Breast cancer frequently metastasizes to bone where it leads to osteolysis and poor clinical prognosis;however, the underlying roles of hydroxyapatite (HA) - a key component of breast microcalcifications (i.e., a negative prognostic factor for breast cancer) and the bone mineral matrix - remain unclear in this process, due in part to a lack of appropriate model systems. In the presence of a tumor, the physicochemical properties of HA (e.g., crystallinity, chemical composition, size, and aspect ratio) vary with disease state at both the primary (breast) and secondary (bone) sites. The overall hypothesis guiding the current investigator is: tumor-mediated changes to HA materials properties enhance breast cancer metastasis to bone by inducing a bone-metastatic phenotype at the primary site. These cells, in turn, promote premetastatic bone remodeling, which ultimately fosters bone colonization. We have previously developed mineral-containing 3-D tumor models, which permit testing of the importance of the physicochemical properties of HA in breast cancer spreading to bone. Using this system, coupled with advanced materials characterization techniques, we will test three subhypotheses: 1) HA in microcalcifications associated with more aggressive breast cancer is characterized by increased size and crystallinity and leads to the up-regulation of bone metastatic properties in breast cancer cells due in part to varied non-specific protein adsorption; 2) HA in the bones of tumor-bearing mice is characterized by decreased size and crystallinity even prior to metastatic colonization. These changes favor tumor cell seeding and growth, which are mediated by tumor-secreted endocrine signals that differentially regulate bone cell behavior;3) Increased bone-metastatic potential of breast cancer cells due to interactions with HA enhances premetastatic bone remodeling, which, in turn, increases the osteotropism of breast cancer cells;pharmacological intervention with this process can decrease bone metastasis. There are three specific aims designed to test these hypotheses:
In Aim 1, we will characterize HA materials properties in breast microcalcifications, and assess their impact on the bone-metastatic potential of tumor cells.
In Aim 2, we will characterize HA materials properties in the bones of tumor-bearing animals pre- and post-colonization with breast cancer cells, and identify their role in secondary tumor formation.
In Aim 3, we will assess the integrated effects of breast microcalcifications and premetastatic bone remodeling on breast cancer bone metastasis. The novel combination of cancer biology with engineering and materials science approaches will result in a highly reproducible and pathologically relevant culture platform that will allow us to deconvolute the complexity of bone metastasis and identify molecular targets for improved therapies. By elucidating the importance of materials-based mechanisms, the proposed research has the potential to challenge the currently accepted paradigm of bone metastasis as a disease that is solely mediated by cellular and molecular changes.

Public Health Relevance

Bone metastasis is the leading cause of breast cancer-related deaths among women worldwide;however, the role of the mineral hydroxyapatite, a key component of breast microcalcifications (a negative prognostic factor for breast cancer) and the bone mineral matrix, in this process remains unclear. This research will apply state-of-the-art characterization techniques, coupled with three-dimensional cell culture platforms, to systematically elucidate the functional relationship between breast microcalcifications, the bone mineral matrix, mammary tumor cell behavior, and metastatic osteolysis. Our studies will combine materials science with engineering and cancer biology, and this interdisciplinary approach has the potential to revolutionize our understanding and treatment of bone metastasis.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA173083-03
Application #
8706099
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Mohla, Suresh
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Cornell University
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Seo, Bo Ri; Delnero, Peter; Fischbach, Claudia (2014) In vitro models of tumor vessels and matrix: engineering approaches to investigate transport limitations and drug delivery in cancer. Adv Drug Deliv Rev 69-70:205-16
Lynch, Maureen E; Fischbach, Claudia (2014) Biomechanical forces in the skeleton and their relevance to bone metastasis: biology and engineering considerations. Adv Drug Deliv Rev 79-80:119-34
Infanger, David W; Lynch, Maureen E; Fischbach, Claudia (2013) Engineered culture models for studies of tumor-microenvironment interactions. Annu Rev Biomed Eng 15:29-53
Lynch, Maureen E; Brooks, Daniel; Mohanan, Sunish et al. (2013) In vivo tibial compression decreases osteolysis and tumor formation in a human metastatic breast cancer model. J Bone Miner Res 28:2357-67
DelNero, Peter; Song, Young Hye; Fischbach, Claudia (2013) Microengineered tumor models: insights & opportunities from a physical sciences-oncology perspective. Biomed Microdevices 15:583-93