Establishment and characterization of prostate organoids from treatment‑naïve patients with prostate cancer

Cheaito,Katia; Cheaito,Katia; Cheaito,Katia; Bahmad,Hisham F.; Bahmad,Hisham F.; Bahmad,Hisham F.; Hadadeh,Ola; Hadadeh,Ola; Hadadeh,Ola; Msheik,Hiba; Msheik,Hiba; Msheik,Hiba; Monzer,Alissar; Monzer,Alissar; Monzer,Alissar; Ballout,Farah; Ballout,Farah; Ballout,Farah; Dagher,Christelle; Dagher,Christelle; Dagher,Christelle; Telvizian,Talar; Telvizian,Talar; Telvizian,Talar; Saheb,Nour; Saheb,Nour; Saheb,Nour; Tawil,Ayman; Tawil,Ayman; Tawil,Ayman; El‑Sabban,Marwan; El‑Sabban,Marwan; El‑Sabban,Marwan; El‑Hajj,Albert; El‑Hajj,Albert; El‑Hajj,Albert; Mukherji,Deborah; Mukherji,Deborah; Mukherji,Deborah; Al‑Sayegh,Mohamed; Al‑Sayegh,Mohamed; Al‑Sayegh,Mohamed; Abou‑Kheir,Wassim; Abou‑Kheir,Wassim; Abou‑Kheir,Wassim

doi:10.3892/ol.2021.13124

Establishment and characterization of prostate organoids from treatment‑naïve patients with prostate cancer

Authors:
- Katia Cheaito
- Hisham F. Bahmad
- Ola Hadadeh
- Hiba Msheik
- Alissar Monzer
- Farah Ballout
- Christelle Dagher
- Talar Telvizian
- Nour Saheb
- Ayman Tawil
- Marwan El‑Sabban
- Albert El‑Hajj
- Deborah Mukherji
- Mohamed Al‑Sayegh
- Wassim Abou‑Kheir
View Affiliations

Affiliations: Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107‑2020, Lebanon, Department of Internal Medicine, Division of Hematology/Oncology, Faculty of Medicine, American University of Beirut Medical Center, Beirut 1107‑2020, Lebanon, Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut 1107‑2020, Lebanon, Department of Surgery, Division of Urology, American University of Beirut Medical Center, Beirut 1107‑2020, Lebanon, Biology Division, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
Published online on: November 5, 2021 https://doi.org/10.3892/ol.2021.13124
Article Number: 6
Copyright: © Cheaito et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Three‑dimensional (3D) organoid culture systems are emerging as potential reliable tools to investigate basic developmental processes of human disease, especially cancer. The present study used established and modified culture conditions to report successful generation and characterization of patient‑derived organoids from fresh primary tissue specimens of patients with treatment‑naïve prostate cancer (PCa). Fresh tissue specimens were collected, digested enzymatically and the resulting cell suspensions were plated in a 3D environment using Matrigel as an extracellular matrix. Previously established 12‑factor medium for organoid culturing was modified to create a minimal 5‑factor medium. Organoids and corresponding tissue specimens were characterized using transcriptomic analysis, immunofluorescent analysis, and immunohistochemistry. Furthermore, patient‑derived organoids were used to assess the drug response. Treatment‑naïve patient‑derived PCa organoids were obtained from fresh radical prostatectomy specimens. These PCa organoids mimicked the heterogeneity of corresponding parental tumor tissue. Histopathological analysis demonstrated similar tissue architecture and cellular morphology, as well as consistent immunohistochemical marker expression. Also, the results confirmed the potential of organoids as an in vitro model to assess potential personalized treatment responses as there was a differential drug response between different patient samples. In conclusion, the present study investigated patient‑derived organoids from a cohort of treatment‑naïve patients. Derived organoids mimicked the histological features and prostate lineage profiles of their corresponding parental tissue and may present a potential model to predict patient‑specific treatment response in a pre‑clinical setting.

