Purification and direct transformation of epithelial progenitor cells from primary human prostate
Open accessAbstract
Epithelial cell transformation has been demonstrated in numerous animal models for the study of solid tumor biology. However, little evidence exists for human epithelial cell transformation without previous immortalization via genetic influences such as SV40 T-antigen, thus limiting our knowledge of the events that can transform naive human epithelium. Here we describe a system developed in our laboratory to directly transform freshly isolated primary human prostate epithelial cells without previous culture or immortalization. Prostate tissue is obtained from patients and benign tissue is separated from malignant tissue. Benign and malignant tissues are mechanically and enzymatically dissociated to single cells overnight, and immune cells and epithelial subsets are isolated on the basis of differential expression of surface antigens. Epithelial progenitor cells are transduced with lentiviruses expressing oncogenes and combined with inductive stroma for in vivo studies. At 8-16 weeks after transplantation into immune-deficient mice, the development of lesions, histologically classified as benign prostate, prostatic intraepithelial neoplasia and adenocarcinoma, can be evaluated.
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Lot-to-lot variations of Matrigel compound the difficulty of identifying the signals necessary for organoid structure and function.
“The undefined nature of Matrigel makes it difficult to identify the signals necessary for organoid structure and function; this difficulty is compounded by lot-to-lot variations of Matrigel45–48.”
From Towards organoid culture without Matrigel (2021) · cites this paper as [45]
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- [11]Lawson DA Basal epithelial stem cells are efficient targets for prostate cancer initiation. Proc Natl Acad Sci U S A 2010 107 2610 5 20133806 PMC2823887
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“[29] to obtain a cell suspension enriched in normal prostatic epithelial-cells.”
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“The Witte group developed a similar method to isolate and genetically modify epithelial progenitor cells from human prostates (42).”
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Aging of the progenitor cells that initiate prostate cancer
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“We and others have utilized an approach to transform primary benign human prostate epithelial cells and evaluate the capacity of distinct cell-types to initiate cancer in immune deficient mice[57, 58].”
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“The epithelial cell transformation and organoid method have been described in detail previously (17, 57).”
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CD38 is methylated in prostate cancer and regulates extracellular NAD+
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“While spheroid culture methodology has previously been reported for prostate cancer cell lines or prostate stem/progenitor cells [25], the methodology described by Kondo et al.”
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“A human tissue recombination assay was developed to test the transformation capacity of naı̈ve benign basal and luminal epithelial cells taken from freshly isolated clinical specimens (Goldstein et al. 2011).”
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“However, it has recently been demonstrated that both basal (Xin et al. 2007, Lamb et al. 2010, Lukacs et al. 2010, Goldstein et al. 2011, Hofner et al. 2015) and luminal (Wang et al. 2009, Karthaus et al. 2014) progenitors can be propagated and differentiated ex vivo under optimized culture…”
BackgroundSelf-citation3D Human Organoids: The Next “Viral” Model for the Molecular Basis of Infectious Diseases
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Cells of Origin for Prostate Cancer
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“These results are comparable to those obtained in transplantation experiments performed with PESCs isolated from primary prostate biopsies (Goldstein et al., 2010, 2011; Lukacs et al., 2010).”
BackgroundMethodResultInfluentialProstate epithelial stem and progenitor cells.
Kwon, O., & Xin, L. (2014) · PubMed Central · Cited by 24 · see citing works
Divergent FOXA1 mutations drive prostate tumorigenesis and therapy-resistant cellular plasticity
Eyunni, S., Mannan, R., Zhang, Y., Young, E., Zhang, Q., Luo, J., Pang, M., Mahapatra, S., Tien, J. C.-Y., George, J. M., et al. (2025) · Science · doi:10.1126/science.adv2367 · Cited by 27 · see citing works
“In vitro CRE recombination was achieved by adenoviral delivery of CRE recombinase-containing virus or empty vector based on previously published protocols (48).”
