Cancer and pregnancy: proteomic, transcriptomic and metabolic alterations in placenta from pregnant women with cancer and Wistar pregnant Walker 256 tumour-bearing rats

Abstract

The incidence of cancer during pregnancy is increasing significantly due to advanced maternal age. Cancer during pregnancy represents a major therapeutic challenge, as maternal and fetal/neonatal health need to be considered. Women diagnosed with cancer during pregnancy may have changes in the placenta, which is the main organ responsible for ensuring successful pregnancy and fetal health. These placental alterations can have a multifactorial origin, such as changes in gene, transcriptional, protein and metabolic levels. However, these changes are still unknown, even with the high incidence of complications in cancer during pregnancy, such as intra uterine growth restriction and preterm birth. Preterm birth is the leading cause of neonatal mortality and is associated with an increase of up to 75% in long-term morbidity. Because the exact mechanisms responsible for changes in the placenta when it develops simultaneously with cancer are not known, there are no therapeutic treatments to maintain the health of the placenta and fetus. Thus, the elucidation of the molecular mechanisms involved in the placenta during cancer may bring possibilities for future therapeutic development. In this line, preclinical experiments using animal models are necessary, as they allow greater manipulation/intervention and control of variables. In this sense, Walker 256 carcinosarcoma, originally a mammary adenocarcinoma in rat, is a tumor model widely used in our laboratory and by other researchers. In addition to investigating these changes in animal models, the confirmation/mirroring of the mechanisms responsible for these changes with the human model would represent a great advance for knowledge in the area. So, the validation of an animal model of cancer during pregnancy will enable the development of therapeutic strategies, since in the pre-clinical model, interventions can be made more easily and quickly, and can later be applied to patients. Therefore, a translational study with mirroring between pre-clinical and clinical models is necessary, allowing, in the future, the development of therapeutic strategies for the preservation of placental health when this is associated with tumor growth. Objective: To identify and compare the genetic, protein and metabolic alterations that occur in the placenta of rats with Walker 256 carcinosarcoma and in the placentas of women with cancer undergoing treatment (active disease), in order to validate the experimental model, through the mirroring of the studies pre-clinical and clinical. Materials and methods: The study will be divided into a pre-clinical and clinical. For the pre-clinical study, placenta tissues will be collected from healthy pregnant Wistar rats (Control group) and from Walker 256 tumor carriers with chemotherapy treatment after the first third of pregnancy (Cancer + Chemotherapy group). The clinical study will be developed at the Center for Integral Attention to Women's Health (CAISM) of the State University of Campinas (UNICAMP) where we will carry out a case-control study, with a pairing between the usual risk (Control group) and complicated pregnancies for cancer with chemotherapy treatment (active disease) after the third month of pregnancy (Cancer + Chemotherapy group). The placenta tissues from the two studies will be processed and analyzed using systems biology tools such as transcriptomics, proteomics and metabolomics for the global and integrative characterization of the changes that affect the placenta in this framework. For data analysis, Student's t tests will be considered, considering the comparison of the two experimental groups with continuous variables and normal distribution. P values less than 0.05 will be considered significant. (AU)