The development of effective cancer therapeutics depends largely on availability of experimental models that reflect the biology and pharmacological susceptibility of the tumor type they represent. Prostate cancer is the second leading cause of cancer death in men in the United States. Most prostate cancers can be treated effectively with surgery or radiation therapy. However, when prostate cancer metastasizes to other organs, systemic therapies are needed. Prostate cancer is highly dependent on growth promoting action of male hormones. Hormone therapy, namely a treatment with agents that block the effect of the male hormone androgen, is a highly effective way to suppress prostate cancer growth. But although most men initially respond to pharmacological androgen deprivation therapy, resistance to this treatment emerges in almost all patients as tumors progress to an androgen deprivation-insensitive, or castrate-resistant prostate cancer (CRPC) stage. Treatment options are very limited for CRPC and 5-year survival decreases to 31% according to the American Cancer Society. It is critical, therefore, to develop therapies that effectively treat CRPC. Senior author Dr. Michael Haffner of the Human Biology Division says: “There is a large number of resistance mechanisms which were mostly characterized by analyzing patient samples. This contrasts to a very small number of experimental models that are representative of CRPC. In general, the spectrum of prostate cancer cell lines is limited, and the number of cell line models has not significantly increased over the past decades.”
The Haffner group recently published a report describing the development and characterization of two cell line models of CRPC in the journal The Prostate. The researchers started with two androgen-sensitive prostate cancer cell lines, LAPC4 and VCaP, isolated from metastatic prostate tissue samples. Each cell line was implanted into immunodeficient male mice with normal levels of male hormones or androgens. Once the tumors grew, the tumor-bearing mice were surgically castrated. Just as in patients, the absence of androgen forced the emergence of androgen-independent or castrate-resistant (CRPC) tumor in the mice. The tumors that grew under androgen depravation conditions were removed and expanded in culture. In each case, the CRPC lines, LAPC4-CR and VCaP-CR, grew robustly in male immunodeficient castrate mice, as expected. Interestingly, when treated with androgen receptor (AR) antagonists in vitro, the two newly generated CRPC lines showed slightly different responses. The LAPC4-CR line was insensitive to growth inhibition by enzalutamide and bicalutamide, two clinically important FDA-approved therapeutics for CRPC as well as by dihydrotestosterone (DHT), a strong AR agonist. The VCaP-CR line, on the other hand, shows growth inhibitions with all three drugs, including DHT. The seemingly contradictory result that an AR agonist inhibits growth of cells that are insensitive to growth suppression by AR antagonists has been previously described for other CRPC cell lines.
To characterize the two pairs of cell lines, the authors carried out transcriptomic analysis with RNA-Seq. As expected, the two CRPC lines, LAPC4-CR and VCaP-CR were highly similar to their androgen-dependent parental lines, LAPC4 and VCaP. Interestingly, the two pairs of lines were quite distinct from each other in their transcriptomic profiles suggesting that intrinsic differences between individual tumors persist even when the initially androgen-dependent tumor becomes castrate resistant. The two pairs of prostate cancer cell lines can now be added to the armamentarium of pre-clinical models to develop new therapeutics to combat advanced prostate cancer. Haffner states: “We demonstrated that these cell lines recapitulate changes observed in clinical samples of mCRPC suggesting that these models can be used to potentially unmask novel biological features of advanced prostate cancer. The comprehensive transcriptomic and proteomic characterization of the cell lines presented here will serve as a useful resource to study intrinsic pathways for castration resistant prostate cancer and to develop new therapies for CRPC.”
This research was supported by grants from the National Institutes of Health, the U.S. Department of Defense Prostate Cancer Research Program, the Swiss National Science Foundation, the Prostate Cancer Foundation, the Safeway Foundation, the Commonwealth Foundation and the Irving Hansen Memorial Foundation.
Fred Hutch/UW Cancer Consortium member Michael Haffner contributed to this study.
Haffner MC,Bhamidipati A,Tsai HK,Esopi DM,Vaghasia AM,Low JY,Patel RA,Guner G,Pham MT,Castagna N,Hicks J,Wyhs N,Aebersold R,De Marzo AM,Nelson WG,Guo T,Yegnasubramanian S. (2021). Phenotypic characterization of two novel cell line models of castration-resistant prostate cancer. Prostate. doi: 10.1002/pros.24210.