RESUMO
It is well known that oocytes are produced during fetal development and that the total number of primary follicles is determined at birth. In humans, there is a constant loss of follicles after birth until about two years of age. The number of follicles is preserved until the resumption of meiosis at puberty and there is no renewal of the oocytes; this dogma was maintained in the last century because there were no suitable techniques to detect and obtain stem cells. However, following stem cell markers, several scientists have detected them in developing and adult human ovarian tissues, especially in the ovarian surface epithelial cells. Furthermore, many authors using different methodological strategies have indicated this possibility. This evidence has led many scientists to explore this hypothesis; there is no definitive consensus to accept this idea. Interestingly, oocyte retrieval from mature ovaries and other tissue sources of stem cells has contributed to the development of strategies for the retrieval of mature oocytes, useful for assisted reproductive technology. Here, we review the evidence and controversies on oocyte neooogenesis in adult women; in addition, we agree with the idea that this process may occur in adulthood and that its alteration may be related to various pathologies in women, such as polycystic ovary syndrome, premature ovarian insufficiency, diminished ovarian reserve and several infertility and genetic disorders.
RESUMO
BACKGROUND: Based in epidemiological evidence, repetitive ovulation has been proposed to play a role in the origin of ovarian cancer by inducing an aberrant wound rupture-repair process of the ovarian surface epithelium (OSE). Accordingly, long term cultures of isolated OSE cells undergo in vitro spontaneous transformation thus developing tumorigenic capacity upon extensive subcultivation. In this work, C57BL/6 mouse OSE (MOSE) cells were cultured up to passage 28 and their RNA and DNA copy number profiles obtained at passages 2, 5, 7, 10, 14, 18, 23, 25 and 28 by means of DNA microarrays. Gene ontology, pathway and network analyses were focused in passages earlier than 20, which is a hallmark of malignancy in this model. RESULTS: At passage 14, 101 genes were up-regulated in absence of significant DNA copy number changes. Among these, the top-3 enriched functions (>30 fold, adj p < 0.05) comprised 7 genes coding for centralspindlin, chromosome passenger and minichromosome maintenance protein complexes. The genes Ccnb1 (Cyclin B1), Birc5 (Survivin), Nusap1 and Kif23 were the most recurrent in over a dozen GO terms related to the mitotic process. On the other hand, Pten plus the large non-coding RNAs Malat1 and Neat1 were among the 80 down-regulated genes with mRNA processing, nuclear bodies, ER-stress response and tumor suppression as relevant terms. Interestingly, the earliest discrete segmental aneuploidies arose by passage 18 in chromosomes 7, 10, 11, 13, 15, 17 and 19. By passage 23, when MOSE cells express the malignant phenotype, the dysregulated gene expression repertoire expanded, DNA imbalances enlarged in size and covered additional loci. CONCLUSION: Prior to early aneuploidies, overexpression of genes coding for the mitotic apparatus in passage-14 pre-malignant MOSE cells indicate an increased proliferation rate suggestive of replicative stress. Concomitant down-regulation of nuclear bodies and RNA processing related genes suggests altered control of nuclear RNA maturation, features recently linked to impaired DNA damage response leading to genome instability. These results, combined with cytogenetic analysis by other authors in this model, suggest that transcriptional profile at passage 14 might induce cytokinesis failure by which tetraploid cells approach a near-tetraploid stage containing primary chromosome aberrations that initiate the tumorigenic drive.