ABSTRACT
The fields of tissue bioengineering, -omics, and spatial biology are advancing rapidly, each offering the opportunity for a paradigm shift in breast cancer research. However, to date, collaboration between these fields has not reached its full potential. In this review, we describe the most recently generated 3D breast cancer models regarding the biomaterials and technological platforms employed. Additionally, their biological evaluation is reported, highlighting their advantages and limitations. Specifically, we focus on the most up-to-date -omics and spatial biology techniques, which can generate a deeper understanding of the biological relevance of bioengineered 3D breast cancer in vitro models, thus paving the way towards truly clinically relevant microphysiological systems, improved drug development success rates, and personalised medicine approaches.
Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/genetics , Biomedical Engineering , Bioengineering , Biocompatible MaterialsABSTRACT
Breast cancer is still the leading cause of women's death due to relapse and metastasis. In vitro tumor models are considered reliable tools for drug screening and understanding cancer-driving mechanisms due to the possibility of mimicking tumor heterogeneity. Herein, a 3D breast cancer model (3D-BCM) is developed based on enzymatically-crosslinked silk fibroin (eSF) hydrogels. Human MCF7 breast cancer cells are encapsulated into eSF hydrogels, with and without human mammary fibroblasts. The spontaneously occurring conformational change from random coil to ß-sheet is correlated with increased eSF hydrogels' stiffness over time. Moreover, mechanical properties analysis confirms that the cells can modify the stiffness of the hydrogels, mimicking the microenvironment stiffening occurring in vivo. Fibroblasts support cancer cells growth and assembly in the eSF hydrogels up to 14 days of culture. Co-cultured 3D-BCM exhibits an upregulated expression of genes related to extracellular matrix remodeling and fibroblast activation. The 3D-BCM is subjected to doxorubicin and paclitaxel treatments, showing differential drug response. Overall, these results suggest that the co-culture of breast cancer cells and fibroblasts in eSF hydrogels allow the development of a mimetic in vitro platform to study cancer progression. This opens up new research avenues to investigate novel molecular targets for anti-cancer therapy.
Subject(s)
Antineoplastic Agents , Breast Neoplasms , Humans , Female , Coculture Techniques , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Neoplasm Recurrence, Local , Antineoplastic Agents/pharmacology , Hydrogels , Fibroblasts/pathology , Tumor MicroenvironmentABSTRACT
Hydrogels, being capable of mimicking the extracellular matrix composition of tissues, are greatly used as artificial matrices in tissue engineering applications. In this study, the generation of horseradish peroxidase (HRP)-crosslinked silk fibroin (SF) hydrogels, using calcium peroxide as oxidizer is reported. The proposed fast forming calcium-containing SF hydrogels spontaneously undergo SF conformational changes from random coil to ß-sheet during time, exhibiting ionic, and pH stimuli responsiveness. In vitro response shows calcium-containing SF hydrogels' encapsulation properties and their ability to promote SaOs-2 tumor cells death after 10 days of culturing, upon complete ß-sheet conformation transition. Calcium-containing SF hydrogels' angiogenic potential investigated in an in ovo chick chorioallantoic membrane (CAM) assay, show a high number of converging blood vessels as compared to the negative control, although no endothelial cells infiltration is observed. The in vivo response evaluated in subcutaneous implantation in CD1 and nude NCD1 mice shows that calcium-containing SF hydrogels are stable up to 6 weeks after implantation. However, an increased number of dead cells are also present in the surrounding tissue. The results suggest the potential of calcium-containing SF hydrogels to be used as novel in situ therapeutics for bone cancer treatment applications, particularly to osteosarcoma.