The aims of this project were to study the male reproductive systems of nonhuman primates that are commonly used in research in order to evaluate their suitability as models for PSA biology studies in particular and for prostatic diseases in general. Preliminary data reported in this study suggest the macaque species are more suitable for these studies.
New World monkeys like the marmoset are not useful models for studies of PSA biology and prostatic diseases because they do not have the PSA gene. A previous study had reported the presence of the PSA gene in a number of nonhuman primates including orangutans, chimpanzees, gorillas, and macaques but not in dogs, mice, rats, or cows [8
]. However, the nonhuman primate species examined in these studies did not include New World monkeys. More recent studies have reported the absence of the PSA gene in both the marmoset and cotton-top tamarin [9
]. Our failure to detect PSA in marmoset serum in this study confirms the absence of the PSA gene. However, the possibility that the human antibodies used in our studies cannot detect marmoset PSA cannot be ruled out. Probably the PSA gene arose in the Catarrhine primates (Old World monkeys, anthropoid apes and humans) after their phylogenetic lineage separated from the Platyrrhines (New World primates) approximately 35 to 45 million years ago [12
Prostate specific antigen, also called human kallikrein 3 (hK3), is one of the 15 members of the tissue kallikrein family that are located in a 300-kb region on chromosome 19q13.3–19q13.4 in humans. The sequences of two members of this group, KLK1 and KLK2, are 62% and 80% similar to PSA, respectively [14
] and it is highly likely that the PSA gene could be a result of a duplication and further mutation of one of these two genes.
Serum PSA was detected in all the Old World monkeys we studied (cynomolgus macaques, rhesus macaques, and baboons). However, there were significant differences in quantity and correlation to age. Both macaque species exhibited greater abundance and stronger correlation with age than the baboons. Both macaque species also had more PSA in prostate tissue than the baboon. The significance of having higher PSA per unit of tissue is not clearly understood, but PSA’s main function is to liquefy coagulated semen. Although this study did not investigate the differences in mating behavior of these four species, we speculate that the higher concentration of proteins related to reproduction, and larger size of the testis, epididymis and prostate in macaques compared to baboons might be related to breeding patterns, seasonality of breeding, and dominance structure. We speculate that large testis able to produce enough sperm, large seminal vesicles and epididymis able to store and nourish the sperm, and large prostate for the production of PSA that maintains semen fluidity are advantageous or necessary for reproductive success.
Serum PSA values reported in both rhesus macaques and cynomolgus macaques are similar to those reported in a recent study by Williams et al. [17
] and are comparable to those in humans [18
] despite the fact that these animals are smaller in size compared to humans. The upper limit of normal for PSA in humans is currently set at 4.0 ng/ml. This is the threshold above which a patient is referred for further diagnostic workup. It is interesting to note that two cynomolgus macaques in our study had serum PSA values of 5.23 and 6.2 ng/ml, which are higher than the human upper limit of normal (see supplementary Table 2
). One cynomolgus macaque with a PSA value of 2.07 ng/ml was found to have prostatic hyperplasia and one rhesus macaque with a PSA value of 2.35 ng/ml had pathological lesions in its prostate. The trend of increasing PSA with age is significant in both rhesus macaques and cynomolgus macaques studied. In fact the linear regression lines for the two species are generally parallel, indicating a similar trend through life. Serum PSA distributions from both these two species also includes clear outliers with unusually high values.
The finding that pathological changes in the prostate may be accompanied by increases in serum PSA is significant, and further lends credence to exploring nonhuman primate (especially the macaque species) as models of PSA biology and prostate diseases in humans.
Significant changes in body weight, and the weights of the testis, prostate, and other reproductive organs occurred as the animals reached sexual maturity at 4 to 5 years in rhesus macaques and cynomolgus macaques and at 6 to 7 years in baboons. These findings are similar to those reported previously [19
In light of the data presented here and our previously published research on the baboon [21
], it is appropriate to revisit the notion that nonhuman primates do not naturally develop prostatic diseases, especially prostate cancer. A closer look at the literature shows that pathological lesions in the prostate have been reported in nonhuman primates (both Old and New World species). Benign prostatic hyperplasia has been reported in tamarins [22
], baboons [23
] and chimpanzees [24
]. Prostate cancer and prostatic basal cell hyperplasia has also been reported in rhesus macaques [25
We are of the view that the macaque species, especially the cynomolgus macaques can be used as animal models for studies of PSA biology. Cynomolgus macaques are native to Southeast Asia but are now readily available in breeding colonies in the USA. They can also be easily imported from their natural habitats and are of reasonably large size.
Further studies are needed to characterize fully the pathology of the male genitourinary system of macaque species, especially the cynomolgus macaque. Based on our preliminary studies, we envision both cynomolgus macaques and rhesus macaques to be a potential models not only for studies of PSA biology, as shown in this paper but also in studies concerning the role of diet and individual genetic variation in determining serum PSA levels. Another potential area of research in which nonhuman primate can be used involves their use in developing PSA based targeted therapies for prostatic diseases. PSA is an androgen-regulated serine protease which is secreted by prostate cancer cells and normal prostate cells. Intensive efforts are on going to utilize the enzyme activity and specificity of PSA production by prostate cancer cells for therapeutic purposes [28
]. PSA is inactive when it is in circulation because it is bound to protease inhibitors. It is only active enzymatically when it is in prostate tissue or in tumor microenvironments. One of the many approaches for the use of PSA for therapeutic purposes is the construction of PSA cleavable prodrugs. The prodrugs circulate in the body but only exhibit their anticancer effects at the tumor sites. The tumor cells secrete PSA that cleaves the prodrugs and therefore activates them. Nonhuman primates are ideal models in which to develop, test and study these PSA-based therapeutic agents.