View Figures

View References

1	Siegel RL, Miller KD, Fuchs HE and Jemal A: Cancer statistics, 2021. CA Cancer J Clin. 71:7–33. 2021. View Article : Google Scholar : PubMed/NCBI
2	Shoag J and Barbieri CE: Clinical variability and molecular heterogeneity in prostate cancer. Asian J Androl. 18:543–548. 2016. View Article : Google Scholar : PubMed/NCBI
3	Williams JL, Greer PA and Squire JA: Recurrent copy number alterations in prostate cancer: An in silico meta-analysis of publicly available genomic data. Cancer Genet. 207:474–488. 2014. View Article : Google Scholar : PubMed/NCBI
4	Karantanos T, Corn PG and Thompson TC: Prostate cancer progression after androgen deprivation therapy: Mechanisms of castrate resistance and novel therapeutic approaches. Oncogene. 32:5501–5511. 2013. View Article : Google Scholar : PubMed/NCBI
5	Gao D and Chen Y: Organoid development in cancer genome discovery. Curr Opin Genet Dev. 30:42–48. 2015. View Article : Google Scholar : PubMed/NCBI
6	Horoszewicz JS, Leong SS, Kawinski E, Karr JP, Rosenthal H, Chu TM, Mirand EA and Murphy GP: LNCaP model of human prostatic carcinoma. Cancer Res. 43:1809–1818. 1983.PubMed/NCBI
7	Kaighn ME, Narayan KS, Ohnuki Y, Lechner JF and Jones LW: Establishment and characterization of a human prostatic carcinoma cell line (PC-3). Invest Urol. 17:16–23. 1979.PubMed/NCBI
8	Korenchuk S, Lehr JE, MClean L, Lee YG, Whitney S, Vessella R, Lin DL and Pienta KJ: VCaP, a cell-based model system of human prostate cancer. In vivo. 15:163–168. 2001.PubMed/NCBI
9	Navone NM, Olive M, Ozen M, Davis R, Troncoso P, Tu SM, Johnston D, Pollack A, Pathak S, von Eschenbach AC and Logothetis CJ: Establishment of two human prostate cancer cell lines derived from a single bone metastasis. Clin Cancer Res. 3:2493–2500. 1997.PubMed/NCBI
10	Sramkoski RM, Pretlow TG II, Giaconia JM, Pretlow TP, Schwartz S, Sy MS, Marengo SR, Rhim JS, Zhang D and Jacobberger JW: A new human prostate carcinoma cell line, 22Rv1. In Vitro Cell Dev Biol Anim. 35:403–409. 1999. View Article : Google Scholar : PubMed/NCBI
11	Mertz KD, Setlur SR, Dhanasekaran SM, Demichelis F, Perner S, Tomlins S, Tchinda J, Laxman B, Vessella RL, Beroukhim R, et al: Molecular characterization of TMPRSS2-ERG gene fusion in the NCI-H660 prostate cancer cell line: A new perspective for an old model. Neoplasia. 9:200–206. 2007. View Article : Google Scholar : PubMed/NCBI
12	Schwank G, Andersson-Rolf A, Koo BK, Sasaki N and Clevers H: Generation of BAC transgenic epithelial organoids. PLoS One. 8:e768712013. View Article : Google Scholar : PubMed/NCBI
13	Drost J, Karthaus WR, Gao D, Driehuis E, Sawyers CL, Chen Y and Clevers H: Organoid culture systems for prostate epithelial tissue and prostate cancer tissue. Nat Protoc. 11:347–358. 2016. View Article : Google Scholar : PubMed/NCBI
14	Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, van Es JH, Abo A, Kujala P, Peters PJ and Clevers H: Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 459:262–265. 2009. View Article : Google Scholar : PubMed/NCBI
15	Koo BK, Stange DE, Sato T, Karthaus W, Farin HF, Huch M, van Es JH and Clevers H: Controlled gene expression in primary Lgr5 organoid cultures. Nat Methods. 9:81–83. 2011. View Article : Google Scholar : PubMed/NCBI
16	Bartucci M, Ferrari AC, Kim IY, Ploss A, Yarmush M and Sabaawy HE: Personalized medicine approaches in prostate cancer employing patient derived 3D organoids and humanized mice. Front Cell Dev Biol. 4:642016. View Article : Google Scholar : PubMed/NCBI
17	Barker N, Huch M, Kujala P, van de Wetering M, Snippert HJ, van Es JH, Sato T, Stange DE, Begthel H, van den Born M, et al: Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell stem cell. 6:25–36. 2010. View Article : Google Scholar : PubMed/NCBI
