In Vivo Models for Prostate Cancer Research
Abstract
:Simple Summary
Abstract
1. Introduction
Historical Timeline of PCa Models
2. Patient-Derived Xenografts and Organoids of PCa
3. Comparing and Contrasting Types of PCa Models
4. Mouse Models Based on Tumor Stage Progression
4.1. Hyperplasia
4.2. Prostatic Intraepithelial Neoplasia
4.3. Microinvasive Carcinoma
4.4. Invasive Carcinoma
4.4.1. Adenocarcinoma
4.4.2. Squamous Cell Carcinoma
4.4.3. Neuroendocrine Carcinoma
Model | Alteration | Driver and/or Add. Genetic Alteration | Phenotype | Reference |
---|---|---|---|---|
Ptenflox/flox | Loss of expression | Nkx3.1-CreERT2 driver | Microinvasive AD with areas of poorly differentiated AD; squamous metaplasia | [79,80] |
RARγ | Loss of expression | C57BL/6 F1 background strain | Squamous metaplasia in prostate and seminal vesicles | [81] |
MYCN | Gain of expression | Homozygous loss of Pten (conditional Pten allele) | Invasive adenocarcinoma with neuroendocrine PCa (NEPC) | [82] |
TRAMP | Gain of expression | PB promoter driving expression of SV40 early region | Androgen independent tumors are 100% synaptophysin positive, and metastases are 67% positive | [83] |
LADY | Gain of expression | Large PB (LPB) promoter driving expression of SV40 large T-antigen (Tag) | Visceral metastasis; NEPC | [84] |
LADY | Gain of expression | LPB driver, 12T-7s line; crossed with PB-Hepsin | Adenocarcinoma with neuroendocrine differentiation (NED); NE metastasis to liver, lung, and bone | [85] |
LADY | Gain of expression | LPB driver, 12T-7s line; crossed with β-catenin | Adenocarcinoma with focal NED, but without apparent NEPC | [86] |
Kras G12D | Gain of expression | Homozygous loss of Pten (conditional Pten allele) | Invasive adenocarcinoma, sarcomatoid differentiation, with extensive metastasis | [87,88] |
Pten and p53 | Loss of expression | PB-Cre mediated deletion of Pten and Trp53; activation of ROSA-LSL luciferase reporter | Fast-growing, lethal sarcomatoid tumors; local invasive PCa | [89] |
ALK and N-myc | Gain of expression | FVB/NJ and NSG background strains | Neuroblastoma development; metastasis with NED | [90] |
4.4.4. Sarcomatoid Carcinoma
4.5. Metastasis
5. Mouse Models Based on Signaling Pathways
5.1. AR Pathway
5.2. PI3K Pathway
5.3. TP53 Pathway
5.4. DNA Repair Pathway
5.5. MYC Pathway
5.6. Wnt Pathway
6. Future Directions
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Model | Availability, Ease of Use, Cost | Major Applications | Advantages | Disadvantages |
---|---|---|---|---|
2D Cell Lines | -High availability -Easy to use -Low cost | -Molecular and mechanistic studies -Drug screening studies -Validation experiments -Epigenetic studies | -Relatively quick results -Data may be made available online -Phenotypic analysis by microscopy studies | -Results may only apply to particular cell line, unless repeated in multiple cell lines -Lacks intra-tumor heterogeneity -Intrinsic effects due to high level passaging -Lacks phenotypic characteristics of parental tumors |
3D Organoids, Spheroids | -High availability -Requires more time and elaborate methods for observations and experiments -Intermediate cost | -Molecular and mechanistic studies -Drug screening studies -Imaging and observational studies | -Data can be easily obtained in a relatively short time -Phenotypic analysis by microscopy studies -High content data such as drug screens -More relevant to human cancer -Easily accessible for DNA and mRNA sequence analysis -Presence of ECM | -Longer timescale than 2D cell lines -Requires more extensive analysis -Data obtained is dependent on environment, causing high variability |
