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Le cancer de la prostate (CaP) représente le premier cancer chez l'homme avec une incidence de 40 000 cas par an en France et la seconde cause de mortalité par cancer avec 12 000 décès par an. Même si le dépistage permet un diagnostic du cancer à un stade plus précoce, il persiste un problème thérapeutique pour les formes localement avancées et métastatiques pour lesquelles le traitement hormonal et plus récemment la chimiothérapie à base de taxane ne permettent qu'une approche palliative. La capacité des cellules tumorales prostatiques à résister au traitement hormonal représente donc un échec thérapeutique et la compréhension de ce phénomène devrait permettre de découvrir de nouvelles cibles thérapeutiques. Le concept actuel pour comprendre les mécanismes impliqués dans la progression vers l'hormonorésistance met en jeu plusieurs voies métaboliques. L'identification de ces différents mécanismes est probablement nécessaire pour définir une stratégie thérapeutique efficace. Le challenge est d'identifier des cibles thérapeutiques pouvant être plurielles et différentes pour chaque patient. Notre équipe a récemment identifié une nouvelle voie de signalisation impliquée dans l'acquisition de la résistance des cellules tumorales prostatiques au traitement hormonal par la découverte et la caractérisation d'une nouvelle protocadhérine, la protocadhérine-PC (PCDH-PC). Ce rapport retrace les étapes de cette découverte et rend hommage au professeur Dominique Chopin l'initiateur de ce projet.

Castration initiates extensive apoptosis of the secretory epithelial cells lining the ducts of the rat ventral prostate, resulting in the striking regression of this male sexual accessory tissue. We had previously described the paradox of finding similar cascades of gene activity (c-fos greater than c-myc greater than hsp-70) induced during the early period of ventral prostate regression and during the regrowth of the ventral prostate gland initiated by testosterone replenishment. This common pattern of protooncogene expression during periods of predominant cellular apoptosis or proliferation caused us to examine further the possibility that the two cellular events occur through identical early molecular pathways. In the present study we demonstrate that apoptotic prostate epithelial cells incorporate bromodeoxyuridine into nuclear high-molecular-weight DNA prior to nuclear DNA fragmentation. The DNA synthetic activity occurs in coordination with a massive induction of proliferative cell nuclear antigen, a proliferation marker, in the nuclei of androgen-deprived prostatic epithelial cells. Moreover, this activity is also associated with the increased expression of mRNA encoding p53, a suppressor gene well known as a cell cycle-blocking agent. Our data indicate that quiescent (G0) prostate epithelial cells undergo apoptosis due to two sequential events initiated by testosterone depletion. The first event is the active reentry of these cells into the cell cycle. The second event is the apoptotic destruction resulting from the inability of the differentiated cells to successfully complete this cycle.

A multiparametric analysis to demonstrate that even brief periods of arterial clamping can initiate extensive cell loss in a rat kidney through the process of apoptosis during the 48-hour period after reperfusion was performed. Microscopic examination of rat renal tissues subject to a 5-, 30-, or 45-minute period of complete ischemia showed the presence of apoptotic bodies both within and occasionally between renal tubules, appearing as early 12 hours after reperfusion, and increasing in numbers at 24 hours. Furthermore, DNA extracted from such reperfused renal tissue demonstrated the appearance of a distinct "ladder" pattern of DNA fragments after electrophoresis in agarose gels, a phenomenon commonly associated with cells undergoing apoptosis and in contrast to the predominant smear pattern obtained after electrophoresis of DNA extracted from necrotic renal tissue. Finally, messenger RNA (mRNA) encoding sulfated glycoprotein-2, a gene product previously identified to apoptotic renal cells, was found to be highly expressed in the 30-minute arterial clamped rat kidney after 24 hours of reperfusion, but was not detectable in mRNA extracted from renal tissue after 24 hours chronic infarction. This study demonstrates that a combination of morphologic, biochemical, and molecular markers can be used to distinguish predominant modes of cell death in varying forms of tissue injury. Application of these analytical techniques to renal vascular injury has distinguished that brief periods of complete ischemia initiates a form of cell death (apoptosis) during a subsequent reperfusion phase that is drastically different from cellular necrosis induced by prolonged severe ischemia.

Several in vitro studies have provided evidence that the tumor suppressor protein, p53, is involved in the cell death process referred to as apoptosis. The recent development of p53 knock-out mice has enabled further investigation into the function of p53 for apoptosis, in vivo. Radiation-induced apoptosis is suppressed in such mice, yet other forms of apoptosis do not seem to be significantly affected. In this report, we present evidence that such male p53 nullizygous mice have less apoptosis in the prostate glands associated with the first 4 days following castration. Ventral prostate glands were obtained from normal, heterozygous p53-null and p53 nullizygous mice at daily intervals after castration. These tissues were stained for apoptosis with the use of the in situ and labeling method and apoptotic bodies were quantified by microscopy. Although labeled apoptotic bodies were observed in post-castrated tissues from all of these genetic variant mice, the onset of apoptosis was delayed and the occurrence of apoptosis was significantly reduced in the p53 nullizygous mice when compared to normal controls. Heterozygous p53-null mice were intermediate for these criteria. Examination of the internucleosomal DNA fragmentation pattern at 2 days of castration supports a significant diminution of prostate cell apoptosis in nullizygous p53 mice. Additionally, large nucleated and multinucleated cells were detected in the prostate epithelium of noncastrated p53 nullizygous mice and these abnormal cells were increased after castration. Flow cytometric analysis of these tissues confirmed a high number of 4C and 8C DNA content cells in the p53 nullizygous prostates and their frequency was increased by castration. In concordance with an earlier study, we conclude that functional p53 protein is not essential for prostate epithelial cells to undergo castration-induced apoptosis. However, wild-type p53 does appear to enhance this process, especially in the early period following castration, and this protein may regulate an aberrant prostate cell cycling activity that follows castration.

The oncoprotein encoded by bc1-2 is unique because of its intracellular location (a mitochondrial membrane protein) and apparent mode of action (suppression of apoptosis). To date, this oncogene has been associated only with the development of certain forms of human B-cell lymphoma. In this report, we describe our experience with a monoclonal antibody made against a synthetic peptide for bc1-2 that can recognize the bc1-2 protein and identify cells in human prostate glands expressing this proto-oncogene with in situ immunohistochemical procedures. These procedures were utilized to survey a series of 62 human tissues to evaluate whether bc1-2 might have a role in the developing prostate gland or in prostate oncogenesis. While all primordial epithelial cells in a fetal prostate gland immunostain for bc1-2, normal and hypertrophic prostate glands of the adult show bc1-2 expression restricted to the basal cells. All epithelial cells in areas of prostatic intraepithelial neoplasia were stained by this antibody, as were most (62%) localized invasive prostatic carcinomas. In contrast, all primary prostatic carcinomas and metastases obtained from metastatic prostate cancer patients after hormone treatment (hormone-refractory tumors) stained positive for bc1-2. This study demonstrates that the oncoprotein encoded by bc1-2 can be detected at sequential stages in the natural history of human prostate cancer. Since the bc1-2 oncoprotein is known to suppress the cellular response to apoptotic stimuli, it will be important to determine whether bc1-2 expression is a factor in the development of prostate cancers and in the survival of hormone-refractory prostate cancer cells.