18	Stange DE, Koo BK, Huch M, Sibbel G, Basak O, Lyubimova A, Kujala P, Bartfeld S, Koster J, Geahlen JH, et al: Differentiated Troy+ chief cells act as reserve stem cells to generate all lineages of the stomach epithelium. Cell. 155:357–368. 2013. View Article : Google Scholar : PubMed/NCBI
19	Sachs N and Clevers H: Organoid cultures for the analysis of cancer phenotypes. Curr Opin Genet Dev. 24:68–73. 2014. View Article : Google Scholar : PubMed/NCBI
20	Jung P, Sato T, Merlos-Suarez A, Barriga FM, Iglesias M, Rossell D, Auer H, Gallardo M, Blasco MA, Sancho E, et al: Isolation and in vitro expansion of human colonic stem cells. Nat Med. 17:1225–1227. 2011. View Article : Google Scholar : PubMed/NCBI
21	Taguchi A, Kaku Y, Ohmori T, Sharmin S, Ogawa M, Sasaki H and Nishinakamura R: Redefining the in vivo origin of metanephric nephron progenitors enables generation of complex kidney structures from pluripotent stem cells. Cell Stem Cell. 14:53–67. 2014. View Article : Google Scholar : PubMed/NCBI
22	Takasato M, Er PX, Becroft M, Vanslambrouck JM, Stanley EG, Elefanty AG and Little MH: Directing human embryonic stem cell differentiation towards a renal lineage generates a self-organizing kidney. Nat Cell Biol. 16:118–126. 2014. View Article : Google Scholar : PubMed/NCBI
23	Antonica F, Kasprzyk DF, Opitz R, Iacovino M, Liao XH, Dumitrescu AM, Refetoff S, Peremans K, Manto M, Kyba M and Costagliola S: Generation of functional thyroid from embryonic stem cells. Nature. 491:66–71. 2012. View Article : Google Scholar : PubMed/NCBI
24	Koehler KR, Mikosz AM, Molosh AI, Patel D and Hashino E: Generation of inner ear sensory epithelia from pluripotent stem cells in 3D culture. Nature. 500:217–221. 2013. View Article : Google Scholar : PubMed/NCBI
25	Eiraku M, Takata N, Ishibashi H, Kawada M, Sakakura E, Okuda S, Sekiguchi K, Adachi T and Sasai Y: Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature. 472:51–56. 2011. View Article : Google Scholar : PubMed/NCBI
26	Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, Homfray T, Penninger JM, Jackson AP and Knoblich JA: Cerebral organoids model human brain development and microcephaly. Nature. 501:373–379. 2013. View Article : Google Scholar : PubMed/NCBI
27	Agarwal S, Hynes PG, Tillman HS, Lake R, Abou-Kheir WG, Fang L, Casey OM, Ameri AH, Martin PL, Yin JJ, et al: Identification of different classes of luminal progenitor cells within prostate tumors. Cell Rep. 13:2147–2158. 2015. View Article : Google Scholar : PubMed/NCBI
28	Kim J, Koo BK and Knoblich JA: Human organoids: Model systems for human biology and medicine. Nat Rev Mol Cell Biol. 21:571–584. 2020. View Article : Google Scholar : PubMed/NCBI
29	Velasco S, Kedaigle AJ, Simmons SK, Nash A, Rocha M, Quadrato G, Paulsen B, Nguyen L, Adiconis X and Regev A: Individual brain organoids reproducibly form cell diversity of the human cerebral cortex. Nature. 570:523–527. 2019. View Article : Google Scholar : PubMed/NCBI
30	Karthaus WR, Iaquinta PJ, Drost J, Gracanin A, van Boxtel R, Wongvipat J, Dowling CM, Gao D, Begthel H, Sachs N, et al: Identification of multipotent luminal progenitor cells in human prostate organoid cultures. Cell. 159:163–175. 2014. View Article : Google Scholar : PubMed/NCBI
31	Gao D, Vela I, Sboner A, Iaquinta PJ, Karthaus WR, Gopalan A, Dowling C, Wanjala JN, Undvall EA, Arora VK, et al: Organoid cultures derived from patients with advanced prostate cancer. Cell. 159:176–187. 2014. View Article : Google Scholar : PubMed/NCBI
32	Vela I and Chen Y: Prostate cancer organoids: A potential new tool for testing drug sensitivity. Expert Rev Anticancer Ther. 15:261–263. 2015. View Article : Google Scholar : PubMed/NCBI
33	Puca L, Bareja R, Prandi D, Shaw R, Benelli M, Karthaus WR, Hess J, Sigouros M, Donoghue A, Kossai M, et al: Patient derived organoids to model rare prostate cancer phenotypes. Nat Commun. 9:24042018. View Article : Google Scholar : PubMed/NCBI
