Journal Article

A Comprehensive Panel of Three-Dimensional Models for Studies of Prostate Cancer Growth, Invasion and Drug Responses

Lötjönen, Jyrki, Virtanen, Johannes, Nees, Matthias, Härmä, Ville, Mäkelä, Rami, Knuuttila, Matias, Kallioniemi, Olli, Mpindi, John-Patrick, Kohonen, Pekka, Happonen, Antti

2010

Overview

Prostate epithelial cells from both normal and cancer tissues, grown in three-dimensional (3D) culture as spheroids, represent promising in vitro models for the study of normal and cancer-relevant patterns of epithelial differentiation. We have developed the most comprehensive panel of miniaturized prostate cell culture models in 3D to date (n = 29), including many non-transformed and most currently available classic prostate cancer (PrCa) cell lines. The purpose of this study was to analyze morphogenetic properties of PrCa models in 3D, to compare phenotypes, gene expression and metabolism between 2D and 3D cultures, and to evaluate their relevance for pre-clinical drug discovery, disease modeling and basic research. Primary and non-transformed prostate epithelial cells, but also several PrCa lines, formed well-differentiated round spheroids. These showed strong cell-cell contacts, epithelial polarization, a hollow lumen and were covered by a complete basal lamina (BL). Most PrCa lines, however, formed large, poorly differentiated spheroids, or aggressively invading structures. In PC-3 and PC-3M cells, well-differentiated spheroids formed, which were then spontaneously transformed into highly invasive cells. These cell lines may have previously undergone an epithelial-to-mesenchymal transition (EMT), which is temporarily suppressed in favor of epithelial maturation by signals from the extracellular matrix (ECM). The induction of lipid and steroid metabolism, epigenetic reprogramming, and ECM remodeling represents a general adaptation to 3D culture, regardless of transformation and phenotype. In contrast, PI3-Kinase, AKT, STAT/interferon and integrin signaling pathways were particularly activated in invasive cells. Specific small molecule inhibitors targeted against PI3-Kinase blocked invasive cell growth more effectively in 3D than in 2D monolayer culture, or the growth of normal cells. Our panel of cell models, spanning a wide spectrum of phenotypic plasticity, supports the investigation of different modes of cell migration and tumor morphologies, and will be useful for predictive testing of anti-cancer and anti-metastatic compounds.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: 1-Phosphatidylinositol 3-kinase / AKT protein / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Basal lamina / Biochemistry/Drug Discovery / Biotechnology / Cancer / Cancer research / Cell adhesion & migration / Cell Biology/Cell Adhesion / Cell Biology/Cell Signaling / Cell Biology/Developmental Molecular Mechanisms / Cell Biology/Extra-Cellular Matrix / Cell Biology/Gene Expression / Cell culture / Cell migration / Cell Proliferation - drug effects / Cell Shape - drug effects / Cell Transformation, Neoplastic - genetics / Cell Transformation, Neoplastic - pathology / Collagen - pharmacology / Computational Biology/Systems Biology / Drug Combinations / Drug discovery / Drug resistance / Drug therapy / Epigenetic inheritance / Epigenetics / Epithelial cells / Epithelial Cells - drug effects / Epithelial Cells - pathology / Epithelium - drug effects / Epithelium - pathology / Extracellular matrix / Fibroblasts / Gene expression / Gene Expression Regulation, Neoplastic - drug effects / Genes / Genetic transformation / Genetics and Genomics/Cancer Genetics / Genetics and Genomics/Disease Models / Genetics and Genomics/Gene Expression / Growth / Homeostasis / Humans / Integrins / Interferon / Intracellular Signaling Peptides and Proteins - antagonists & inhibitors / Invasiveness / Ionizing radiation / Laminin - pharmacology / Lipid metabolism / Male / Medical research / Mesenchyme / Mesoderm - drug effects / Mesoderm - pathology / Metabolism / Metastases / Metastasis / Models, Biological / Molecular Biology/Bioinformatics / Molecular Biology/Translational Regulation / Motility / Neoplasm Invasiveness / Neoplasm Proteins - metabolism / Oncology/Prostate Cancer / Ovarian cancer / Pharmacology/Drug Development / Phenotype / Phenotypic plasticity / Phosphatidylinositol 3-Kinases - antagonists & inhibitors / Phosphatidylinositol 3-Kinases - metabolism / Physiological aspects / Principal Component Analysis / Prostate - drug effects / Prostate - pathology / Prostate cancer / Prostatic Neoplasms - drug therapy / Prostatic Neoplasms - enzymology / Prostatic Neoplasms - genetics / Prostatic Neoplasms - pathology / Protein-Serine-Threonine Kinases - antagonists & inhibitors / Proteoglycans - pharmacology / Proto-Oncogene Proteins c-akt - antagonists & inhibitors / Proto-Oncogene Proteins c-akt - metabolism / RNA, Messenger - genetics / RNA, Messenger - metabolism / Rodents / Signal Transduction - drug effects / Signaling / Spheroids / Spheroids, Cellular - drug effects / Spheroids, Cellular - enzymology / Spheroids, Cellular - pathology / Stem cells / Three dimensional models / Tissues / TOR Serine-Threonine Kinases / Transformation / Tumor cell lines / Tumor Cells, Cultured / Urology/Prostate Cancer