Engineering Prostate Cancer from Induced Pluripotent Stem Cells—New Opportunities to Develop Preclinical Tools in Prostate and Prostate Cancer Studies
Abstract
:1. Introduction
2. Challenges in Current Preclinical Prostate Cancer Models
2.1. Cell Lines
2.2. Primary Culture Cells
2.3. Patient-Derived Xenografts (PDXs)
2.4. Patient-Derived Organoids (PDOs)
3. Human iPSCs for Disease Modelling
3.1. Human iPSC-Derived Tissue and Organ Models
3.1.1. Cerebral iDOs
3.1.2. Retinal iDOs
3.1.3. Intestine iDOs
3.1.4. Liver iDOs
3.1.5. Kidney iDOs
3.1.6. Lung iDOs
4. Emerging Approaches in Preclinical Prostate Cancer Research
4.1. Transformation of Primary Prostate Cells
4.2. Prostate iDOs
4.3. Genome Editing Technology and Precision Medicine
5. Final Remarks
Funding
Conflicts of Interest
Abbreviations
AR | Androgen receptor |
CRPC | Castration-resistant prostate cancer |
CRPC-NE | Castration-resistant prostate cancer neuroendocrine |
CF | Cystic fibrosis |
ESC | Embryonic stem cells |
iPSCs | Induced-pluripotent stem cells |
iDOs | iPSC-derived organoids |
PAM | Protospacer-adjacent motif |
PDOs | Patient-derived organoids |
PDXs | Patient-derived xenografts |
PSA | Prostate-specific antigen |
sgRNA | Single-guide RNA sequence |
UGM | Urogenital mesenchyme |
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Model | Advantages | Disadvantages |
---|---|---|
Cancer cell lines | Easy and cheap to grow; Useful for basic science; High throughput drug screening | Limited to 2D; Mutation accumulation over time; Limited number available |
Primary cells | Derived from patients; Initial drug studies; Use for PDXs, PDOs and iPSCs | Difficult to grow; Tissue accessibility; Limited to 2D; Mutation accumulation over time |
Patient-derived xenografts (PDXs) | Retain 3D tissue architecture; Intact endocrine system; Disease stage-specific models available | Time consuming and expensive; Low engraftment efficiencies; Mouse has deficient immunity and different microenvironment |
Patient-derived organoids (PDOs) | Retain 3D tissue architecture; Histological and molecular resemblance to tissue of origin; Drug testing responses more accurate | At present only established from aggressive prostate cancer specimens; Low establishment rate; Lack microenvironment and immune influence |
iPSC-derived organoids (iDOs) | Retain 3D tissue architecture; Unlimited source of iPSCs; Isogenic lines; Gene editing to introduce patient-specific mutations; High throughput drug screening; ‘avatar’ for precision medicine | Lack microenvironment and immune influence |
Tissue/Organ | Method | Key Small Molecules | References |
---|---|---|---|
Brain | Self-organisation by embryoid bodies formation, and the addition of temporal small molecules | IWR1 and SB431542 | [91,92] |
Eye | Self-organisation by embryoid bodies formation, and the addition of temporal small molecules | BMP4 and IGF1 | [93,94,95] |
Intestine | Extracellular support matrix and culture medium supplemented with pro-intestine growth factors | Activin A, WNT3A and FGF4 | [96] |
Liver | Co-culture of iPSCs with mesenchymal and endothelial cells followed by self-organisation by cell-to-cell contact or self-organisation by embryoid bodies formation on 3D perfusable chip | Activin-A, bFGF and HGF | [97,98] |
Kidney | Mesoderm induction step followed by self-organisation in 3D culture | CHIR99021 and FGF9 | [99] |
Lung | Endoderm induction, addition of temporal small molecules and culture in extracellular support matrix or transwell inserts | Activin A, Noggin, SB431542, SAG, FGF4, CHIR99021 and FGF10 | [96,100,101,102] |
Prostate | Endoderm induction step and co-culture of iPSCs with rodent urogenital sinus mesenchyme (UGM), followed by self-organisation by cell-to-cell contact in extracellular support matrix | Activin A, EGF, R-spondin1, Noggin, and A83-01 | [69] |
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Hepburn, A.C.; Sims, C.H.C.; Buskin, A.; Heer, R. Engineering Prostate Cancer from Induced Pluripotent Stem Cells—New Opportunities to Develop Preclinical Tools in Prostate and Prostate Cancer Studies. Int. J. Mol. Sci. 2020, 21, 905. https://doi.org/10.3390/ijms21030905
Hepburn AC, Sims CHC, Buskin A, Heer R. Engineering Prostate Cancer from Induced Pluripotent Stem Cells—New Opportunities to Develop Preclinical Tools in Prostate and Prostate Cancer Studies. International Journal of Molecular Sciences. 2020; 21(3):905. https://doi.org/10.3390/ijms21030905
Chicago/Turabian StyleHepburn, Anastasia C., C. H. Cole Sims, Adriana Buskin, and Rakesh Heer. 2020. "Engineering Prostate Cancer from Induced Pluripotent Stem Cells—New Opportunities to Develop Preclinical Tools in Prostate and Prostate Cancer Studies" International Journal of Molecular Sciences 21, no. 3: 905. https://doi.org/10.3390/ijms21030905