Zhang, D., Lin, K., Lu, Y., Rycaj, K., Zhong, Y., Chao, H., Calhoun‐Davis, T., Shen, J., & Tang, D. G. (2016) · Stem Cells Translational Medicine · doi:10.5966/sctm.2016-0243 · Cited by 23 · see citing works
Isolation and analysis of discreet human prostate cellular populations
Strand, D. W., Aaron, L., Henry, G. H., Franco, O. E., & Hayward, S. W. (2015) · Differentiation · doi:10.1016/j.diff.2015.10.013 · Cited by 22 · see citing works
“Per previous protocols (Goldstein et al., 2011; Hofner et al., 2015), we began by digesting with 1 mg/ml collagenase I, II or IV overnight.”
A Single-Organelle Optical Omics Platform for Cell Science and Biomarker Discovery
Pliss, A., Kuzmin, A. N., Lita, A., Kumar, R., Celiku, O., Atilla‐Gokcumen, G. E., Gökçümen, Ö., Chandra, D., Larion, M., & Prasad, P. N. (2021) · Analytical Chemistry · doi:10.1021/acs.analchem.1c01131 · Cited by 21 · see citing works
Butler, W., Xu, L., Zhou, Y., Cheng, Q., Hauck, J. S., He, Y., Marek, R. D., Hartman, Z. C., Liang Cheng, C., Yang, Q., et al. (2023) · The Journal of Pathology · doi:10.1002/path.6063 · Cited by 20 · see citing works
“Six patient samples were collected at Duke University Hospital representing the spectrum of PCa (hormonesensitive adenocarcinoma [4], localized CRPC [1], metastatic CRPC [1], and SCNC [1]), as previously published [25,26].”
ResultSelf-citationKozlowski, M. T., Zook, H. N., Chigumba, D. N., Johnstone, C. P., Caldera, L. F., Shih, H.-P., Tirrell, D. A., & Ku, H. T. (2023) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2023.1144209 · Cited by 20 · see citing works
“Matrigel also suffers from lot-to-lot variation, which affects cellular fate decisions (Vukicevic et al., 1992; Goldstein et al., 2011).”
BackgroundLiu, S. T., Cadaneanu, R. M., Zhang, B., Huo, L., Lai, K., Li, X., Galet, C., Grogan, T., Elashoff, D. A., Freedland, S. J., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0163232 · Cited by 20 · see citing works
Dambal, S., Baumann, B., McCray, T., Williams, L., Richards, Z. A., Deaton, R. J., Prins, G. S., & Nonn, L. (2017) · Scientific Reports · doi:10.1038/s41598-017-07979-y · Cited by 19 · see citing works
In Vivo Imaging of Methionine Aminopeptidase II for Prostate Cancer Risk Stratification
Xie, J., Rice, M. A., Chen, Z., Cheng, Y., Hsu, E., Chen, M., Song, G., Cui, L., Zhou, K., Castillo, J. B., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-2969 · Cited by 16 · see citing works
“High levels of MetAP2 are predictive for biochemical recurrence in prostate cancer We first measured the protein levels of MetAP2 in a panel of prostate cell lines, including a benign human prostate epithelial cell line, PrEC (28), and prostate cancer cell lines PC3, DU145, and 22Rv1, and their corresponding tumor xen…”
BackgroundInfluentialRole of CEACAM1 and CEACAM20 in an In Vitro Model of Prostate Morphogenesis
Zhang, H., Eisenried, A., Zimmermann, W., & Shively, J. E. (2013) · PLoS ONE · doi:10.1371/journal.pone.0053359 · Cited by 16 · see citing works
“Cells on Matrigel were washed with PBS once before incubation with 1 mg/mL dispase solution (Invitrogen, dispase was dissolved in ProstaLife Medium Complete Kit) for 1 h at 37uC [18].”
