Engineered 3D Silk‐Based Metastasis Models: Interactions Between Human Breast Adenocarcinoma, Mesenchymal Stem Cells and Osteoblast‐Like Cells

Abstract

Bone metastasis occurs in 70% of breast cancer patients and is a frequent cause of morbidity in cancer patients. A delicate balance exists in the bone microenvironment, but the functional dynamics underlying the tumor cell‐microenvironment interactions remain poorly understood. 3D in vitro model systems of metastasis can throw new light on this phenomenon. Silk protein fibroin scaffolds, are cytocompatible for 3D cancer cell culture. They are structurally more resistant to protease degradation than other native biomaterials making these matrices suitable for cancer modeling. In this report, human breast adenocarcinoma cells, human osteoblast like cells and mesenchymal stem cells are co‐cultered. Cancer cells and osteoblast‐like cells are found to interact through secreted products. Decreased population of osteoblast‐like cells and mineralization of extracellular matrix are observed as a result of co‐culture. Significantly increased migration of breast cancer cells is observed in the bone‐like constructs than in non‐seeded scaffolds. The co‐culture constructs show significant increase in drug resistance, invasiveness and angiogenicity. Co‐culture of breast cancer cells with osteoblast like cells and mesenchymal stem cells also indicate that the interaction of cancer cells with bone microenvironment varies with spatial organization, presence of osteogenic factors as well as stromal cell type. Here, results show that 3D in vitro co‐culture models is possibly a better system to study and target cancer progression.

Three‐Dimensional Osteosarcoma Models for Advancing Drug Discovery and Development

“…At the same time, the design of a platform for specific delivery of anticancer drugs has also been a focus, particularly in the nanomedicine field. [112] In this study, an anticancer drug for breast cancer, paclitaxel, was tested in the co-culture 3D model showing a significant increase in drug resistance when compared with breast cancer monoculture [111] (Figure 5A,B). [110] Folate conjugated fibroin nanoparticles loaded with doxorubicin were fabricated and its efficiency was evaluated in a coculture of MG-63 osteoblast-like cells with MDA-MD-231 human adenocarcinoma cell line.…”

“…Matrigel Hydrogel HOS, 143B -pLKO.1 shsFRP2 vector [73] 143B, MG-63, U2OS, hFOB1.19 -Paris polyphylla ethanol extract [75] MG-63 -miR-29b-1 overexpression [76] K7M2 -Bromodomain inhibitor JQ1 [77] Collagen Hydrogel U2OS -Kinase inhibitor PI103 [43] Type I MG-63 -Tyrosin phosphorylation inhibitor (ACM-14) [91] LM8 -Pazopanib [96] Sponge hFOB 1.19 (osteoblasts) PC3, LNCaP siRNA-based gene knockdown [97] Matrigel/Collagen Hydrogel MOS, U2OS, 143B, ZK58, KPD, SaOS-2 Trametinib, AZD8330, and TAK-733 kinase inhibitors [79] MOS, U2OS, 143B, ZK58, KPD -siAven [78] Silk Fibroin Sponge 143.98.2, SaOS-2, U2OS -Doxorubicin, cisplatin [108] U2OS Bone marrow fibroblasts, HUVECs MAB208 (anti-IL-8), Avastin (anti-VEGF-A) [109] MG-63 MDA-MB-231 Doxorubicin [110] MG-63 MDA-MB-231, MSCs Paclitaxel [111] Chitosan Sponge MG-63, MNNG -Doxorubicin [139] Alginate Hydrogel MG-63 -Tetracycline hydrochloride [115] Fibers MG-63 HUVECs - [116] Spheres Dunn, LM8 NF-кB decoy oligodeoxy-nucleotide [124] Synthetic Biomaterials…”

Biomimetic strategies to recapitulate organ specific microenvironments for studying breast cancer metastasis

“…Following colonization, BCCs are known to affect the differentiation of bone marrow stem cells into osteoblasts and osteoclasts giving rise to a vicious cycle of BCBM. Biomaterials like silk fibroin support the differentiation of pre‐osteoblasts and have been used to recapitulate the differentiation process of these cells in presence of BCCs . MDA‐MB‐231 BCCs in presence of differentiating osteoblasts were found to secrete chemokines and cytokines such as IL‐ β, TGF‐β and TNF‐α which mediates the BCCs‐OBs interaction .…”

Engineering 3D Models of Tumors and Bone to Understand Tumor-Induced Bone Disease and Improve Treatments

“…In another high-impact study, porous silk fibroin scaffolds prepared directly from the silk fibroin protein of silk worms [76] were used in a 3D culture system to investigate the response of metastatic tumor cells to external stimuli in the presence of osteoblasts and mesenchymal stem cells (MSC) [77]. The silk fibroin scaffolds were hypothesized to be an ideal scaffold for investigating metastatic breast cancer behavior due to its mechanical properties in the range of adipose breast cancer in breast cancer patients, its inherent possession of Asp-Gly-Asp (RGD) peptide sequences known to promote cytocompatibility and cell adhesion, and based on the results of previous studies showing that MSCs undergo osteogenic differentiation on the scaffolds.…”