Xenografts, Allografts | -High availability -Technical expertise required to use -High cost | -Drug response studies and novel drug screening studies -Confirmation of molecular and mechanistic studies | -Comparable to in vivo context -Drug approval studies -Easily accessible for DNA and mRNA sequence analysis | -More time-consuming than 2D or 3D models -Drug response associated with genotype -Immunosuppression limits understanding the role of the immune system in tumor response (alleviated for allografts) |
Patient Derived Xenografts (PDXs) | -Limited availability -Patient consent required to use -Technical expertise required to use -High cost | -Heterotopic injection or transplant -Understanding tumor heterogeneity -Personalized drug testing for effective therapy -Maintenance of tumor architecture -In vivo physiology | -Easily accessible for DNA and mRNA sequence analysis -Understanding of drug resistance response -May lead to specific identification for treatment target | -Subsequent confirmation studies more difficult as each model is unique to each patient -Immunosuppression limits understanding the role of the immune system in tumor response |
Genetically Engineered (GE) Mice -With transgene expression -Knockouts (KOs) -Constitutive -Conditional | -Limited number of models -Animal colony maintenance required -High cost | -Establishment of in vivo functions of oncogenes and tumor suppressor genes -Genetic interactions -Tumor progression studies -Epithelial-stromal interactions -Immunological studies -Platform for studying metastasis | -Definitive functional studies, including metastatic potential -Establishment of in vivo functions in context of different tissues -Easily accessible for DNA and mRNA sequence analysis | -Long-term studies, with long tumor latency -Time and high cost associated with breeding skills and genotyping -Many common genotypes not represented -Patented strains unavailable -Phenotype may be influenced by strain -Spontaneous, strain-dependent tumorigenesis independent from genetic engineering |
Model | Alteration | Driver and/or Add. Genetic Alteration | Phenotype | Reference |
---|---|---|---|---|
p27Kip1(1) | Loss of expression | Created by gene targeting in embryonic stem cells | Hyperplasia of multiple organs, including prostate, testis, and thymus | [36] |
Nkx3.1 | Loss of expression | Genomic clones isolated from λFIXII library from 129Sv/J genomic DNA | Prostatic epithelial hyperplasia and dysplasia; decreased bulbourethral gland size | [37] |
Rbflox | Loss of expression | PBCre4 driver (2) | Focal areas of epithelial hyperplasia; loss of basement membrane and smooth muscle layer integrity | [38] |
IGF-1flox | Gain of expression | PBCre4 driver (2) | Cell autonomous proliferation; hyperplasia | [39] |
FOXA1 | Loss of expression | PBCre4 driver (2) | Progressive hyperplasia with extensive cribriform patterning | [40] |
Model | Alteration | Driver and/or Add. Genetic Alteration | Phenotype | Reference |
---|---|---|---|---|
KDM5B | Gain of expression | Loss of Pten function | HGPIN | [42] |
Sox9 | Gain of expression | Hemizygous loss of Pten (germline heterozygous Pten allele) | HGPIN | [43] |
Ptenflox/flox | Loss of expression | K14-CreERT2 driver (1) | PIN development | [44] |
Pten | Loss of expression | Mouse Pten disrupted by homologous recombination | PIN development; formation of aberrant embryoid bodies | [45] |
Pten x p53 | Loss of expression | Recombination of adult prostatic epithelium with embryonic rat seminal vesicle mesenchyme | HGPIN | [46] |
Abi1 | Loss of expression | PBCre4 driver (2) | PIN development | [47] |
EAF2 | Loss of expression | PB-CreERT2 driver (3) | Luminal epithelial hyperplasia and mPIN | [48] |
ACSS3 | Loss of expression | Transfection of overexpressing lentivirus and sgRNA (CRISPR/Cas9) | PIN in anterior prostate; increased proliferation, migration, and invasion | [49] |
CSF-1 | Gain of expression | PBCre4 driver | Immune cell infiltration into prostate; LGPIN | [50] |
Model | Alteration | Driver and/or Add. Genetic Alteration | Phenotype | Reference |
---|---|---|---|---|