MethodSelf-citationTaipale, K., Tähtinen, S., Havunen, R., Koski, A., Liikanen, I., Pakarinen, P. I., Koivisto-Korander, R., Kankainen, M., Joensuu, T. K., Kanerva, A., et al. (2018) · Oncotarget · doi:10.18632/oncotarget.23967 · Cited by 16 · see citing works
Chen, X., Liu, B., Li, Q., Honorio, S., Liu, X., Liu, C., Multani, A. S., Calhoun‐Davis, T., & Tang, D. G. (2013) · PLoS ONE · doi:10.1371/journal.pone.0056903 · Cited by 14 · see citing works
Maturation of the developing human fetal prostate in a rodent xenograft model
Saffarini, C. M., McDonnell, E. V., Amin, A., Spade, D. J., Huse, S. M., Kostadinov, S., Hall, S. J., & Boekelheide, K. (2013) · The Prostate · doi:10.1002/pros.22713 · Cited by 13 · see citing works
“[70] isolated primary human basal epithelial cells to demonstrate that transformed basal cells in particular are capable of developing into BPH in a xenotransplantation model [71], thus providing further evidence that separating the compartments of the prostate can provide invaluable information on prostate cancer ini…”
BackgroundPeek, E. M., Wang, S., Zhang, H., Huang, J., & Chin, A. I. (2015) · The Prostate · doi:10.1002/pros.22932 · Cited by 13 · see citing works
“Preliminary studies have shown that a kidney implantation model holds promise in dissecting out the various compartments [48].”
BackgroundSelf-citationDNA polymerase ζ deficiency causes impaired wound healing and stress-induced skin pigmentation
Lange, S. S., Bhetawal, S., Reh, S., Powell, K. L., Kusewitt, D. F., & Wood, R. D. (2018) · Life Science Alliance · doi:10.26508/lsa.201800048 · Cited by 11 · see citing works
Inflammation promotes prostate differentiation
Liu, X., & Goldstein, A. S. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1323181111 · Cited by 9 · see citing works
Self-citationThe molecular basis for ethnic variation and histological subtype differences in prostate cancer
Zong, Y., Goldstein, A. S., & Huang, J. (2013) · Science China Life Sciences · doi:10.1007/s11427-013-4522-0 · Cited by 8 · see citing works
Self-citationFox, J. J., Navarro, H. I., Hashimoto, T., Garcia, A. J., & Goldstein, A. S. (2019) · PubMed Central · Cited by 8 · see citing works
Self-citationModulation of the cytoskeleton for cancer therapy
Matov, A. (2026) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1681065 · Cited by 7 · see citing works
Microtubule regulation in cancer cells
Matov, A. (2026) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1677302 · Cited by 2 · see citing works
“If this step yielded too much contamination with non-epithelial cells, for instance during processing of primary prostate tumors, the protocol incorporated additional washes and red blood cell lysis (Goldstein et al., 2011).”
Estrogen modulates epithelial progenitor cells in rat vagina
Chung, H. S., Lee, H.-S., & Park, K. (2021) · Korean journal of urology · doi:10.4111/icu.20200513 · Cited by 7 · see citing works
“Several studies have investigated EPCs and their role at different sites, including the urogenital tract and female reproductive tract [6,7,14].”
BackgroundMu, J., Li, R., Yu, Z., Lu, Y., Ма, Л., Yin, L., Zhang, M., Ma, W., Chang, M., Liu, A., et al. (2024) · Stem Cell Research & Therapy · doi:10.1186/s13287-024-03917-8 · Cited by 6 · see citing works
Höfner, T., Klein, C., Eisen, C., Rigo‐Watermeier, T., Haferkamp, A., & Sprick, M. R. (2016) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.12785 · Cited by 6 · see citing works
“However, basal PESCs are rare, with a frequency of 1– 5% within all prostatic cells, which clearly complicates biological studies using these cells [5, 6].”
BackgroundAng, L. T., Zheng, S. L., Liu, K. J., Masaltseva, A., Winters, J., Jha, S. K., Yin, Q., Qian, C., Xiong, X., Dailamy, A., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.11.681838 · Cited by 6 · see citing works
Computational analysis of treatment resistant cancer cells
Matov, A. (2026) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1723251 · Cited by 5 · see citing works
“As much as such results seem unlikely, they might indicate that early-stage PC might be a purely histological phenomenon which reverses when the hypoxia-inducible factor 1 α (HIF1 α ) and the glycogen synthase kinase 3 (GSK3) are downregulated; they also suggest a strategy to reverse the…”
Patierno, B. M., Foo, W., Allen, T. A., Somarelli, J. A., Ware, K. E., Gupta, S. K., Wise, S. S., Wise, J. P., Qin, X., Zhang, D., et al. (2021) · Prostate Cancer and Prostatic Diseases · doi:10.1038/s41391-021-00460-y · Cited by 5 · see citing works
“PCPDX generation All animal studies were performed under a Duke University Animal Care and Use Committee (IACUC) approved protocol and PDXs were developed, as previously described [16, 17].”
