title: Three-Dimensional Breast Cancer Models Mimic Hallmarks of Size-Induced Tumor Progression.
abstract: Tumor size is strongly correlated with breast cancer metastasis and patient survival. Increased tumor size contributes to hypoxic and metabolic gradients in the solid tumor and to an aggressive tumor phenotype. Thus, it is important to develop three-dimensional (3D) breast tumor models that recapitulate size-induced microenvironmental changes and, consequently, natural tumor progression in real time without the use of artificial culture conditions or gene manipulations. Here, we developed size-controlled multicellular aggregates ("microtumors") of subtype-specific breast cancer cells by using non-adhesive polyethylene glycol dimethacrylate hydrogel microwells of defined sizes (150-600 μm). These 3D microtumor models faithfully represent size-induced microenvironmental changes, such as hypoxic gradients, cellular heterogeneity, and spatial distribution of necrotic/proliferating cells. These microtumors acquire hallmarks of tumor progression in the same cell lines within 6 days. Of note, large microtumors of hormone receptor-positive cells exhibited an aggressive phenotype characterized by collective cell migration and upregulation of mesenchymal markers at mRNA and protein level, which was not observed in small microtumors. Interestingly, triple-negative breast cancer (TNBC) cell lines did not show size-dependent upregulation of mesenchymal markers. In conclusion, size-controlled microtumor models successfully recapitulated clinically observed positive association between tumor size and aggressive phenotype in hormone receptor-positive breast cancer while maintaining clinically proven poor correlation of tumor size with aggressive phenotype in TNBC. Such clinically relevant 3D models generated under controlled experimental conditions can serve as precise preclinical models to study mechanisms involved in breast tumor progression as well as antitumor drug effects as a function of tumor progression. Cancer Res; 76(13); 3732-43. ©2016 AACR.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Manjulata
authors.initials: M
authors.lastname: Singh
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Shilpaa
authors.initials: S
authors.lastname: Mukundan
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Maria
authors.initials: M
authors.lastname: Jaramillo
authors.affiliation: Women's Cancer Research Center, Magee-Womens Research Institute, University of Pittsburgh Cancer Institute, School of Medicine, Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Steffi
authors.initials: S
authors.lastname: Oesterreich
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania. Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania. McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. shs149@pitt.edu.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Sant
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D059630:Mesenchymal Stem Cells / Q000473:pathology*; D008954:Models, Biological; D015398:Signal Transduction; D047368:Tumor Burden; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
chemical_list: D014408:Biomarkers, Tumor; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate