A Novel 3-D Mineralized Tumor Model to Study Breast Cancer Bone Metastasis

Abstract

BackgroundMetastatic bone disease is a frequent cause of morbidity in patients with advanced breast cancer, but the role of the bone mineral hydroxyapatite (HA) in this process remains unclear. We have developed a novel mineralized 3-D tumor model and have employed this culture system to systematically investigate the pro-metastatic role of HA under physiologically relevant conditions in vitro.Methodology/Principal FindingsMDA-MB231 breast cancer cells were cultured within non-mineralized or mineralized polymeric scaffolds fabricated by a gas foaming-particulate leaching technique. Tumor cell adhesion, proliferation, and secretion of pro-osteoclastic interleukin-8 (IL-8) was increased in mineralized tumor models as compared to non-mineralized tumor models, and IL-8 secretion was more pronounced for bone-specific MDA-MB231 subpopulations relative to lung-specific breast cancer cells. These differences were pathologically significant as conditioned media collected from mineralized tumor models promoted osteoclastogenesis in an IL-8 dependent manner. Finally, drug testing and signaling studies with transforming growth factor beta (TGFβ) confirmed the clinical relevance of our culture system and revealed that breast cancer cell behavior is broadly affected by HA.Conclusions/SignificanceOur results indicate that HA promotes features associated with the neoplastic and metastatic growth of breast carcinoma cells in bone and that IL-8 may play an important role in this process. The developed mineralized tumor models may help to reveal the underlying cellular and molecular mechanisms that may ultimately enable more efficacious therapy of patients with advanced breast cancer.

Zinc finger E‐box binding homeobox 1 promotes invasion and bone metastasis of small cell lung cancer in vitro and in vivo

“…Compared with breast cancer (26,27) and prostate cancer, (28) the research on lung cancer bone metastasis is only in its infancy. ZEB1 is a crucial factor of the EMT pathway and has been found to be expressed in many kinds of human cancers, (29,30) including breast cancer, (11,12) colon cancer, (31,32) gastric cancer (33) and hepatocellular carcinoma.…”

Modeling Tumor Microenvironments In Vitro

“…For example, using this model, E-P-, and L-selectins have been found to mediate adhesion events [94,101,102]. However, numerous clinical observations have demonstrated that different tumor types have distinct organ-specific metastatic potential [44,103,104], and organ-specific chemokines are known to promote relevant tumor cell adhesion to endothelium and facilitate processes of extravasation into the target tissue [105,106], To this end, the Fischbach lab developed a mineralized 3D tumor model to investigate the roles of mineral hydroxyapatite (HA) in breast tumor cell progression and found that tumor cell adhesion, proliferation, and secretion of pro-osteoclastic IL-8 was increased in mineralized tumor models as compared to nonmineralized tumor models [107]. However, our understanding of how the physical and chemical microenvironments at the ectopic site impact the initiation and growth of a new tumor remain limited, and more physiologically relevant in vitro models are needed that incorporate target tissue cells underneath the endothelial cells.…”

Modeling tumor microenvironments using custom-designed biomaterial scaffolds

“…Subsequent studies incorporating hydroxyapatite (HA), the main mineral component of bone, into the PLG scaffolds provided a bone-like microenvironment in which to study breast cancer metastasis [38]. Also, poly(ε-caprolactone) (PCL), another polymer popular in tissue engineering applications, was electrospun into a porous, fibrous scaffold and seeded with TC-71 Ewing’s sarcoma cells.…”