A comprehensive panel of three-dimensional models for studies of prostate cancer growth, invasion and drug responses

Ville Härmä, Johannes Virtanen, Rami Mäkelä, Antti Happonen, John Mpindi, Matias Knuuttila, Pekka Kohonen, Jyrki Lötjönen, Olli Kallioniemi, Matthias Nees (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

201 Citations (Scopus)

Abstract

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.
Original languageEnglish
Article numbere10431
Number of pages17
JournalPLoS ONE
Volume5
Issue number5
DOIs
Publication statusPublished - 2010
MoE publication typeA1 Journal article-refereed

Fingerprint

prostatic neoplasms
Prostatic Neoplasms
drugs
Cells
Growth
Phosphatidylinositol 3-Kinases
Cell culture
Metabolism
Pharmaceutical Preparations
Prostate
cells
neoplasms
Epithelial Cells
extracellular matrix
Cell growth
Extracellular Matrix
Gene expression
Integrins
Neoplasms
phosphotransferases (kinases)

Cite this

Härmä, V., Virtanen, J., Mäkelä, R., Happonen, A., Mpindi, J., Knuuttila, M., ... Nees, M. (2010). A comprehensive panel of three-dimensional models for studies of prostate cancer growth, invasion and drug responses. PLoS ONE, 5(5), [e10431]. https://doi.org/10.1371/journal.pone.0010431
Härmä, Ville ; Virtanen, Johannes ; Mäkelä, Rami ; Happonen, Antti ; Mpindi, John ; Knuuttila, Matias ; Kohonen, Pekka ; Lötjönen, Jyrki ; Kallioniemi, Olli ; Nees, Matthias. / A comprehensive panel of three-dimensional models for studies of prostate cancer growth, invasion and drug responses. In: PLoS ONE. 2010 ; Vol. 5, No. 5.
@article{d2afb2200b6140bf952ff64035ecd3da,
title = "A comprehensive panel of three-dimensional models for studies of prostate cancer growth, invasion and drug responses",
abstract = "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.",
author = "Ville H{\"a}rm{\"a} and Johannes Virtanen and Rami M{\"a}kel{\"a} and Antti Happonen and John Mpindi and Matias Knuuttila and Pekka Kohonen and Jyrki L{\"o}tj{\"o}nen and Olli Kallioniemi and Matthias Nees",
year = "2010",
doi = "10.1371/journal.pone.0010431",
language = "English",
volume = "5",
journal = "PLoS ONE",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "5",

}

Härmä, V, Virtanen, J, Mäkelä, R, Happonen, A, Mpindi, J, Knuuttila, M, Kohonen, P, Lötjönen, J, Kallioniemi, O & Nees, M 2010, 'A comprehensive panel of three-dimensional models for studies of prostate cancer growth, invasion and drug responses', PLoS ONE, vol. 5, no. 5, e10431. https://doi.org/10.1371/journal.pone.0010431

A comprehensive panel of three-dimensional models for studies of prostate cancer growth, invasion and drug responses. / Härmä, Ville; Virtanen, Johannes; Mäkelä, Rami; Happonen, Antti; Mpindi, John; Knuuttila, Matias; Kohonen, Pekka; Lötjönen, Jyrki; Kallioniemi, Olli; Nees, Matthias (Corresponding Author).

In: PLoS ONE, Vol. 5, No. 5, e10431, 2010.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - A comprehensive panel of three-dimensional models for studies of prostate cancer growth, invasion and drug responses

AU - Härmä, Ville

AU - Virtanen, Johannes

AU - Mäkelä, Rami

AU - Happonen, Antti

AU - Mpindi, John

AU - Knuuttila, Matias

AU - Kohonen, Pekka

AU - Lötjönen, Jyrki

AU - Kallioniemi, Olli

AU - Nees, Matthias

PY - 2010

Y1 - 2010

N2 - 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.

AB - 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.

U2 - 10.1371/journal.pone.0010431

DO - 10.1371/journal.pone.0010431

M3 - Article

VL - 5

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 5

M1 - e10431

ER -