Timp3 | Loss of expression | Homozygous loss of Pten (conditional Pten allele) | HGPIN with microinvasion | [51] |
mpAkt | Gain of expression | Myc gain of expression under control of PB driver; loss of Pten function | mPIN followed by microinvasive carcinoma, disruption of basement membrane integrity, stromal remodeling, and lymphocyte infiltration | [52] |
Nkx3.1 | Loss of expression | Myc gain of expression under control of CMV enhancer and β-actin promoter | HGPIN with microinvasion | [53] |
Pten | Loss of expression | Myc gain of expression under control of CMV enhancer and β-actin promoter | Microinvasive cancer with disruption of smooth muscle actin | [54] |
Model | Alteration | Driver and/or Add. Genetic Alteration | Phenotype | Reference |
---|---|---|---|---|
Nkx3.1 | Loss of expression | Hemizygous loss of Pten (germline heterozygous Pten allele) | HGPIN with invasive adenocarcinoma | [55,56] |
p27Kip1 | Loss of expression | Hemizygous loss of Pten (germline heterozygous Pten allele) | HGPIN with invasive adenocarcinoma | [57,58] |
Aft3 | Loss of expression | Homozygous loss of Pten (conditional Pten allele) | HGPIN with invasive adenocarcinoma | [59] |
Apcflox | Loss of expression | PBCre4 driver | HGPIN followed by local adenocarcinoma | [60] |
Bmi1 | Gain of expression | Hemizygous loss of Pten (germline heterozygous Pten allele) | Locally invasive and highly vascularized adenocarcinoma, with frequent bladder outlet obstruction | [61] |
Tsc2 | Loss of expression | Hemizygous loss of Pten (germline heterozygous Pten allele) | Invasive adenocarcinoma; enhanced lymphoid proliferation; development of skin cancer | [62] |
Phlpp1 | Loss of expression | Hemizygous loss of Pten (germline heterozygous Pten allele) | Invasive adenocarcinoma at full penetrance with onset of 8 months | [63] |
Chk1 | Loss of expression | Hemizygous loss of Pten (germline heterozygous Pten allele) | Progression of HGPIN into invasive adenocarcinoma | [64] |
PKCε | Gain of expression | Hemizygous loss of Pten (germline heterozygous Pten allele) | Invasive adenocarcinoma, preferentially in ventral prostate | [65] |
Gata3 | Loss of expression | Homozygous loss of Pten (conditional Pten allele) | Acceleration of invasive adenocarcinoma | [66] |
Erg | Gain of expression | Homozygous loss of Pten (conditional Pten allele) | Foci of invasive adenocarcinoma with varying levels of Erg expression | [67,68] |
Etv1 | Gain of expression | Homozygous loss of Pten (conditional Pten allele) | Invasive adenocarcinoma with homogenous Etv1 expression | [69] |
Junb | Loss of expression | Homozygous loss of Pten (conditional Pten allele) | Invasive adenocarcinoma in anterior prostate, with strong histological similarity to human PCa | [70] |
SPOP- F133V | Gain of expression | Homozygous loss of Pten (conditional Pten allele) | Invasive, poorly differentiated, and highly proliferative adenocarcinoma | [71] |
PSGR | Gain of expression | Homozygous loss of Pten (conditional Pten allele) | Invasive adenocarcinoma featuring Akt activation and extensive inflammatory cell infiltration | [72] |
Zbtb7a | Loss of expression | Homozygous loss of Pten (conditional Pten allele) | Highly penetrant invasive adenocarcinoma at 11 weeks | [73] |
Hepsin | Gain of expression | Myc gain of expression under control of PB driver | Invasive adenocarcinoma lacking glandular prostate differentiation and clear basement membrane contour | [74] |
MMP7 | Gain of expression | Loss of Pten function | Invasive adenocarcinoma through induction of epithelial-to-mesenchymal transition (EMT) | [75] |
Ptenadcre+(1) | Loss of expression | Cre-expressing adenovirus via intraductal injection into anterior- posterior prostate | Invasive adenocarcinoma with onset of 8–16 weeks | [76] |
Kindlin-3 | Loss of expression | Xenograft | Subcutaneous prostate cancer tumor growth | [77] |
Model | Alteration | Driver and/or Add. Genetic Alteration | Phenotype | Reference |