34	Richards Z, McCray T, Marsili J, Zenner ML, Manlucu JT, Garcia J, Kajdacsy-Balla A, Murray M, Voisine C, Murphy AB, et al: Prostate stroma increases the viability and maintains the branching phenotype of human prostate organoids. iScience. 12:304–317. 2019. View Article : Google Scholar : PubMed/NCBI
35	Drost J and Clevers H: Organoids in cancer research. Nat Rev Cancer. 18:407–418. 2018. View Article : Google Scholar : PubMed/NCBI
36	Elbadawy M, Abugomaa A, Yamawaki H, Usui T and Sasaki K: Development of prostate cancer organoid culture models in basic medicine and translational research. Cancers (Basel). 12:7772020. View Article : Google Scholar : PubMed/NCBI
37	Gleave AM, Ci X, Lin D and Wang Y: A synopsis of prostate organoid methodologies, applications, and limitations. Prostate. 80:518–526. 2020. View Article : Google Scholar : PubMed/NCBI
38	Beshiri ML, Tice CM, Tran C, Nguyen HM, Sowalsky AG, Agarwal S, Jansson KH, Yang Q, McGowen KM, Yin J, et al: A PDX/organoid biobank of advanced prostate cancers captures genomic and phenotypic heterogeneity for disease modeling and therapeutic screening. Clin Cancer Res. 24:4332–4345. 2018. View Article : Google Scholar : PubMed/NCBI
39	Njoroge RN, Unno K, Zhao JC, Naseem AF, Anker JF, McGee WA, Nonn L and Abdulkadir SA: Organoids model distinct vitamin E effects at different stages of prostate cancer evolution. Sci Rep. 7:162852017. View Article : Google Scholar : PubMed/NCBI
40	Santamaria PG, Moreno-Bueno G, Portillo F and Cano A: EMT: Present and future in clinical oncology. Mol Oncol. 11:718–738. 2017. View Article : Google Scholar : PubMed/NCBI
41	Park JW, Lee JK, Phillips JW, Huang P, Cheng D, Huang J and Witte ON: Prostate epithelial cell of origin determines cancer differentiation state in an organoid transformation assay. Proc Natl Acad Sci USA. 113:4482–4487. 2016. View Article : Google Scholar : PubMed/NCBI
42	Berger MF, Lawrence MS, Demichelis F, Drier Y, Cibulskis K, Sivachenko AY, Sboner A, Esgueva R, Pflueger D, Sougnez C, et al: The genomic complexity of primary human prostate cancer. Nature. 470:214–220. 2011. View Article : Google Scholar : PubMed/NCBI
43	Fontugne J, Davis K, Palanisamy N, Udager A, Mehra R, McDaniel AS, Siddiqui J, Rubin MA, Mosquera JM and Tomlins SA: Clonal evaluation of prostate cancer foci in biopsies with discontinuous tumor involvement by dual ERG/SPINK1 immunohistochemistry. Mod Pathol. 29:157–165. 2016. View Article : Google Scholar : PubMed/NCBI
44	Barbieri CE, Bangma CH, Bjartell A, Catto JW, Culig Z, Grönberg H, Luo J, Visakorpi T and Rubin MA: The mutational landscape of prostate cancer. Eur Urol. 64:567–576. 2013. View Article : Google Scholar : PubMed/NCBI
45	Haffner MC, Mosbruger T, Esopi DM, Fedor H, Heaphy CM, Walker DA, Adejola N, Gürel M, Hicks J, Meeker AK, et al: Tracking the clonal origin of lethal prostate cancer. J Clin Invest. 123:4918–4922. 2013. View Article : Google Scholar : PubMed/NCBI
46	Gundem G, Van Loo P, Kremeyer B, Alexandrov LB, Tubio JM, Papaemmanuil E, Brewer DS, Kallio HM, Högnäs G, Annala M, et al: The evolutionary history of lethal metastatic prostate cancer. Nature. 520:353–357. 2015. View Article : Google Scholar : PubMed/NCBI
47	Cheaito K, Bahmad HF, Jalloul H, Hadadeh O, Msheik H, El-Hajj A, Mukherji D, Al-Sayegh M and Abou-Kheir W: Epidermal growth factor is essential for the maintenance of novel prostate epithelial cells isolated from patient-derived organoids. Front Cell Dev Biol. 8:5716772020. View Article : Google Scholar : PubMed/NCBI
48	Bahmad HF, Cheaito K, Chalhoub RM, Hadadeh O, Monzer A, Ballout F, El-Hajj A, Mukherji D, Liu YN, Daoud G and Abou-Kheir W: Sphere-formation assay: Three-dimensional in vitro culturing of prostate cancer stem/progenitor sphere-forming cells. Front Oncol. 8:3472018. View Article : Google Scholar : PubMed/NCBI
