ABSTRACT
Breast cancer patients often develop locoregional or distant recurrence years after mastectomy. Understanding the mechanism of metastatic recurrence after dormancy is crucial for improving the cure rate for breast cancer. Here, we characterize a bone metastasis dormancy model to show that aberrant expression of vascular cell adhesion molecule 1 (VCAM-1), in part dependent on the activity of the NF-κB pathway, promotes the transition from indolent micrometastasis to overt metastasis. By interacting with the cognate receptor integrin α4ß1, VCAM-1 recruits monocytic osteoclast progenitors and elevates local osteoclast activity. Antibodies against VCAM-1 and integrin α4 effectively inhibit bone metastasis progression and preserve bone structure. These findings establish VCAM-1 as a promising target for the prevention and inhibition of metastatic recurrence in bone.
Subject(s)
Bone Neoplasms/secondary , Breast Neoplasms/pathology , Integrin alpha4beta1/metabolism , Osteoclasts/metabolism , Osteolysis/diagnostic imaging , Stem Cells/metabolism , Vascular Cell Adhesion Molecule-1/metabolism , Animals , Antibodies, Monoclonal/therapeutic use , Bone Neoplasms/metabolism , Bone Neoplasms/prevention & control , Breast Neoplasms/metabolism , Cell Adhesion , Cell Differentiation , Cell Line, Tumor , Cell Proliferation , Chemotaxis , Female , Humans , Integrin alpha4beta1/immunology , Mice , Mice, Inbred BALB C , Mice, Nude , Molecular Targeted Therapy , NF-kappa B/metabolism , Neoplasm Micrometastasis , Neoplasm Transplantation , Osteoclasts/pathology , Radiography , Stem Cells/pathology , Transplantation, Heterologous , Vascular Cell Adhesion Molecule-1/genetics , Vascular Cell Adhesion Molecule-1/immunologyABSTRACT
Mammary stem cells (MaSCs) play essential roles for the development of the mammary gland and its remodeling during pregnancy. However, the precise localization of MaSCs in the mammary gland and their regulation during pregnancy is unknown. Here we report a transgenic mouse model for luciferase-based single marker detection of MaSCs in vivo that we used to address these issues. Single transgene expressing mammary epithelial cells were shown to reconstitute mammary glands in vivo while immunohistochemical staining identified MaSCs in basal and luminal locations, with preponderance towards the basal position. By quantifying luciferase expression using bioluminescent imaging, we were able to track MaSCs non-invasively in individual mice over time. Using this model to monitor MaSC dynamics throughout pregnancy, we found that MaSCs expand in both total number and percentage during pregnancy and then drop down to or below baseline levels after weaning. However, in a second round of pregnancy, this expansion was not as extensive. These findings validate a powerful system for the analysis of MaSC dynamics in vivo, which will facilitate future characterization of MaSCs during mammary gland development and breast cancer.
