p53 protein aggregation promotes platinum resistance in ovarian cancer.

High-grade serous ovarian carcinoma (HGSOC), the most lethal gynecological cancer, often leads to chemoresistant diseases. The p53 protein is a key transcriptional factor regulating cellular homeostasis. A majority of HGSOCs have inactive p53 because of genetic mutations. However, genetic mutation is not the only cause of p53 inactivation. The aggregation of p53 protein has been discovered in different types of cancers and may be responsible for impairing the normal transcriptional activation and pro-apoptotic functions of p53. We demonstrated that in a unique population of HGSOC cancer cells with cancer stem cell properties, p53 protein aggregation is associated with p53 inactivation and platinum resistance. When these cancer stem cells differentiated into their chemosensitive progeny, they lost tumor-initiating capacity and p53 aggregates. In addition to the association of p53 aggregation and chemoresistance in HGSOC cells, we further demonstrated that the overexpression of a p53-positive regulator, p14ARF, inhibited MDM2-mediated p53 degradation and led to the imbalance of p53 turnover that promoted the formation of p53 aggregates. With in vitro and in vivo models, we demonstrated that the inhibition of p14ARF could suppress p53 aggregation and sensitize cancer cells to platinum treatment. Moreover, by two-dimensional gel electrophoresis and mass spectrometry we discovered that the aggregated p53 may function uniquely by interacting with proteins that are critical for cancer cell survival and tumor progression. Our findings help us understand the poor chemoresponse of a subset of HGSOC patients and suggest p53 aggregation as a new marker for chemoresistance. Our findings also suggest that inhibiting p53 aggregation can reactivate p53 pro-apoptotic function. Therefore, p53 aggregation is a potential therapeutic target for reversing chemoresistance. This is paramount for improving ovarian cancer patients' responses to chemotherapy, and thus increasing their survival rate.

Constitutive proteasomal degradation of TWIST-1 in epithelial-ovarian cancer stem cells impacts differentiation and metastatic potential.

Epithelial-mesenchymal transition (EMT) is a critical process for embryogenesis but is abnormally activated during cancer metastasis and recurrence. This process enables epithelial cancer cells to acquire mobility and traits associated with stemness. It is unknown whether epithelial stem cells or epithelial cancer stem cells are able to undergo EMT, and what molecular mechanism regulates this process in these specific cell types. We found that epithelial-ovarian cancer stem cells (EOC stem cells) are the source of metastatic progenitor cells through a differentiation process involving EMT and mesenchymal-epithelial transition (MET). We demonstrate both in vivo and in vitro the differentiation of EOC stem cells into mesenchymal spheroid-forming cells (MSFCs) and their capacity to initiate an active carcinomatosis. Furthermore, we demonstrate that human EOC stem cells injected intraperitoneally in mice are able to form ovarian tumors, suggesting that the EOC stem cells have the ability to 'home' to the ovaries and establish tumors. Most interestingly, we found that TWIST-1 is constitutively degraded in EOC stem cells, and that the acquisition of TWIST-1 requires additional signals that will trigger the differentiation process. These findings are relevant for understanding the differentiation and metastasis process in EOC stem cells.

Primary health care lessons from the northeast of Brazil: the Agentes de Saúde Program.

Market-led economic reforms are usually viewed as being in conflict with government-stimulated socioeconomic development for disadvantaged groups. Nevertheless, Ceará, a poor state in the Northeast of Brazil, has since 1987 pursued both of those strategies simultaneously. One part of that approach has been a program of nurse-directed auxiliary health workers serving about 5 million people--almost all the persons outside the capital city and half of those in the capital. The system requires that the auxiliaries, called agentes de saúde, live in the local communities that they serve. The health agents visit each home once a month to carry out a small number of priority health activities. While health agent positions are in high demand, the minimum-wage salary that the agents receive makes up only a small portion of the state budget. A key aspect of the system is timely and comprehensive information, which is based on agent visits and is managed by trained nurses. Since the health agents system was launched, there has been a rapid decline in infant mortality, a rapid rise in immunization, identification of bottlenecks limiting the utilization of other medical resources, and timely interventions in times of crisis. The health agents system has combined administrative decentralization with financial centralization during a period of electoral democratization. The system has strengthened Ceará's commitment to primary care even as market-oriented changes have reduced the overall role of government. The Ceará program is being copied throughout the Northeast and other regions of Brazil. The key role that nurses play in the Ceará program in organizing and leading a system of basic primary care in poor neighborhoods and rural areas may provide useful lessons for other countries. In addition, Ceará does not have many of the favorable characteristics of other countries that have successfully invested in primary health care. Ceará thus represents a more achievable model for other countries, where, like Brazil, income, educational levels, and land tenure equity are limited.