49	Love MI, Huber W and Anders S: Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15:5502014. View Article : Google Scholar : PubMed/NCBI
50	Nelson JW, Sklenar J, Barnes AP and Minnier J: The START app: A web-based RNAseq analysis and visualization resource. Bioinformatics. 33:447–449. 2017.PubMed/NCBI
51	Edgar R, Domrachev M and Lash AE: Gene expression omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 30:207–210. 2002. View Article : Google Scholar : PubMed/NCBI
52	Reimand J, Isserlin R, Voisin V, Kucera M, Tannus-Lopes C, Rostamianfar A, Wadi L, Meyer M, Wong J, Xu C, et al: Pathway enrichment analysis and visualization of omics data using g:Profiler, GSEA, cytoscape and EnrichmentMap. Nat Protoc. 14:482–517. 2019. View Article : Google Scholar : PubMed/NCBI
53	Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES and Mesirov JP: Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 102:15545–15550. 2005. View Article : Google Scholar : PubMed/NCBI
54	Schaefer CF, Anthony K, Krupa S, Buchoff J, Day M, Hannay T and Buetow KH: PID: The pathway interaction database. Nucleic Acids Res. 37:D674–D679. 2009. View Article : Google Scholar : PubMed/NCBI
55	Kandasamy K, Mohan SS, Raju R, Keerthikumar S, Kumar GS, Venugopal AK, Telikicherla D, Navarro JD, Mathivanan S, Pecquet C, et al: NetPath: A public resource of curated signal transduction pathways. Genome Biol. 11:R32010. View Article : Google Scholar : PubMed/NCBI
56	Romero P, Wagg J, Green ML, Kaiser D, Krummenacker M and Karp PD: Computational prediction of human metabolic pathways from the complete human genome. Genome Biol. 6:R22005. View Article : Google Scholar : PubMed/NCBI
57	Croft D, O'Kelly G, Wu G, Haw R, Gillespie M, Matthews L, Caudy M, Garapati P, Gopinath G, Jassal B, et al: Reactome: A database of reactions, pathways and biological processes. Nucleic Acids Res. 39:D691–697. 2011. View Article : Google Scholar : PubMed/NCBI
58	Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, et al: Gene ontology: Tool for the unification of biology. The gene ontology consortium. Nat Genet. 25:25–29. 2000. View Article : Google Scholar : PubMed/NCBI
59	Mi H, Lazareva-Ulitsky B, Loo R, Kejariwal A, Vandergriff J, Rabkin S, Guo N, Muruganujan A, Doremieux O, Campbell MJ, et al: The PANTHER database of protein families, subfamilies, functions and pathways. Nucleic Acids Res. 33:D284–288. 2005. View Article : Google Scholar : PubMed/NCBI
60	Martin AM, Nirschl TR, Nirschl CJ, Francica BJ, Kochel CM, van Bokhoven A, Meeker AK, Lucia MS, Anders RA, DeMarzo AM and Drake CG: Paucity of PD-L1 expression in prostate cancer: Innate and adaptive immune resistance. Prostate Cancer Prostatic Dis. 18:325–332. 2015. View Article : Google Scholar : PubMed/NCBI
61	Zhu YP, Wan FN, Shen YJ, Wang HK, Zhang GM and Ye DW: Reactive stroma component COL6A1 is upregulated in castration-resistant prostate cancer and promotes tumor growth. Oncotarget. 6:14488–14496. 2015. View Article : Google Scholar : PubMed/NCBI
62	Rasool RU, Natesan R, Deng Q, Aras S, Lal P, Effron SS, Mitchell-Velasquez E, Posimo JM, Carskadon S, Baca SC, et al: CDK7 inhibition suppresses castration-resistant prostate cancer through MED1 inactivation. Cancer Discov. 9:1538–1555. 2019. View Article : Google Scholar : PubMed/NCBI
63	Velardi E, Tsai JJ, Radtke S, Cooper K, Argyropoulos KV, Jae-Hung S, Young LF, Lazrak A, Smith OM, Lieberman S, et al: Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury. Nat Med. 24:239–246. 2018. View Article : Google Scholar : PubMed/NCBI
