied by downregulation of tumor-promoting chemokines and upregulation of apoptosis-inducing and tumor-suppressing proteins such as p53. The antitumor effect was also observed with osteocyte-derived CM that was pretreated with a Wnt-activating compound. Notably, silencing Lrp5 in tumors inhibited tumor progression, while silencing Lrp5 in osteocytes in conditional knockout mice promoted tumor progression. Osteocytes exhibited elevated Lrp5 expression in response to tumor cells, implying that osteocytes protect bone through canonical Wnt signaling. Thus, our results suggest that the Lrp5/β-catenin axis activates tumor-promoting signaling in tumor cells but tumor-suppressive signaling in osteocytes. We envision that osteocytes with Wnt activation potentially offer a novel cell-based therapy for breast cancer and osteolytic bone metastasis.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR52144)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (R03CA238555, R01AR053237)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute
- School of Medicine, Indiana University
This publication has 45 references indexed in Scilit:
- Knee loading reduces MMP13 activity in the mouse cartilageBMC Musculoskeletal Disorders, 2013
- RUNX2 in mammary gland development and breast cancerJournal of Cellular Physiology, 2013
- Breast tumor-associated osteoblast-derived CXCL5 increases cancer progression by ERK/MSK1/Elk-1/Snail signaling pathwayOncogene, 2012
- Constitutively Activated NLRP3 Inflammasome Causes Inflammation and Abnormal Skeletal Development in MicePLOS ONE, 2012
- Inhibition of Collagen Receptor Discoidin Domain Receptor-1 (DDR1) Reduces Cell Survival, Homing, and Colonization in Lung Cancer Bone MetastasisClinical Cancer Research, 2012
- TGF-β in the Bone Microenvironment: Role in Breast Cancer MetastasesCancer Microenvironment, 2011
- PC3 is a cell line characteristic of prostatic small cell carcinomaThe Prostate, 2011
- Wnt/β-Catenin Signaling: Components, Mechanisms, and DiseasesDevelopmental Cell, 2009
- The Regulation of Exosome Secretion: a Novel Function of the p53 ProteinCancer Research, 2006
- Breast cancer metastasis: markers and modelsNature Reviews Cancer, 2005