Research focus: Prostasomes and reproduction
The prostasomes have an important role in the fertilising process and that implicates a sperm-prostasome interaction. At ejaculation, when the prostate secretion with the prostasomes is added to the testis fluids, the prostasomes will adhere onto and, at least to some extent, fuse with sperm cells. The fusion was shown to be cation-independent, and strictly dependent on pH and required one or more proteins on sperm and prostasome surfaces. We have also demonstrated with immunostaining that washed spermatozoa incubated with prostasomes in vitro are coated with prostasomes. Membrane fusion is required for many biological events and the sperm cells will thereby acquire several abilities essential for the normal sperm function.
Prostasome and sperm fusion is of high physiological importance. The transfer of lipids and biologically active proteins underlies many of the functions that prostasomes confer on sperm. Such transfer from prostasomes to spermatozoa represents a means of modifying the composition and biological properties of the sperm membrane [1,2].
Sperm motility is vital for natural fertility in the human male and if abnormal contributes significantly to infertility. Sperm motility and movement quality are important factors in the migration of sperm through the female genital tract, especially moving through cervical mucus and penetrating the zona pellucida.
We have shown that prostasomes promote forward motility of the sperm and prostasome inclusion in swim-up medium resulted in an enhanced recruitment of motile spermatozoa. Cryopreservation of spermatozoa results in a considerable decrease in motility and pregnancy rate. We also found a dramatic increase in the number of post-thaw motile spermatozoa by prostasome inclusion in swim-up medium and also a higher proportion of forwardly motile sperms with a higher amplitude of head displacement, both parameters being positively correlated to the fertilizing potential of spermatozoa .
Immunosuppressive activity of prostasomes
Human seminal plasma contains a unique range of immunosuppressive compounds, which would prevent cell-mediated and humoral responses to spermatozoa in the female reproductive tract. Prostasomes may play a complementary role to prostaglandins and other compounds in neutralizing the immune defenses of the female genital tract. They were identified as inhibitors of mitogen-induced lymphocyte proliferation and phagocytic cell activity. This activity accounts for a significant proportion of the immunosuppressive activity of human seminal plasma. Since the prostasomes have the ability to adhere to spermatozoa, there is the probability that the immunosuppressive effect associated with the prostasomes can be carried up the female genital tract with the spermatozoa.
Prostasomes contribute to local modulation of complement activation, providing the C3, C9 and membrane attack complex inhibitors. CD55 (decay-accelerating factor) and CD46 (membrane cofactor protein) are C3 convertase inhibitors or inhibitors of complement activation, and CD59 is an inhibitor of the membrane attack complex. All three proteins are membrane-bound to prostasomes.
Due to the high content of unsaturated fatty acids within their membranes, human sperm are very sensitive to oxidative stress which results in peroxidative damage. Free radicals are also proposed to be involved in inflammation and the process of carcinogenesis. Free radicals are known to be produced by polymorphonuclear neutrophils (PMNs) and this could be one mechanism by which sperm are damaged by the female immune system. Prostasomes have been shown to have antioxidant properties enabling them to inhibit superoxide generation by leucocytes. This antioxidant activity occurs through the inhibition of NAPDH oxidase activity, which is present in PMNs. This arises by rigidification of the PMN plasma membrane through lipid transfer following fusion with the prostasome .
Several studies have suggested the presence of an antibacterial agent associated with prostasomes. We observed a dose-dependent growth inhibition when prostasomes were incubated in a medium containing Bacillus megaterium. More recently there have been suggestions as to what may provide this antibacterial activity. One suggestion is the human cationic antimicrobial protein hCAP-18, one of several antimicrobial peptides discovered to act as effector molecules in innate immunity. It has also been shown that 70% of the hCAP-18 in seminal plasma is localized to the prostasomal component [5,6].
Antisperm antibodies (ASA) are present in 5% of men with infertility, but the corresponding antigens are poorly characterized. We have shown that 97% of immunoinfertile patients’ sera contained antibodies against seminal prostasomes.
The prostasomal antigens recognized by high titre-antisera of infertile men were generally different from the sperm antigens recognized by the same sera. Characterization revealed that the two dominant immunogens were prolactin-inducible protein and clusterin [7,8].