64	O'Neill AJ, Prencipe M, Dowling C, Fan Y, Mulrane L, Gallagher WM, O'Connor D, O'Connor R, Devery A, Corcoran C, et al: Characterisation and manipulation of docetaxel resistant prostate cancer cell lines. Mol Cancer. 10:1262011. View Article : Google Scholar : PubMed/NCBI
65	Shen MM and Abate-Shen C: Molecular genetics of prostate cancer: New prospects for old challenges. Genes Dev. 24:1967–2000. 2010. View Article : Google Scholar : PubMed/NCBI
66	Peehl DM: Primary cell cultures as models of prostate cancer development. Endocr Relat Cancer. 12:19–47. 2005. View Article : Google Scholar : PubMed/NCBI
67	Rosenbluth JM, Schackmann RCJ, Gray GK, Selfors LM, Li CM, Boedicker M, Kuiken HJ, Richardson A, Brock J, Garber J, et al: Organoid cultures from normal and cancer-prone human breast tissues preserve complex epithelial lineages. Nat Commun. 11:17112020. View Article : Google Scholar : PubMed/NCBI
68	Donjacour AA, Thomson AA and Cunha GR: FGF-10 plays an essential role in the growth of the fetal prostate. Dev Biol. 261:39–54. 2003. View Article : Google Scholar : PubMed/NCBI
69	Yamamoto H, Masters JR, Dasgupta P, Chandra A, Popert R, Freeman A and Ahmed A: CD49f is an efficient marker of monolayer- and spheroid colony-forming cells of the benign and malignant human prostate. PLoS One. 7:e469792012. View Article : Google Scholar : PubMed/NCBI
70	Guo C, Liu H, Zhang BH, Cadaneanu RM, Mayle AM and Garraway IP: Epcam, CD44, and CD49f distinguish sphere-forming human prostate basal cells from a subpopulation with predominant tubule initiation capability. PLoS One. 7:e342192012. View Article : Google Scholar : PubMed/NCBI
71	Fatehullah A, Tan SH and Barker N: Organoids as an in vitro model of human development and disease. Nat Cell Biol. 18:246–254. 2016. View Article : Google Scholar : PubMed/NCBI
72	Gjorevski N, Sachs N, Manfrin A, Giger S, Bragina ME, Ordóñez-Morán P, Clevers H and Lutolf MP: Designer matrices for intestinal stem cell and organoid culture. Nature. 539:560–564. 2016. View Article : Google Scholar : PubMed/NCBI
73	Huang Y, Hamana T, Liu J, Wang C, An L, You P, Chang JY, Xu J, Jin C, Zhang Z, et al: Type 2 fibroblast growth factor receptor signaling preserves stemness and prevents differentiation of prostate stem cells from the basal compartment. J Biol Chem. 290:17753–17761. 2015. View Article : Google Scholar : PubMed/NCBI
74	Cook C, Vezina CM, Allgeier SH, Shaw A, Yu M, Peterson RE and Bushman W: Noggin is required for normal lobe patterning and ductal budding in the mouse prostate. Dev Biol. 312:217–230. 2007. View Article : Google Scholar : PubMed/NCBI
75	Bjerke GA, Yang CS, Frierson HF, Paschal BM and Wotton D: Activation of Akt signaling in prostate induces a TGFβ-mediated restraint on cancer progression and metastasis. Oncogene. 33:3660–3667. 2014. View Article : Google Scholar : PubMed/NCBI
76	Qin J, Wu SP, Creighton CJ, Dai F, Xie X, Cheng CM, Frolov A, Ayala G, Lin X, Feng XH, et al: COUP-TFII inhibits TGF-β-induced growth barrier to promote prostate tumorigenesis. Nature. 493:236–240. 2013. View Article : Google Scholar : PubMed/NCBI
77	Ding Z, Wu CJ, Chu GC, Xiao Y, Ho D, Zhang J, Perry SR, Labrot ES, Wu X, Lis R, et al: SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. Nature. 470:269–273. 2011. View Article : Google Scholar : PubMed/NCBI
78	Montanari M, Rossetti S, Cavaliere C, D'Aniello C, Malzone MG, Vanacore D, Franco RD, Mantia EL, Iovane G, Piscitelli R, et al: Epithelial-mesenchymal transition in prostate cancer: An overview. Oncotarget. 8:35376–35389. 2017. View Article : Google Scholar : PubMed/NCBI
79	Lu X and Kang Y: Epidermal growth factor signalling and bone metastasis. Br J Cancer. 102:457–461. 2010. View Article : Google Scholar : PubMed/NCBI
80	Wang S, Gao D and Chen Y: The potential of organoids in urological cancer research. Nat Rev Urol. 14:401–414. 2017. View Article : Google Scholar : PubMed/NCBI