Vitamin D in Human Ovarian and Prostate Cancer

Abstract

Ihmisellä pääosa D-vitamiinista muodostuu iholla auringon ultraviolettisäteilyn vaikutuksesta ja loput saadaan ravinnosta. D-vitamiini ylläpitää elimistön kalsiumtasapainoa, mitä tarvitaan sekä luuston mineralisoitumiseen että moniin muihin elintärkeisiin toimintoihin kuten lihasten toimintaan, solujen signaalivälitykseen ja aineenvaihduntaan. Sen lisäksi D-vitamiinin on havaittu estävän esimerkiksi tiettyjen syöpäsolujen kasvua sekä edistävän erilaistumista, mikä on herättänyt laajaa kiinnostusta tutkijoiden keskuudessa. Joitain kokeita D-vitamiinin hyödyllisyydestä syöpäpotilaiden hoidossa on tehty, mutta tällä hetkellä sen kliinistä käyttöä rajoittaa elimistön kalsiumpitoisuuden liiallisesta lisääntymisestä johtuvat haittavaikutukset. Viime aikoina kehitetyt synteettiset D-vitamiinijohdannaiset voivat mahdollistaa D-vitamiinin kliinisen käytön myös syöpäpotilailla.

Tämän tutkimuksen tarkoituksena oli selventää D-vitamiinin sekä sitä solun sisällä sitovan ja vaikutuksia välittävän erityisen reseptoriproteiinin osuutta eturauhas- ja munasarjasyövässä. Epidemiologisen tutkimuksemme tulokset osoittavat, että alhainen seerumin D-vitamiinipitoisuus lisää merkittävästi riskiä sairastua eturauhassyöpään. Aiemmin on havaittu, että eturauhassyöpä, munasarjasyöpä ja useat muutkin syöpämuodot ovat yleisempiä vähäiselle auringon ultraviolettisäteilylle altistuvilla alueilla, joilla seerumin D-vitamiinipitoisuudet ovat usein talvella nykysuosituksia matalampia. Tämä yhdessä uuden tuloksemme ja kokeellisten tutkimusten kanssa osoittaa, että D-vitamiini saattaa suojata eturauhasta syövän synnyltä ja etenemiseltä. Lisäksi tutkimuksemme munasarjasyöpäsoluilla osoittavat, että D-vitamiini, D-vitamiinireseptori ja aktiivisen D-vitamiinin määrää säätelevät entsyymit saattaisivat vaikuttaa syöpäsolujen kasvuun. Tutkimustulokset antavat viitteitä siitä, että D-vitamiinijohdannaisista saattaisi olla hyötyä syövän hoidon lisäksi myös syövän ennaltaehkäisyssä. Jatkotutkimuksia kuitenkin tarvitaan turvallisen annoksen ja antotavan löytämiseksi.

The main function of pleiotropic vitamin D is to preserve calcium and phosphorus homeostasis, together with other factors, in order to promote skeletal mineralization and to maintain signal transduction, metabolic activities, and neuromuscular function. In addition to the classic target organs involved in mineral homeostasis (intestine, kidney, bone and parathyroid glands), vitamin D regulates cell growth and differentiation in variety of other tissues, controls other hormonal systems and modulates immunologically mediated processes. The metabolic activation of vitamin D synthesized in skin or obtained from diet occurs in two stages by enzymes 25-hydroxylase and 1a-hydroxylase leading to the hormonally active form of vitamin D, 1á,25-dihydroxyvitamin D3 (1á,25(OH)2D3). The action of 1á,25(OH)2D3 is terminated by enzyme 24-hydroxylase. Two distinct signalling systems are involved in vitamin D mediated effects. Majority of the actions of vitamin D are mediated through 1á,25(OH)2D3 binding to nuclear vitamin D receptor (VDR) that can directly modulate the transcription of the genes possessing a functional binding site for the VDR in their regulatory region. The non-genomic effects of vitamin D involve stimulation of signal transduction systems on plasma membrane.

