Osteoblast-Derived Paracrine and Juxtacrine Signals Protect Disseminated Breast Cancer Cells from Stress

Abstract

Metastatic breast cancer in bone is incurable and there is an urgent need to develop new therapeutic approaches to improve survival. Key to this is understanding the mechanisms governing cancer cell survival and growth in bone, which involves interplay between malignant and accessory cell types. Here, we performed a cellular and molecular comparison of the bone microenvironment in mouse models representing either metastatic indolence or growth, to identify mechanisms regulating cancer cell survival and fate. In vivo, we show that regardless of their fate, breast cancer cells in bone occupy niches rich in osteoblastic cells. As the number of osteoblasts in bone declines, so does the ability to sustain large numbers of breast cancer cells and support metastatic outgrowth. In vitro, osteoblasts protected breast cancer cells from death induced by cell stress and signaling via gap junctions was found to provide important juxtacrine protective mechanisms between osteoblasts and both MDA-MB-231 (TNBC) and MCF7 (ER+) breast cancer cells. Combined with mathematical modelling, these findings indicate that the fate of DTCs is not controlled through the association with specific vessel subtypes. Instead, numbers of osteoblasts dictate availability of protective niches which breast cancer cells can colonize prior to stimulation of metastatic outgrowth.

Stromal Co-Cultivation for Modeling Breast Cancer Dormancy in the Bone Marrow

“…This is a potential mechanism for promoting cancer cell migration from sinusoidal capillaries to the bone marrow space [ 105 ]. Osteoblasts also support chemoresistance in cancer cells [ 106 ]. MC3T3-E1 pre-osteoblasts and osteoblasts protect ER+ and ER- BC cells from serum deprivation-induced and oxidation-induced cell death by direct contact through integrins and gap junctions [ 106 ].…”

“…Osteoblasts also support chemoresistance in cancer cells [ 106 ]. MC3T3-E1 pre-osteoblasts and osteoblasts protect ER+ and ER- BC cells from serum deprivation-induced and oxidation-induced cell death by direct contact through integrins and gap junctions [ 106 ]. Osteoblasts and MDA-MB-231 co-conditioned medium, with and without heat inactivation, also protect ER- cells but not MCF-7 cells from oxidation-induced cell death, while pre-osteoblast CM alone does not [ 106 ].…”

“…MC3T3-E1 pre-osteoblasts and osteoblasts protect ER+ and ER- BC cells from serum deprivation-induced and oxidation-induced cell death by direct contact through integrins and gap junctions [ 106 ]. Osteoblasts and MDA-MB-231 co-conditioned medium, with and without heat inactivation, also protect ER- cells but not MCF-7 cells from oxidation-induced cell death, while pre-osteoblast CM alone does not [ 106 ]. The induction of osteoblast senescence by p27 Kip1 promotes metastatic seeding, tumor growth and osteoclastogenesis mediated by IL-6 synthesis in mice [ 107 ].…”

3D Printing and Bioprinting to Model Bone Cancer: The Role of Materials and Nanoscale Cues in Directing Cell Behavior

“…Among the different types of carcinomas that metastasize to bone, breast cancer is the most frequent and, hence, the most studied in the field of 3D bioprinting. In particular, breast cancer cells are often co-cultured with stromal cells of the bone microenvironment, such as the MSCs and the osteoblasts [19,78,147,[170][171][172][173][174], since they support the key events in breast carcinoma metastasization and progression, including migration and drug resistance [175,176].…”

Twelfth Annual ENBDC Workshop: Methods in Mammary Gland Biology and Breast Cancer

“…She presented a model of tumor dormancy in bone, allowing comparison of conditions in which DTC will develop in metastasis or remain dormant based simply on the age of mice (which impacts the bone microenvironment) at the onset of the experiment. By expanding the osteoblast number with parathyroid hormone prior to tumor cell injection, she showed that the osteoblasts were important for tumor cell survival and progression but not for DTC homing [29]. She also described studies of the effect of osteoclast activity on DTC by ovariectomizing (OVX) mice.…”