BackgroundTumorigenic transformation of human epithelial cells in vitro has been described experimentally as the potential result of spontaneous immortalization. This process is characterized by a series of cell–state transitions, in which normal epithelial cells acquire first a senescent state which is later surpassed to attain a mesenchymal stem–like phenotype with a potentially tumorigenic behavior. In this paper we aim to provide a system–level mechanistic explanation to the emergence of these cell types, and to the time–ordered transition patterns that are common to neoplasias of epithelial origin. To this end, we first integrate published functional and well–curated molecular data of the components and interactions that have been found to be involved in such cell states and transitions into a network of 41 molecular components. We then reduce this initial network by removing simple mediators (i.e., linear pathways), and formalize the resulting regulatory core into logical rules that govern the dynamics of each of the network components as a function of the states of its regulators.ResultsComputational dynamic analysis shows that our proposed Gene Regulatory Network model recovers exactly three attractors, each of them defined by a specific gene expression profile that corresponds to the epithelial, senescent, and mesenchymal stem–like cellular phenotypes, respectively. We show that although a mesenchymal stem–like state can be attained even under unperturbed physiological conditions, the likelihood of converging to this state is increased when pro–inflammatory conditions are simulated, providing a systems–level mechanistic explanation for the carcinogenic role of chronic inflammatory conditions observed in the clinic. We also found that the regulatory core yields an epigenetic landscape that restricts temporal patterns of progression between the steady states, such that recovered patterns resemble the time–ordered transitions observed during the spontaneous immortalization of epithelial cells, both in vivo and in vitro.ConclusionOur study strongly suggests that the in vitro tumorigenic transformation of epithelial cells, which strongly correlates with the patterns observed during the pathological progression of epithelial carcinogenesis in vivo, emerges from underlying regulatory networks involved in epithelial trans–differentiation during development.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-017-0393-5) contains supplementary material, which is available to authorized users.

Cissus trifoliata (L.) L belongs to the Vitaceae family and is an important medicinal plant used in Mexico for the management of infectious diseases and tumors. The present study aimed to evaluate the metabolic profile of the stems of C. trifoliata and to correlate the results with their antibacterial and cytotoxic activities. The hexane extract was analyzed using gas chromatography coupled with mass spectrometry (GC-MS) and the CHCl3-MeOH and aqueous extracts by ultraperformance liquid chromatography quadrupole time of fly mass spectrometry (UPLC-QTOF-MS). The antibacterial activity was determined by broth microdilution and the cytotoxicity was evaluated using MTS cell proliferation assay. Forty-six metabolites were putatively identified from the three extracts. Overall, terpenes, flavonoids and stilbenes characterize the metabolic profile. No antibacterial activity was found in any extract against the fifteen bacteria strains tested (MIC >500 µg/mL). However, high cytotoxic activity (IC50 ≤ 30 µg/mL) was found in the hexane and aqueous extracts against hepatocarcinoma and breast cancer cells (Hep3B, HepG2 and MCF7). This is the first report of the bioactive compounds of C. trifoliata stems and their antibacterial and cytotoxic properties. The metabolic profile rich in anticancer compounds correlate with the cytotoxic activity of the extracts from the stems of C. trifoliata. This study shows the antitumor effects of this plant used in the traditional medicine and justifies further research of its anticancer activity.

IntroductionThe hormone leptin, which is produced in the adipose tissue, may influence tumorigenesis directly via its receptor (Ob-R). Thus, a role for Ob-R in endometrial carcinogenesis has been proposed. However, most studies neither included samples of the entire histological progression of endometrial carcinoma nor examined Ob-R jointly with the estrogen and progesterone receptors (ER and PR, respectively).Material and methodsTo determine the fluctuations of Ob-R, ER, and PR during the histological progression of endometrial carcinoma, we assessed their expression via immunohistochemistry (IHC) in six histological types of endometrium (proliferative, secretory, nonatypical and atypical hyperplasia, and endometrioid and nonendometrioid endometrial carcinoma), in which we performed histopathological and digital scoring for the quantification of receptors.ResultsWe found that Ob-R expression was positively correlated with that of ER and PR (r = 1, p < 0.001; r = 0.943, p < 0.005, respectively), and there was a significant difference in Ob-R expression among proliferative normal endometrium, hyperplasias, and carcinomas, according to their relative digitally scored Ob-R expression (p < 0.001). In addition, we observed that Ob-R expression in the secretory endometrium was more similar to that of carcinomas than to its proliferative counterpart.ConclusionsThese results indicate that Ob-R expression fluctuates during endometrial carcinogenesis in correlation with ER and PR, suggesting that Ob-R expression in vivo is highly dependent on estrogen and progesterone activities in the endometrium and on its ER and PR status, as suggested previously by in vitro studies.

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