---|---|---|---|---|
Ptenflox/flox (exon 5) | Loss of expression | PBCre4 driver | Invasive adenocarcinoma with metastasis to lungs, rarely to lymph nodes | [91] |
Nr2f2 (COUP-TFII) | Gain of expression | Homozygous loss of Pten (conditional Pten allele) | Invasive adenocarcinoma with metastasis to lymph nodes | [92] |
NCoA2 | Gain of expression | Homozygous loss of Pten (conditional Pten allele) | Invasive adenocarcinoma with metastasis to lymph nodes, lungs | [93] |
NSD2 (Whsc-1) | Gain of expression | Homozygous loss of Pten (conditional Pten allele) | Invasive adenocarcinoma with metastasis to lymph nodes, lungs, bone | [94] |
Trp53 | Loss of expression | Homozygous loss of Pten (conditional Pten allele) | Invasive adenocarcinoma with metastasis to lymph nodes, spleen, liver, organs near GU tract excluding bladder | [95,96,97] |
Rb | Loss of expression | Homozygous loss of Pten (conditional Pten allele) | Invasive adenocarcinoma with metastasis to lymph nodes, lungs, liver that resembles NEPC | [98] |
Jnk1/2 | Loss of expression | Homozygous loss of Pten (conditional Pten allele) | Invasive adenocarcinoma with metastasis to lymph nodes | [99] |
Stat3 and IL-6 | Loss of expression | Homozygous loss of Pten (conditional Pten allele) | Poorly differentiated cancer with metastasis to liver, lungs | [100] |
NICD | Gain of expression | Homozygous loss of Pten (conditional Pten allele) | Invasive adenocarcinoma with metastasis to liver, lungs | [101] |
Smad4 | Loss of expression | Homozygous loss of Pten (conditional Pten allele) | Invasive adenocarcinoma with metastasis | [102] |
Smad4/p53 | Loss of expression | Homozygous loss of Pten (conditional Pten allele) | Invasive adenocarcinoma with metastasis to bone | [103] |
HoxB13/Myc | Gain of expression | Homozygous loss of Pten (conditional Pten allele) | Invasive adenocarcinoma with metastasis to lymph nodes, liver, lungs | [104] |
Braf V600E (1) | Gain of expression | Homozygous loss of Pten (conditional Pten allele) | Invasive adenocarcinoma with metastasis to lymph nodes, bone marrow, lungs | [105] |
p53floxRbflox | Loss of expression | Homozygous loss of Pten (conditional Pten allele) PBCre4 driver (2) | Metastatic carcinoma, with distant metastases | [106] |
* NPKEYFP | Nkx3.1 loss of expression Pten loss of expression Kras gain of expression | Nkx3.1CreERT2/+ (3) Ptenflox/flox KrasLSL-G12D/+ (4) | Invasive adenocarcinoma with metastasis to bone | [107] |
SIRT-6 | Gain of expression | Luciferase expressing PC3M cells in an orthotopic xenograft mouse model | Metastasis to liver; upregulation of N-cadherin and vimentin, downregulation of E-cadherin in vitro | [108] |
RIPK2 | Gain of expression | Injection of RIPK2-KO 22Rv1 cells into male SCID/Beige mice | Invasive adenocarcinoma with metastasis to bone | [109] |
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Adamiecki, R.; Hryniewicz-Jankowska, A.; Ortiz, M.A.; Li, X.; Porter-Hansen, B.A.; Nsouli, I.; Bratslavsky, G.; Kotula, L. In Vivo Models for Prostate Cancer Research. Cancers 2022, 14, 5321. https://doi.org/10.3390/cancers14215321
Adamiecki R, Hryniewicz-Jankowska A, Ortiz MA, Li X, Porter-Hansen BA, Nsouli I, Bratslavsky G, Kotula L. In Vivo Models for Prostate Cancer Research. Cancers. 2022; 14(21):5321. https://doi.org/10.3390/cancers14215321
Chicago/Turabian StyleAdamiecki, Robert, Anita Hryniewicz-Jankowska, Maria A. Ortiz, Xiang Li, Baylee A. Porter-Hansen, Imad Nsouli, Gennady Bratslavsky, and Leszek Kotula. 2022. "In Vivo Models for Prostate Cancer Research" Cancers 14, no. 21: 5321. https://doi.org/10.3390/cancers14215321
APA StyleAdamiecki, R., Hryniewicz-Jankowska, A., Ortiz, M. A., Li, X., Porter-Hansen, B. A., Nsouli, I., Bratslavsky, G., & Kotula, L. (2022). In Vivo Models for Prostate Cancer Research. Cancers, 14(21), 5321. https://doi.org/10.3390/cancers14215321