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Elucidating the contribution of bone to breast cancer metastasis using an engineered bone scaffold
Tumor Cell Biology II
a) Background: While important advances have been made in the treatment of breast cancer (BrCa), little progress has been made in developing therapies for metastasis to bone, a complication which signals entry of the disease into an incurable phase. The process of identifying genes and gene signatures of BrCa associated with metastasis has begun. In contrast, knowledge of the contributions of bone to tumor--stroma interaction is rudimentary. Elucidation of the mechanisms on the bone-side of tumor--stroma interactions should provide novel insights that could translate into new metastasis-specific therapies. b) Objectives/Hypothesis: The tumor--stroma interaction for BrCa and bone is based on mutual recognition. By using tissue-engineered human bone (which can be manipulated in controlled fashion) in an "all-human" mouse model that recapitulates the steps of BrCa metastasis from breast to bone, we will be able to identify the components within bone that enable it to serve as a BrCa target. We also hypothesize that BrCa induces changes, such as gene expression, in bone stroma that support metastases. By isolating bone stromal cells exposed to metastatic BrCa cells, we can identify the critical (osteotropism) genes in bone up- and down-regulated as a result of tumor--stroma interactions. c) Specific Aim 1: Identify the essential components (cells, growth factors, matrix proteins, etc.) within bone that enable it to serve as a target for BrCa cells and as a supportive microenvironment for BrCa proliferation. d) Specific Aim 2: Identify changes in gene expression in human bone stromal cells resulting from tumor--stroma interactions (bone-side osteotropism genes). e) Study Design: In the experiments of aim 1, tissue-engineered bone containing or absent potentially critical components will be created. By scanning these components, the role of each in attracting and sustaining BrCa metastases will be determined. In aim 2, we will partially compartmentalize bone, keeping stromal elements and BrCa cells separate, but allowing them to interface. We will then harvest and isolate stromal cells and, using DNA microarray methods, perform transcriptional profiling to elucidate genes in bone that are regulated in response to tumor. f) Potential Outcomes and Benefits: Using a unique "all-human" mouse model and engineered bone, this research promises to generate novel insights into the contributions of human bone to the process of BrCa metastasis. We will identify the components of bone critical to its function as a BrCa target. We will also identify key genetic responses of bone to BrCa metastasis. These findings should point to new bone-specific approaches to prevent and treat the serious complications of BrCa metastasis to the skeleton.
a) Background: The most common site of spread for breast cancer (BrCa) is to the skeleton. Once BrCa forms metastases in bone, the disease essentially enters an incurable phase. As metastases expand, they can cause fractures (with pain, compromised mobility, and even paralysis), life-threateningly high levels of calcium in blood, and other serious complications. Despite important advances made in the treatment of BrCa, there is little understanding of the reasons BrCa has such a predilection to spread to bone and little in the way of therapy. b) Objectives/Hypothesis: If we understood the mechanisms involved, we might be able to select targets for the design of therapies tailor-made for bone metastases. Despite the large unmet and urgent medical need, few metastasis-specific therapies exist now. It is even conceivable that elucidating the mechanisms involved in BrCa spread to bone will reveal steps in a final common pathway used by other cancers that metastasize to the skeleton. c) Specific Aims: We propose a novel set of experiments directed at understanding the contribution of bone to the mutual attraction of BrCa and bone for each other. Until recently, almost all research in this area has focused on BrCa contributions, in part because of the challenge of working with a ?hard tissue? like bone. d) Study Design: To identify the features of bone that make it a target for BrCa, we devised a unique ?all-human? mouse model. We fabricate pieces of engineered bone by adding human bone stem cells to a platform of silk fibers. This tissue-engineered bone becomes as strong as natural bone and nearly identical microscopically. We have implanted such bone into a strain of mouse incapable of rejecting human tissue. When human BrCa cells are injected into the breasts of such mice, tumors develop in the breast and spread to the engineered human bone (but not the mouse skeleton). The creation of this system opens the door for studying how bone attracts BrCa and, in turn, how BrCa alters bone for its own purposes. By controlling the content of the bone, we plan to identify the components essential for its ability to serve as a target. When a set of such components is identified, we plan to build a BrCa target that will make study of the bone-tumor interaction much more straightforward. Using modern techniques for probing genes, we will also obtain novel insights regarding BrCa?s influence on bone and identify ?bone-side? genes involved in ?osteotropism.? e) Potential Outcomes and Benefits: Our studies promise to provide fundamental insights into the mechanisms underlying BrCa metastasis to bone that could be disrupted as an approach to developing metastasis-specific therapies.