Cholangiocarcinoma Malignant Traits Are Promoted by Schwann Cells through TGFß Signaling in a Model of Perineural Invasion.

The term cholangiocarcinoma (CCA) defines a class of epithelial malignancies originating from bile ducts. Although it has been demonstrated that CCA patients with perineural invasion (PNI) have a worse prognosis, the biological features of this phenomenon are yet unclear. Our data show that in human intrahepatic CCA specimens with documented PNI, nerve-infiltrating CCA cells display positivity of the epithelial marker cytokeratin 7, lower with respect to the rest of the tumor mass. In an in vitro 3D model, CCA cells move towards a peripheral nerve explant allowing contact with Schwann cells (SCs) emerging from the nerve. Here, we show that SCs produce soluble factors that favor the migration, invasion, survival and proliferation of CCA cells in vitro. This effect is accompanied by a cadherin switch, suggestive of an epithelial-mesenchymal transition. The influence of SCs in promoting the ability of CCA cells to migrate and invade the extracellular matrix is hampered by a specific TGFß receptor 1 (TGFBR1) antagonist. Differential proteomic data indicate that the exposure of CCA cells to SC secreted factors induces the upregulation of key oncogenes and the concomitant downregulation of some tumor suppressors. Taken together, these data concur in identifying SCs as possible promoters of a more aggressive CCA phenotype, ascribing a central role to TGFß signaling in regulating this process.

A New Tool to Study Parkinsonism in the Context of Aging: MPTP Intoxication in a Natural Model of Multimorbidity.

The diurnal rodent Octodon degus (O. degus) is considered an attractive natural model for Alzheimer's disease and other human age-related features. However, it has not been explored so far if the O. degus could be used as a model to study Parkinson's disease. To test this idea, 10 adult male O. degus were divided into control group and MPTP-intoxicated animals. Motor condition and cognition were examined. Dopaminergic degeneration was studied in the ventral mesencephalon and in the striatum. Neuroinflammation was also evaluated in the ventral mesencephalon, in the striatum and in the dorsal hippocampus. MPTP animals showed significant alterations in motor activity and in visuospatial memory. Postmortem analysis revealed a significant decrease in the number of dopaminergic neurons in the ventral mesencephalon of MPTP animals, although no differences were found in their striatal terminals. We observed a significant increase in neuroinflammatory responses in the mesencephalon, in the striatum and in the hippocampus of MPTP-intoxicated animals. Additionally, changes in the subcellular expression of the calcium-binding protein S100ß were found in the astrocytes in the nigrostriatal pathway. These findings prove for the first time that O. degus are sensitive to MPTP intoxication and, therefore, is a suitable model for experimental Parkinsonism in the context of aging.

Octodon degus: a natural model of multimorbidity for ageing research.

Integrating the multifactorial processes co-occurring in both physiological and pathological human conditions still remains one of the main challenges in translational investigation. Moreover, the impact of age-associated disorders has increased, which underlines the urgent need to find a feasible model that could help in the development of successful therapies. In this sense, the Octodon degus has been indicated as a 'natural' model in many biomedical areas, especially in ageing. This rodent shows complex social interactions and high sensitiveness to early-stressful events, which have been used to investigate neurodevelopmental processes. Interestingly, a high genetic similarity with some key proteins implicated in human diseases, such as apolipoprotein-E, ß-amyloid or insulin, has been demonstrated. On the other hand, the fact that this animal is diurnal has provided important contribution in the field of circadian biology. Concerning age-related diseases, this rodent could be a good model of multimorbidity since it naturally develops cognitive decline, neurodegenerative histopathological hallmarks, visual degeneration, type II diabetes, endocrinological and metabolic dysfunctions, neoplasias and kidneys alterations. In this review we have collected and summarized the studies performed on the Octodon degus through the years that support its use as a model for biomedical research, with a special focus on ageing.