Minerals And Metastasis: Hydroxyapatite Promotes Breast Cancer Colonization Of Bone
Bone metastasis commonly causes morbidity and mortality in patients with advanced breast cancer. Despite, better prognoses for breast cancer patients in general, the outlook for those with bone metastasis remains grim, with less than one quarter of those afflicted surviving past five years. Fundamental insights into how microenvironmental cues drive bone metastasis may help to fight the disease. Hydroxyapatite (HA) is a calcium-phosphate mineral that is found both in the bone, to which breast cancer spreads during metastasis, and in the breast tissue of many cancer patients in the form of microcalcifications. Despite the consistent presence of this bioactive mineral in the breast tumor microenvironment, little evidence currently exists to implicate it in cancer pathogenesis. Using a tissue engineering-inspired scaffold that incorporates HA in conjunction with hydrothermal techniques to synthesize well-defined mineral, tumor cellHA interactions were investigated. Soluble factors from these scaffold cultures were collected, analyzed, and used on other cells to study cell-cell interactions pertinent to bone metastasis. Xenograft models were used to understand how exposure to mineral might affect metastasis in vivo, and human patient samples were analyzed to validate findings with our scaffold models. The results suggest that the presence of hydroxyapatite promotes tumor cell growth and adhesion, as well as production of factors such as interleukin-8 (IL-8) that drive bone degradation, a cause of bone pain and pathological fracture in metastasis. Furthermore, tumor cell interactions with hydroxyapatite change gene expression patterns and promote the activation of a migratory axis by enriching levels of stromal-derived factor-1 (SDF-1), possibly dictating the propensity of breast cancer to metastasize to bone. Exposure to mineral promoted bone colonization by tumor cells in mice, and preliminary results indicate that IL-8and the receptor for SDF-1 are elevated in human patients with microcalcifications. The data also suggest that material properties of HA affect cell behavior, as larger, more crystalline particles stimulate the most IL-8 production, while smaller, less crystalline particles promote adhesion and growth. Integrin interactions are potentially involved in controlling cell-HA interactions, as it was found that blocking integrin binding to HA-adsorbed proteins such as osteopontin and fibronectin attenuated many of the observed behaviors stimulated by HA. Hydrothermal synthesis of HA and mineral-containing scaffolds emerged as excellent tools to study breast cancer biology, revealing that microenvironmental HA may play an important role in driving bone metastasis.
breast cancer; tumor microenvironment
Nikitin, Alexander; Estroff, Lara A.
Ph. D., Biomedical Engineering
Doctor of Philosophy
dissertation or thesis