Cancers of the ovary, prostate and several other organs are more common in areas where solar UV-B radiation is limited, and it has been hypothesized that vitamin D may mediate the beneficial effects of sunlight. Results of epidemiological studies on the association between prostate cancer and vitamin D have been inconsistent, but experimental studies have supported the hypothesis envisaging 1á,25(OH)2D3 induced growth inhibition in ovarian and prostate cancer cells. Moreover, 1á,25(OH)2D3 has been reported to stimulate cellular differentiation and inhibit metastatic potential of prostate cancer cells. Various mechanisms have been shown to involve in the anti-cancer action of 1á,25(OH)2D3 on prostate cancer cells, including regulation of cell cycle, induction of programmed cell death (apoptosis), modulation of growth factor, oncogene and tumor suppressor gene expression. Furthermore, vitamin D metabolising enzymes have been reported to modulate the action of vitamin D in prostate cells. Little is known, however, as to the mechanisms of 1á,25(OH)2D3-induced growth inhibition in ovarian cancer cells. This study was undertaken to clarify the controversy raised by epidemiological studies of the role of vitamin D in the etiology of prostate cancer, to reveal the cellular distribution of VDR within normal prostate tissue and to add the knowledge on the actions of vitamin D in ovarian cancer.

The production and characterization of a novel VDR antibody is described, and the antibody is employed to study the cellular distribution of VDR protein in prostate. This approach on the human prostate provides evidence that VDR may be located within epithelial and a few stromal cells of the human prostate and suggests that 1á,25(OH)2D3 may play a direct role in prostate biology. Moreover, the results show that there may be strong variations in VDR protein expression between prostatic samples. Previous experimental data on the anti-cancer activities of vitamin D and the location of VDR mainly in epithelial cells whence the majority of prostate cancers arise suggest that 1á,25(OH)2D3 might be involved in the pathogenesis of prostate cancer.

To gain insight into the possible role of vitamin D and androgens in ovarian cancer, the expression and regulation of their receptors were studied in human ovarian cancer tissue and ovarian cancer cells. The expression of VDR or androgen receptor (AR) proteins in part human ovarian cancer tissues suggests that these ovarian tumors may respond to vitamin D or androgen. VDR and AR protein expression seems to be associated with lower stage of the tumor suggesting that loss of VDR and AR might contribute to ovarian tumor progression. The regulation of VDR and AR proteins by cognate ligands in ovarian cancer cell line OVCAR-3 sheds light on the possible mechanisms modulating the amplitude of responses to 1á,25(OH)2D3 and androgen in ovarian cancer cells. The revealed up-regulation of VDR by androgen and AR by 1á,25(OH)2D3 in OVCAR-3 cells suggests possible cross-talk between 1á,25(OH)2D3 and androgens and their cognate receptors.

The two studies provide evidence that the growth of OVCAR-3 cells may be modulated by various vitamin D compounds (1á,25(OH)2D3, EB 1089 and 25(OH)D3) and by androgen (DHT). The effect of DHT and 25(OH)D3 as well as low concentrations of 1á,25(OH)2D3 and EB 1089 was mitogenic in these studies. Higher concentrations of 1á,25(OH)2D3 and EB 1089 inhibited the growth significantly. The newly found mRNA expression of both vitamin D-activating and -inactivating enzymes, 1á-hydroxylase and 24-hydroxylase, may modulate the growth response to vitamin D compounds in OVCAR-3 cells. The simultaneous expression of inducible VDR and 24-hydroxylase and constitutive 1á-hydroxylase in OVCAR-3 cells suggests that they represent a means for in situ regulation of the response to vitamin D. The possible mitogenic effects of vitamin D compounds should be considered when critically evaluating the possible treatment of ovarian cancer patients with vitamin D.

The availability of stored serum samples collected from men with prostate cancer on average 11 years later, and from men, who remained cancer-free for the same period, provided an opportunity to evaluate the relationship between vitamin D status and risk of prostate cancer. The inverse association between serum 25(OH)D concentration and prostate cancer risk shown in this study suggests that vitamin D may be one of the elements involved in the multifactorial process of prostate carcinogenesis. The highest prostate cancer risk was among men younger than 52 years at entry who had low serum 25(OH)D concentration (£ 40 nmol/l), whereas among older men the risk due to low serum 25(OH)D concentration was minimal. Together with previous experimental data our results suggest that one regulatory mechanism of vitamin D in prostate cancer might be inhibition of invasion and metastasis. The increased relative risk of prostate cancer in men with low vitamin D levels, and younger at entry, is consistent with the hypothesis that vitamin D might be involved directly in the initiation (antiandrogenic effect) and in the regulation of the growth rate (antiproliferative effect) of prostate cancer.

Taken together, the data obtained provide evidence that vitamin D, VDR and vitamin D-metabolizing enzymes constitute one of the factors involved in the complicated process of prostate and ovarian carcinogenesis.