Trophoblast cells of the human placenta proliferate, migrate, and invade the pregnant uterus and its vasculature in order to nourish the developing fetus, in a way that is imitated by malignant tumors. Many similarities exist between embryo implantation and the growth of cancer cells. We begin this article by reviewing decades of studies that have helped unearth the mechanisms that contribute to the tumor-like phenotype of human trophoblast cells. Interestingly, these attributes are only transient in nature, with stringent spatial and temporal confines. The importance of intrinsic molecular controls that effectively circumscribe the extent and duration of trophoblast incursion, becomes increasingly evident in abnormal pregnancies that are characterized by aberrant trophoblast proliferation/invasion. We summarize and discuss the significance of abnormalities in these regulatory mechanisms, and finally, speculate about the use of human trophoblastic cells as model systems for the study of a variety of cellular processes. While on one hand, human placental cells are bestowed with a capacity to proliferate indefinitely and invade extensively, on the other, these cells are also replete with mechanisms to regulate these tumor-like attributes and eventually progress to a senescent apoptotic state. This is therefore, a 'well-behaved' tumor. The comparison in the present review is between the invasive cytotrophoblastic cell type and the tumor cell type.
We investigated the cytotoxic effects of nimbolide, a limonoid present in leaves and flowers of the neem tree (Azadirachta indica) on human choriocarcinoma (BeWo) cells. Treatment with nimbolide resulted in dose- and time-dependent inhibition of growth of BeWo cells with IC(50) values of 2.01 and 1.19 microM for 7 and 24 h respectively, accompanied by downregulation of proliferating cell nuclear antigen. Examination of nuclear morphology revealed fragmentation and condensation indicating apoptosis. Increase in the generation of reactive oxygen species (ROS) that was reversed by addition of reduced glutathione suggested ROS involvement in the cytotoxicity of nimbolide. A decrease in Bcl-2/Bax ratio with increased expression of Apaf-1 and caspase-3, and cleavage of poly(ADP-ribose) polymerase provide compelling evidence that nimbolide-induced apoptosis is mediated by the mitochondrial pathway. The results of the present study suggest that nimbolide has immense potential in cancer prevention and therapy based on its antiproliferative and apoptosis inducing effects.
Oocytes present at birth undergo a progressive process of apoptosis in humans and other mammals as they age. Accepted opinion is that no fresh oocytes are produced other than those present at the time of birth. Studies have shown that DNA repair genes in oocytes of mice and women decline with age, and lack of these genes show higher DNA breaks and increased oocyte death rates. In contrast to the ethical problems associated with monitoring the changes in DNA double-strand breaks in oocytes from young and old humans, it is relatively easy to carry out such a study using a rodent model. In this study, the mRNA levels of DNA repair genes are compared with protein products of some of the genes in the primordial follicles isolated from immature (18-20 days) and aged (400-450 days) female rats. Results revealed a significant decline in mRNA levels of BRAC1 (P < 0.01), RAD51 (P < 0.05), ERCC2 (P < 0.05), and H2AX (P < 0.01) of DNA repair genes and phospho-protein levels of BRAC1 (P < 0.01) and H2AX (P < 0.05) in primordial follicles of aged rats. Impaired DNA repair is confirmed as a mechanism of oocyte ageing.
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