Breast cancer deaths are most commonly caused by the metastasis of tumor cells to distant organ sites that favor their growth. Bone is a frequent site of metastasis of some of the most common human malignancies including breast, prostate and lung cancer. Bone metastases are devastating to the patient as they are associated with intractable pain, hypercalcemia (abnormally high concentration of calcium in the blood), disabling pathologic fractures, and nerve compression syndromes. Statistically these skeletal-related events occur at the rate of 2-4 every 12 months25, and can be reduced by only about 50% with the use of the most effective drugs currently available for managing the host microenvironment, namely the bisphosphonate zoledronic acid (ZA) 26. This strongly suggests that better therapeutic approaches are required to more effectively treat patients with bone metastases. We propose that approaches focusing on early tumor growth and establishment in bone, rather than the later stages that bisphosphonates target will better inhibit tumor- induced bone disease. The late stages of bone disease have been previously well-described as a vicious cycle of bone destruction where TGF-? (transforming growth factor-beta) is released from the bone stimulating tumor cell growth and the production of bone resorbing factors, which in turn releases more TGF-? 27-32. Despite decades of research on these later stages, the early stages of cancer metastasis are not well-understood. However, it is clear that multiple factors and cell types within the tumor-microenvironment are important in these early stages of bone metastases. Our preliminary data and previously published data from other groups suggest that TGF-??is a major contributor to bone metastases and is likely important to these early stages. Based on our preliminary data, it appears that fibroblasts and the myeloid derived suppressor cells (immune cells present in the bone marrow and spleen) can stimulate tumor-induced bone disease, and that their function is regulated at least in part by TGF-beta. Thus, we have generated multiple mouse models in the immune-compromised Rag2 -/- mice with TGF-beta signaling ablated or constitutively activated in either the myeloid or mesenchymal lineage. This will allow us to investigate the importance of TGF-beta signaling in specific cell populations during the development of bone metastases. Furthermore we have obtained a TGF-beta inhibitory antibody for testing in pre-clinical models of breast cancer metastasis to bone. This proposal seeks to better understand the role of TGF-beta signaling in the tumor micro-environment and to develop strategies for treating bone metastases early. We hypothesize that TGF-beta signaling induces a """"""""permissive"""""""" micro- environment for the establishment and growth of cancer cells in bone to initiate bone resorption. Blocking TGF-beta specifically at this early stage, before bone resorption, will inhibit tumor establishment in the bone and subsequent bone destruction. To address this hypothesis we propose to 1) Determine the effect of cell-specific alterations of TGF-beta signaling in the bone microenvironment on tumor establishment, growth, and bone disease. 2) Evaluate the effectiveness of early bone-specific TGF-beta inhibition on bone metastases, 3) Test the effectiveness of combination therapies that inhibit both TGF-beta with Gli2 on bone metastases.
Women are the fastest growing population within the US military, making up nearly 15% of active duty military1. With 1.8 million women Veteran's and recent increases in women in active duty, there will be an increase in women within the VA medical system2. Importantly, Veterans have a higher incidence of breast cancer than civilians3, and have poorer survival 4, 5, likely due to an increase of metastases. Since bone metastases occur in 70% of women with metastatic disease causing severe morbidity and increased mortality, it is critical that more effective therapies for the treatment of bone metastases are developed6. Understanding and targeting earlier stages of tumor metastasis to bone will be more effective for treating bone metastases than current therapies that focus on late stages of disease. This application proposes new therapeutic approaches to inhibit both tumor growth and bone destruction at earlier stages using preclinical animal models. This proposal will contribute significantly to our understanding of tumor-induced bone disease and may lead to new therapies.
|Mulcrone, Patrick L; Campbell, J Preston; Clément-Demange, Lise et al. (2017) Skeletal Colonization by Breast Cancer Cells Is Stimulated by an Osteoblast and ?2AR-Dependent Neo-Angiogenic Switch. J Bone Miner Res 32:1442-1454|
|Dadwal, Ushashi; Falank, Carolyne; Fairfield, Heather et al. (2016) Tissue-engineered 3D cancer-in-bone modeling: silk and PUR protocols. Bonekey Rep 5:842|
|Buenrostro, Denise; Mulcrone, Patrick L; Owens, Philip et al. (2016) The Bone Microenvironment: a Fertile Soil for Tumor Growth. Curr Osteoporos Rep 14:151-8|
|Nyman, Jeffry S; Merkel, Alyssa R; Uppuganti, Sasidhar et al. (2016) Combined treatment with a transforming growth factor beta inhibitor (1D11) and bortezomib improves bone architecture in a mouse model of myeloma-induced bone disease. Bone 91:81-91|
|Johnson, Rachelle W; Finger, Elizabeth C; Olcina, Monica M et al. (2016) Induction of LIFR confers a dormancy phenotype in breast cancer cells disseminated to the bone marrow. Nat Cell Biol 18:1078-1089|
|Wright, Laura E; Ottewell, Penelope D; Rucci, Nadia et al. (2016) Murine models of breast cancer bone metastasis. Bonekey Rep 5:804|
|Guo, R; Lu, S; Merkel, A R et al. (2016) Substrate Modulus Regulates Osteogenic Differentiation of Rat Mesenchymal Stem Cells through Integrin ?1 and BMP Receptor Type IA. J Mater Chem B 4:3584-3593|
|Page, Jonathan M; Merkel, Alyssa R; Ruppender, Nazanin S et al. (2015) Altering adsorbed proteins or cellular gene expression in bone-metastatic cancer cells affects PTHrP and Gli2 without altering cell growth. Data Brief 4:440-6|
|Page, Jonathan M; Merkel, Alyssa R; Ruppender, Nazanin S et al. (2015) Matrix rigidity regulates the transition of tumor cells to a bone-destructive phenotype through integrin ?3 and TGF-? receptor type II. Biomaterials 64:33-44|
|Guo, R; Merkel, A R; Sterling, J A et al. (2015) Substrate modulus of 3D-printed scaffolds regulates the regenerative response in subcutaneous implants through the macrophage phenotype and Wnt signaling. Biomaterials 73:85-95|
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