Self-citationMicrotubule Dysregulation in Prostate Cancer Metastasis to the VertebraePreprint
Matov, A. (2025) · SSRN Electronic Journal · doi:10.2139/ssrn.5112427 · Cited by 5 · see citing works
Human and murine prostate basal/stem cells are not direct targets of prolactin
Sackmann‐Sala, L., Angelergues, A., Boutillon, F., d'Acremont, B., Maidenberg, M., Oudard, S. M., & Goffin, V. (2015) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2015.04.007 · Cited by 4 · see citing works
s-SHIP expression identifies a subset of murine basal prostate cells as neonatal stem cells
Brocqueville, G., Chmelar, R. S., Roy, H. B., Deruy, E., Tian, L., Vessella, R. L., Greenberg, N. M., Rohrschneider, L. R., & Bourette, R. P. (2016) · Oncotarget · doi:10.18632/oncotarget.8709 · Cited by 4 · see citing works
“Using combinations of cellsurface markers, fractionated mouse PSCs have been identified as Lin−Sca-1+ CD133+ CD44+ CD117+ proximal cells [15], Lin−Sca1+ CD49f+ [8] and Lin−Sca1+ CD49fhigh Trop2high basal cells [16–18].”
MethodTissue Recombination Models for the Study of Epithelial CancerPreprint
Zong, Y., Goldstein, A. S., & Witte, O. N. (2015) · Cold Spring Harbor Protocols · doi:10.1101/pdb.top069880 · Cited by 4 · see citing works
“Recently, we successfully established a direct in vivo transformation assay starting with naïve human prostate epithelial cells (Goldstein et al. 2010, 2011).”
Self-citationAnalysis of Genome-Wide Cell-Free DNA Fragment Length Distributions in Colorectal CancerPreprint
Matov, A. (2024) · medRxiv · doi:10.1101/2024.07.17.24310568 · Cited by 4 · see citing works
Cross-species stromal signaling programs human embryonic stem cell differentiation
Taylor, R. A., & Risbridger, G. P. (2014) · Differentiation · doi:10.1016/j.diff.2014.01.003 · Cited by 3 · see citing works
Protocols for Studies on TMPRSS2/ERG in Prostate Cancer
Pakula, H., Linn, D. E., Schmidt, D. R., van Gorsel, M., Heiden, M. G. V., & Li, Z. (2018) · Methods in molecular biology · doi:10.1007/978-1-4939-7845-8_8 · Cited by 2 · see citing works
Measurements of Contractility in Actin Convergence Zone and KIF11-Inhibited Mitotic SpindlesPreprint
Matov, A. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.06.28.601275 · Cited by 3 · see citing works
Analysis of Multiple Myeloma Drug EfficacyPreprint
Matov, A. (2024) · medRxiv · doi:10.22541/au.172495995.58510565/v1 · Cited by 2 · see citing works
Quantitative Cell Division and Migration in MedicinePreprint
Matov, A. (2025) · SSRN Electronic Journal · doi:10.2139/ssrn.5130515 · Cited by 3 · see citing works
Stoyanova, T. I., & Goldstein, A. S. (2014) · Cancer Cell & Microenvironment · doi:10.14800/ccm.90 · Cited by 2 · see citing works
“This assay allows for the isolation of distinct cell types from primary benign human tissues such as basal or luminal cells based on surface marker expression ([3-5]).”
