Related Experiment Video
Updated: Jan 20, 2026
Intra-Cardiac Injection of Human Prostate Cancer Cells to Create a Bone Metastasis Xenograft Mouse Model
Published on: November 4, 2022
Notch3 promotes prostate cancer-induced bone lesion development via MMP-3
Sourik S Ganguly1,2, Galen Hostetter3, Lin Tang2
1Program for Skeletal Disease and Tumor Microenvironment, Center for Cancer and Cell Biology, Grand Rapids, MI, USA.
Abstract:
Prostate cancer metastases primarily localize in the bone where they induce a unique osteoblastic response. Elevated Notch activity is associated with high-grade disease and metastasis. To address how Notch affects prostate cancer bone lesions, we manipulated Notch expression in mouse tibia xenografts and monitored tumor growth, lesion phenotype, and the bone microenvironment. Prostate cancer cell lines that induce mixed osteoblastic lesions in bone expressed 5-6 times more Notch3, than tumor cells that produce osteolytic lesions. Expression of active Notch3 (NICD3) in osteolytic tumors reduced osteolytic lesion area and enhanced osteoblastogenesis, while loss of Notch3 in osteoblastic tumors enhanced osteolytic lesion area and decreased osteoblastogensis. This was accompanied by a respective decrease and increase in the number of active osteoclasts and osteoblasts at the tumor-bone interface, without any effect on tumor proliferation. Conditioned medium from NICD3-expressing cells enhanced osteoblast differentiation and proliferation in vitro, while simultaneously inhibiting osteoclastogenesis. MMP-3 was specifically elevated and secreted by NICD3-expressing tumors, and inhibition of MMP-3 rescued the NICD3-induced osteoblastic phenotypes. Clinical osteoblastic bone metastasis samples had higher levels of Notch3 and MMP-3 compared with patient matched visceral metastases or osteolytic metastasis samples. We identified a Notch3-MMP-3 axis in human prostate cancer bone metastases that contributes to osteoblastic lesion formation by blocking osteoclast differentiation, while also contributing to osteoblastogenesis. These studies define a new role for Notch3 in manipulating the tumor microenvironment in bone metastases.
Insights
Notch3 signaling drives prostate cancer bone metastasis by promoting osteoblastic lesions. This pathway involves MMP-3, influencing both osteoblast and osteoclast activity in the bone microenvironment.
Area of Science:
- Oncology
- Bone Metastasis Research
- Molecular Biology
Background:
- Prostate cancer commonly metastasizes to bone, inducing osteoblastic lesions.
- Notch pathway activation correlates with high-grade prostate cancer and metastasis.
- The specific role of Notch in prostate cancer bone microenvironment modulation is unclear.
Purpose of the Study:
- To investigate the role of Notch signaling, specifically Notch3, in prostate cancer bone metastasis.
- To elucidate the mechanisms by which Notch3 influences the bone microenvironment, including osteoblast and osteoclast activity.
- To identify potential therapeutic targets within the Notch3 pathway for treating bone metastases.
Main Methods:
- Utilized mouse tibia xenograft models of prostate cancer bone metastasis.
- Manipulated Notch3 expression in prostate cancer cell lines and xenografts.
- Analyzed tumor growth, bone lesion phenotype, and the tumor-bone microenvironment.
- Assessed osteoblast and osteoclast activity in vitro and in vivo.
- Investigated the role of Matrix Metalloproteinase-3 (MMP-3) in the observed phenotypes.
Main Results:
- Prostate cancer cells inducing osteoblastic lesions showed significantly higher Notch3 expression than those causing osteolytic lesions.
- Activation of Notch3 (NICD3) in osteolytic tumors reduced osteolytic area and increased osteoblastogenesis, while Notch3 loss in osteoblastic tumors had opposite effects.
- Notch3 modulation altered osteoclast and osteoblast numbers at the tumor-bone interface without affecting tumor proliferation.
- NICD3-expressing cells promoted osteoblast differentiation/proliferation and inhibited osteoclastogenesis in vitro.
- Notch3-expressing tumors secreted elevated MMP-3, and MMP-3 inhibition reversed NICD3-induced osteoblastic phenotypes.
- Clinical osteoblastic bone metastases exhibited higher Notch3 and MMP-3 levels compared to visceral or osteolytic metastases.
Conclusions:
- A Notch3-MMP-3 axis is identified in prostate cancer bone metastases, driving osteoblastic lesion formation.
- Notch3 plays a critical role in modulating the bone microenvironment by inhibiting osteoclastogenesis and promoting osteoblastogenesis.
- This pathway represents a novel therapeutic target for managing prostate cancer bone metastases.
Related Concept Videos
06:32Intra-Cardiac Injection of Human Prostate Cancer Cells to Create a Bone Metastasis Xenograft Mouse Model
11:29miRNA Expression Analyses in Prostate Cancer Clinical Tissues
07:01Pre-clinical Orthotopic Murine Model of Human Prostate Cancer
07:21Establishment and Analysis of Three-Dimensional (3D) Organoids Derived from Patient Prostate Cancer Bone Metastasis Specimens and their Xenografts
11:07Focal Laser Ablation of Prostate Cancer: An Office Procedure
08:54Generation of Tumor Organoids from Genetically Engineered Mouse Models of Prostate Cancer