Prostasomes and prostate cancer
Prostate cancer consistently remains a difficult clinical enigma and the development of novel strategies for diagnosis and treatment of prostate cancer is essential.
Prostasomes are also produced and released by malignant epithelial cells in the prostate. In a recent study we found higher levels of serum antibodies to prostasomes in patients with prostate cancer as compared to healthy controls. The serum antiprostasome antibody titre in prostate cancer patients did not correlate to PSA values but significant, inverse relationships were registered between antiprostasome antibody titre and metastases to bone and/or lymph nodes. We have also identified some of the prostasome-derived proteins that were immunogenic in prostate cancer patients [9,10].
As mentioned earlier, prostasomes have properties that promote sperm function. Ironically, these are properties that could aid the survival and progression of prostate cancer cells. Proteins mediating these effects include phosphorylation proteins, tissue factor and CD59, all present on prostasomes. Two other less well-characterized prostasomal enzymes, ACE and chromogranin A, have also been implicated in the development of prostate cancer. ACE sustains a high concentration of angiotensin II, which favours cell proliferation and thus may contribute to the growth of prostate cancer. Chromogranin A, which is often associated with neuroendocrine cells, is present at higher concentrations (10-fold) on prostasomes derived from prostate cancer bone metastases as compared to those from seminal fluid or native prostate .
Certainly much is still to be established regarding the prostasome and its relationship to prostate cancer development and progression. As the evidence above shows, there is an urgent need to pursue work in this field especially in light of the high incidence of this malignancy, and the financial burden it places on the health service. Finally, further elucidation of the prostasome’s role in promoting fertility may highlight potential avenues for new fertility treatments.
1] Arienti G, Carlini E and Palmerini CA (1997a) Fusion of human sperm to prostasomes at acidic pH. J Membr Biol 155, 89–94.
 Wang J, Lundqvist M, Carlsson L, Nilsson O, Lundkvist O and Ronquist G (2001) Prostasome-like granules from the PC-3 prostate cancer cell line increase the motility of washed human spermatozoa and adhere to the sperm. Eur J Obstet Gynecol Reprod Biol 96, 88-97.
 Carlsson L, Ronquist G, Stridsberg M and Johansson L (1997) Motility stimulant effects of prostasome inclusion in swim-up medium on cryopreserved spermatozoa. Arch Andrology 38, 215-221.
 Skibinski G, Kelly RW, Harkiss D and James K (1992) Immunosuppression by human seminal plasma – extracellular organelles (prostasomes) modulate activity of phagocytic cells. Am J Reprod Immunol 28, 97–103.
 Carlsson L, Pahlson C, Bergquist M, Ronquist G and Stridsberg M (2000b) Antibacterial activity of human prostasomes. Prostate 44, 279–286.
 Andersson E, Sørensen OE, Frohm B, Borregaard N, Egesten A and Malm J (2002) Isolation of human cationic antimicrobial protein-18 from seminal plasma and its association with prostasomes. Hum Reprod 17, 2529–2534.
 Allegrucci C, Ronquist G, Nilsson B, Carlsson L, Lundqvist M, Minelli A and Larsson A (2001) Circulating human antisperm antibodies recognize prostasomes. Am J Reprod Immunol 46,211–219.
 Carlsson L, Ronquist G, Nilsson BO and Larsson A (2004c) Dominant prostasome immunogens for sperm-agglutinating autoantibodies of infertile men. J Androl 25, 699–705.
 Ronquist KG, Carlsson L, Ronquist G, Nilsson S, Larsson A (2006) Prostasome- derived proteins capable of eliciting an immune response in prostate cancer patients. Int J Cancer 119, 847-53.
 Larsson A, Ronquist G, Wulfing C, Eltze E, Bettendorf O, Carlsson L, Nilsson BO and Semjonow A (2006) Antiprostasome antibodies: possible serum markers for prostate cancer metastasizing liability. Urol Oncol 24, 195-200.
 Carlsson L, Nilsson O, Larsson A, Stridsberg M, Sahlen G and Ronquist G (2003) Characteristics of human prostasomes isolated from three different sources. Prostate 54, 322–330.