An original patient‐derived xenograft of prostate cancer with cyst formation

Abstract

BACKGROUND The high rate of failure of new agents in oncology clinical trials indicates a weak understanding of the complexity of human cancer. Recent understanding of the mechanisms underlying castration resistance in prostate cancer led to the development of new agents targeting the androgen receptor pathway; however, their effectiveness is limited. Hence, there is a need for experimental systems that are able to better reproduce the biological diversity of prostate cancer in preclinical settings. In this study, we established a unique patient‐derived xenograft (PDX) model to identify biomarkers for treatment efficacy and resistance and better understand prostate cancer biology. METHODS A prostate cancer tissue sample from a Japanese patient was transplanted subcutaneously into male, severe combined immune‐deficient (SCID) mice and this PDX mouse model was named KUCaP3. Sequential tumor volume changes were observed before and after castration. Androgen receptor (AR), prostate‐specific antigen (PSA), and other molecular markers were examined immunohistochemically. Sequence analysis of AR was also performed to detect mutations. Proteomic analysis of cyst fluid and sera samples of KUCaP3 mice were analyzed by mass spectrometry (MS). RESULTS KUCaP3 cell line, derived from human tissue, was successfully and serially passaged in vivo with approximately 60% take rate. KUCaP3 exhibited cyst formation, showed androgen‐dependent growth initially, and developed castration‐resistant growth several months after castration of the mice. Immunohistochemical analysis showed that KUCaP3 was positive for AR, PSA, CK18, and α‐methyl acyl‐coenzyme A racemase, but negative for CK5/6 and ERG. The AR gene in KUCaP3 cells contained a substitution from CAT (histidine) to TAT (tyrosine) at the nucleotide positions corresponding to codon 875 (H875Y) in the ligand‐binding domain. Chemiluminescent immunoassay revealed higher levels of PSA in cystic fluid and the serum of KUCaP3‐bearing mice. MS analysis detected 23 proteins of human origin in cystic fluids of KUCaP3. CONCLUSIONS We developed KUCaP3, an androgen‐dependent PDX model with cyst formation. Several proteins including PSA were detected in the cystic fluid and sera of tumor‐bearing mice. This original PDX model has the potential to be used as a clinically relevant model to evaluate molecular markers for prostate cancer diagnosis and treatment. Prostate 76:994–1003, 2016. © 2016 Wiley Periodicals, Inc.

Establishment and characterization of a novel treatment‐related neuroendocrine prostate cancer cell line KUCaP13

“…The growth of the tumor was very rapid and could not be suppressed by castration of the host mouse (Figure 1D). After three stable passages, this PDX line was named KUCaP13 as one of the series of PDXs established at our institution 9‐11 …”

Development of patient-derived xenograft models of prostate cancer for maintaining tumor heterogeneity

“…It is generally believed that PDX models with few passages (<10 generations) can maintain the histopathological characteristics and gene integrity of primary tumors, but some studies have also examined the molecular fidelity of 100+ generation PDX models, which showed no significant changes in the long-term passaged mouse model, which maintains the general phenotype of PDX (19,36). The established PDX models were found to reproduce the common genome changes in clinical Pca patients (e.g., PTEN loss, RB1 loss, AR amplification, and TMPRSS2-ERG fusion gene) (19,28) and retained the significant markers of primary tumors in patients: AR, PSA, prostate-specific membrane antigen (PSMA), and alpha-methylacyl-CoAracemase (AMACR; also known as P504S) (18,20,30). Lin et al (35) also established some patient-derived prostate tumor xenograft models that well retained salient features of the primary tumors, including histopathology, clinical marker expression, chromosomal aberration, gene expression profiles, and molecular subtypes of prostate cancer.…”

“…The development of a PDX model can promote the understanding of Pca progression, drug treatment response, and precision medicine. To date, the representative Pca PDX models include the LAPC, KUCaP, and LuCaP series (8,17,18). An outstanding example is the LuCaP PDX series models established by Nguyen and his colleagues (19).…”

Patient-Derived Xenograft Models of Breast Cancer and Their Application

“…As long as PDXs are maintained in vivo by directly passaging from mouse to mouse, their character closely resembles that of their parental tumors for several generations. Though the take rate of first transplantation from patient to mouse varies dependent on tumor types [77,84,85,86,87], the second and subsequent take rates from mouse (or frozen stock) to mouse are generally high. Therefore, if PDXs are successfully established by first transplantation, researchers can use them for many purposes by passaging formed tumors to a larger number of mice.…”