Abstract
Urothelial bladder cancer is the tenth most common cancer worldwide. It is divided into muscle and non-muscle invading bladder cancer. Primary cilia have been related to several cancer hallmarks such as proliferation, epithelial-to-mesenchymal transition (EMT) or tumoral progression mainly through signaling pathways as Hedgehog (Hh). In the present study, we used immunohistochemical and ultrastructural techniques in human tissues of healthy bladder, non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) to study and clarify the activation of epithelial-to-mesenchymal transition and Hedgehog signaling pathway and the presence of primary cilia. Thus, we found a clear correlation between EMT and Hedgehog activation and bladder cancer stage and progression. Moreover, we identified the presence of primary cilia in these tissues. Interestingly, we found that in NMIBC, some ciliated cells cross the basement membrane and localized in lamina propria, near blood vessels. These results show a correlation between EMT beginning from urothelial basal cells and primary cilia assembly and suggest a potential implication of this structure in tumoral migration and invasiveness (likely in a Hh-dependent way). Hence, primary cilia may play a fundamental role in urothelial bladder cancer progression and suppose a potential therapeutic target.
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Authors would like to acknowledge the use of Servicio General de Apoyo a la Investigación—SAI, Universidad de Zaragoza.
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PI, EM and CB performed immunohistochemical experiments. TC and GM performed pathological analyses. PI, TC and CJ performed electron microscopy and its interpretation. PI and CJ wrote the manuscript. TC and CJ designes the study. All the authors read and approved the manuscript.
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418_2021_1965_MOESM1_ESM.tif
Supplementary Figure 1. Other ultrastructural findings in bladder cancer. a) Dark cells sometimes showed specific nuclear structures called Nuclear Envelope-Limited Chromatin Sheets (ECLS) Scale bar = 2μm (inset 500nm) b) In MIBC, apoptotic cells with heterogenous condensed nucleus appeared. Scale bar = 2μm c) Appart from clear and dark cells, in MIBC fusiform cells (f) were found, showing a mesenchymal phenotype and ultrastructure. Scale bar = 10μm d) Autophagic vacuoles containing different organelles (especially rough endoplasmic reticula) were relatively frequent in MIBC. Scale bar = 500nm e) Angiogenesis consisting of new blood vessels formation was found in MIBC Scale bar = 10μm. f) Necroptosis in MIBC cells. While nucleus (n) remains intact, degradation of mitochondria (m) and other cellular organelles is produced. Scale bar = 1μm.; c:centriole; g: Golgi; nv: new vessels (TIF 36005 KB)
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Iruzubieta, P., Castiella, T., Monleón, E. et al. Primary cilia presence and implications in bladder cancer progression and invasiveness. Histochem Cell Biol 155, 547–560 (2021). https://doi.org/10.1007/s00418-021-01965-2
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DOI: https://doi.org/10.1007/s00418-021-01965-2