A carcinogenic trigger to study the function of tumor suppressor genes in Schmidtea mediterranea

Abstract

Planarians have been long known for their regenerative ability, which hinges on pluripotency. Recently, however, the planarian model has been successfully established for routine toxicological screens aimed to assess overproliferation, mutagenicity and tumorigenesis. In this study, we focused on planarian tumor suppressor genes (TSGs) and their role during chemically induced carcinogenic stress in Schmidtea mediterranea. Combining in silico and proteomic screens with exposure to human carcinogen type 1A agent cadmium (Cd), we showed that many TSGs have a function in stem cells and that, in general, exposure to Cd accelerated the onset and increased the severity of the observed phenotype. This suggested that the interaction between environmental and genetic factors plays an important role in tumor development in S. mediterranea. Therefore, we further focused on the synergistic effects of Cd exposure and p53 knockdown (KD) at the cellular and molecular levels. Cd also produced a specific proteomic landscape in homeostatic animals, with 172 proteins differentially expressed, 43 of which were downregulated. Several of these proteins have tumor suppressor function in human and other animals, namely Wilms Tumor 1 Associated Protein (WT1), Heat Shock Protein 90 (HSP90), Glioma Pathogenesis-Related Protein 1 (GLIPR1) and Matrix Metalloproteinase B (Smed-MMPB). Both Glipr1 and MmpB KD produced large outgrowths, epidermal lesions and epidermal blisters. The epidermal blisters that formed as a consequence of Smed-MmpB KD were populated by smedwi1+ cells, many of which were actively proliferating, while large outgrowths contained ectopically differentiated structures, such as photoreceptors, nervous tissue and a small pharynx. In conclusion, Smed-MmpB is a planarian TSG that prevents stem cell proliferation and differentiation outside the proper milieu.

Muscle functions as a connective tissue and source of extracellular matrix in planarians

“…Occasionally small unpigmented growths appeared (Supplementary Fig. 9e), similar to ectopic cell phenotypes reported after inhibition of genes encoding MMPs 35,36 or tumor suppressors 52–55 . By contrast, in hmcn-1(RNAi) animals, clear defects were not apparent in the organization of the sub-epidermal membrane, mitotic neoblasts, or gut structure (Fig.…”

Assessment of iron oxide nanoparticle ecotoxicity on regeneration and homeostasis in the replacement model system Schmidtea mediterranea

“…In order to fully understand the activity of IONs on homeostatic planarians, we performed real time qPCR analysis to investigate whether exposure to IONs could alter expression of the genes involved in the dynamics of the stem cell population. In planarian, adult stem cells are very sensitive to stress (e.g., irradiation) and respond by activating or shutting down genes that regulate the stem cell population (Hayashi et al, 2006;Eisenhoffer et al, 2008;Van Roten et al, 2018). Therefore, changes in the expression of stem and/or progeny cell markers could indicate the effects of a downstream cascade of cellular/molecular mechanisms in response to the stimulus exerted by IONs.…”

“…The exceptionally short time scale by which regeneration progresses, the inexpensive husbandry, and the sensitivity to environmental pollutants make planarians an alternative model to vertebrates for studying the effects of pollutants in vivo (Stevens et al, 2017;Van Roten et al, 2018). In comparison to other alternative models, like zebra fish larvae and nematodes, planarians are capable to react sensitively to several chemicals (Hagstrom et al, 2015), providing the additional opportunity to study nanotoxicity in adult individuals that possess a highly dynamic stem cell population.…”

Planarians as models to investigate the bioactivity of gold(I) complexes in vivo

“…To characterize the biological activity of new gold complexes we can utilize planarians as an in vivo model system. Planarians are free-living flatworms that are commonly used in pharmacology 18 and are also a suitable model for cancer research; 19 – 24 for example, the anti-cancer agent, rapamycin, effectively attenuates RNAi-induced hyper-proliferation and outgrowths in planarians 25 , 26 . Thus, the experimental accessibility of these organisms can be exploited to screen anti-cancer drug bioactivities.…”