Abstract
Abstract Breast cancer frequently metastasizes to bone where it causes osteolytic lesions. Once colonization of bone occurs, an interconnected series of interactions between breast cancer cells and those of the bone microenvironment result in uncontrolled tumor growth. These interactions have been collectively interpreted in terms of the “vicious cycle of bone metastasis”. According to this paradigm, cancer cells secrete pro-inflammatory factors that lead to osteoclast (OC, bone resorbing cells) activation, through intermediary stimulation of osteoblasts (OB, bone building cells). OBs increase production of inflammatory cytokines, which further stimulates OC to differentiate into mature OC that actively resorb bone leading to severe osteopathologies. A complete understanding of cancer in bone thus requires a full appreciation of a network of biochemical signaling occurring between OB, OC and the breast cancer cells at tissue and cellular levels. We hypothesize that breast cancer interaction with the bone microenvironment, simulating a vicious cycle model can be developed in a 3D in vitro bioreactor system. This vicious cycle model would enable further characterization and manipulation of the interactions among the three cell types. A novel bioreactor, based on the principle of simultaneous growth and dialysis, designed and developed in our laboratory, was used to study this three-way interaction between OB, OC and breast cancer cells. We created an in vitro ‘bone-remodeling’ mimic to which metastatic cancer cells can be added and monitored over time. We have been able to differentiate OCs from hematopoietic progenitor cells isolated from murine bone marrow. The pre-osteoclasts cells when introduced onto the OB (MC3T3-E1) tissue grown in the bioreactor, differentiated to form multinucleated bone resorbing OCs. The OCs, positive for TRAP and actin ring staining; digested the OB matrix. From an initial inoculum of 75×104 pre-OCs, the bioreactor cultures yielded a recovery of approximately 2% mature OCs. Re-infusing this co-culture system with pre-OBs resulted in re-filling of OC degraded matrix with proliferating OBs. When metastatic breast cancer cells (MDA-MB-231GFP) were introduced into the OB-OC co-culture, the breast cancer cells migrated towards sites of active remodeling and clustered as an aggregation of cells that further degraded the OB matrix, an observation similar to that described for an in vivo scenario. This 3D in-vitro cell culture system mimicking the vicious cycle of bone metastases will help to further understand the cellular and molecular events that lead to successful breast cancer colonization of bone. Positive outcomes of the work will help clarify the etiology of metastasis but also create a much-needed in vitro tool for study of cancer therapeutics. This work was supported by US Army Medical and Materiel Command Breast Cancer Idea Program (W81XWH-06-1-0432). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4279. doi:10.1158/1538-7445.AM2011-4279
Published Version
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