With November comes the no-shave Movember, annual, month-long event to raise attention to health issues affecting men. Prostate cancer is the second most frequent type of cancer among men, according to the American Cancer Society. One out of seven men will develop the disease during his lifetime. Several treatment options are available depending on the stage of the cancer. Hormone therapy, or also known as androgen deprivation therapy, consists of using drugs or in some cases, castration, to block the production of hormones such as testosterone and is the backbone of treatment for advanced stage prostate cancer. Androgen uptake by cancer cells contributes to key aspects of tumor growth such as cell proliferation. Consequently, androgen deprivation therapy slows down tumor growth. However, many individuals will become resistant to androgen deprivation therapy, leading to the so-called castration-resistant phase of prostate cancer or CRPC, a fatal form of the disease. Androgen deprivation therapy does not fully eliminate hormone levels in the blood or in prostate tumors. Consistent with this, work by Dr. Mostaghel from the Clinical Research Division at the Fred Hutch and colleagues (Dr. Bruce Montgomery (University of Washington) and Dr. Peter Nelson (Human Biology Division)) has found that metastases from patients resistant to androgen deprivation therapy actually contain testosterone levels that are sufficient to stimulate prostate tumor growth. Some prostate tumors may actually develop the ability to synthesize testosterone inside the cancer cell but this does not appear to be the case in all tumors.
While advanced prostate cancer cells exhibit increased expression of certain androgen transporters, scientific research has yet to demonstrate the link between their increased expression and increased hormone uptake from the bloodstream by the tumor in a living organism. In a recent publication in Prostate Cancer and Prostatic Diseases, co-authors Drs. Green and Kaipainen, and Dr. Mostaghel (Clinical Research Division) have established the missing connection.
To investigate the link between the androgen uptake and their transporters’ expression at the surface of the tumor cells, the authors initially established some prostatic cancer cell lines expressing amounts higher than the physiological levels of four different androgen transporters, also called Organic Anion Transporting Polypeptides (OATP1B1, OATP1B3, OATP2B1 and OATP4A1). These four transporters were selected based on their previously demonstrated increased expression in castration-resistant prostate cancer cells. The engineered cells were then incubated in the presence of radioactively labeled androgens commonly found in the serum of men on androgen deprivation therapy, including testosterone or DHEAS (dehydroepiandrosterone sulfate). A higher level of transporter expression at the surface was associated with increased incorporation of some of the tested androgens into the cancer cells.
Based on these data and reports from the scientific literature three of these transporters were also evaluated in vivo. To this end, immunodeficient mice were used to engraft previously established human prostate cancer cells engineered to express one of the transporters. Following tumor development, these mice were androgen-deprived for ten to fourteen days, prior to daily administration of androgens for fourteen more days. Androgen incorporation in the tumor cells was analyzed two weeks later by mass spectrometry. Higher androgen accumulation was detected in the tumors expressing higher levels of specific transporters, especially DHEAS whose incorporation was increased by 4-fold in the presence of the OATP1B1 transporter, and by 2-fold with the OATP2B1 transporter. This higher androgen accumulation was further confirmed by the increased detection of the downstream products of these androgen metabolisms following intracellular uptake.
As stated by the authors, the simultaneously increased expression of several transporters might also lead to an even higher androgen uptake by the tumor cells. This is particularly relevant given that castration-resistant prostate cancer metastases have been found to express several of these transporters. “These data emphasize the ongoing need to block hormone signaling inside tumor cells, even at circulating androgen levels achieved in men treated with advanced androgen deprivation treatments” said Dr. Mostaghel. Targeting and blocking these transporters is not a feasible approach and would affect other critical physiological functions as they are also expressed in the liver and intestines and are not limited to the transport of these hormones. An alternative worth of consideration would be using a drug to block the binding of a specific hormone to its specific transporter, alone or in combination with other drugs inhibiting their downstream metabolism. This study represents a stepping-stone in understanding the intricate prostate cancer etiology and framing the development of new and improved therapeutic solutions.
Green SM, Kaipainen A, Bullock K, Zhang A, Lucas JM, Matson C, Banks WA, Mostaghel EA. 2016. Role of OATP transporters in steroid uptake by prostate cancer cells in vivo. Prostate Cancer and Prostatic Diseases. [Epub ahead of print].
This research was supported by Pacific Northwest Prostate Cancer SPORE, NIH National Cancer Institute and Department of Defense.