BackgroundMethodSelf-citationContribution of the ELRs to the development of advanced in vitro models
Puertas‐Bartolomé, M., Venegas‐Bustos, D., Acosta, S., & Rodríguez‐Cabello, J. C. (2024) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2024.1363865 · Cited by 2 · see citing works
Overview of Primary Cell Culture Models in Preclinical Research of Prostate and Bladder Cancer
Killekar, K., Puranik, S. I., Aimen Akbar, A., Ghagane, S. C., Nerli, R. B., & Hiremath, M. B. (2022) · Biochemistry · doi:10.5772/intechopen.99493 · Cited by 3 · see citing works
Stem Cell Models for Functional Validation of Prostate Cancer Genes
Ulkus, L., Wu, M., & Cramer, S. D. (2013) · Springer eBooks · doi:10.1007/978-1-4614-6498-3_9 · Cited by 1 · see citing works
The clinical potential of patient-derived microphysiological systems: a narrative review
Lee, T., Min, J., Lee, Y., & Ko, J. (2025) · Journal of Korean Medical Association · doi:10.5124/jkma.25.0082 · Cited by 1 · see citing works
Urinary biomarkers for lung cancer detection
Matov, A. (2026) · The Journal of Liquid Biopsy · doi:10.1016/j.jlb.2026.100456 · Cited by 1 · see citing works
“If this step yielded too much contamination with non-epithelial cells, for instance during processing of primary prostate tumors, the protocol incorporated additional washes and red blood cell lysis [26].”
Isolation and Characterization of Prostate Stem Cells
Goldstein, A. S., & Witte, O. N. (2013) · Springer eBooks · doi:10.1007/978-1-4614-6498-3_2
“This strategy enables parallel identifi cation of cell populations from naïve rodent (primarily mouse) and human tissues taken from surgical specimens (Lukacs et al. 2010a ; Goldstein et al. 2011 ).”
BackgroundMethodSelf-citationRegulation of the Prostate Cancer Tumor Microenvironment
Chin, A. I. (2012) · doi:10.21236/ada560887
Deep RNA-Seq analysis reveals unexpected features of human prostate basal epithelial cells
Zhang, D., Park, D., Lü, Y., Shen, J., Iyer, V. R., & Tang, D. G. (2015) · Genomics Data · doi:10.1016/j.gdata.2015.09.003
Goldstein, A. S. (2014) · doi:10.21236/ada611808
Self-citationRegulation of the Prostate Cancer Tumor Microenvironment
Chin, A. I. (2015) · doi:10.21236/ada619861
- Self-citation
Data from In Vivo Imaging of Methionine Aminopeptidase II for Prostate Cancer Risk Stratification
Xie, J., Rice, M. A., Chen, Z., Cheng, Y., Hsu, E., Chen, M., Song, G., Cui, L., Zhou, K., Castillo, J. B., et al. (2023) · doi:10.1158/0008-5472.c.6513415.v1
- Authors
- Goldstein, A. S., Drake, J. M., Burnes, D. L., Finley, D. S., Zhang, H., Reiter, R. E., Huang, J., & Witte, O. N.
- Affiliations
- University of California, Los Angeles (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Witte, Owen N
- ORCID
- Venue
- Nature Protocols
- Published
- 2011-04-21
- Volume
- 6
- Issue
- 5
- Pages
- 656-667
- ISSN
- 1750-2799 (ISSN-L)
- 1754-2189
- PMC
- PMC3092477
- OpenAlex
- W2105504226
- Cited by
- 107
- References
- 18
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 7 · 2023: 7 · 2022: 5 · 2021: 6 · 2020: 3 · 2019: 6 · 2018: 6 · 2017: 5 · 2016: 12 · 2015: 9 · 2014: 9 · 2013: 17 · 2012: 3
- FWCI
- 7.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Protocols (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (T32CA009056)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- epithelial cell transformation, prostate epithelial cells, epithelial progenitor cells, prostatic intraepithelial neoplasia, prostate adenocarcinoma, benign prostatic hyperplasia, xenograft models, cell isolation
- MeSH terms
- Animals, Cell Transformation, Neoplastic, Cells, Cultured, Epithelial Cells, Humans, Male, Prostate, Prostatic Neoplasms, Stem Cells, Mice
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