Abstract
In cancer biology, epithelial-to-mesenchymal transition (EMT) is associated with tumorigenesis, stemness, invasion, metastasis, and resistance to therapy. Evidence of co-expression of epithelial and mesenchymal markers suggests that EMT should be a stepwise process with distinct intermediate states rather than a binary switch. In the present study, we propose a morphological approach that enables the detection and quantification of cancer cells with hybrid E/M states, i.e., which combine partially epithelial (E) and partially mesenchymal (M) states. This approach is based on a sequential immunohistochemistry technique performed on the same tissue section, the digitization of whole slides, and image processing. The aim is to extract quantitative indicators able to quantify the presence of hybrid E/M states in large series of human cancer samples and to analyze their relationship with cancer aggressiveness. As a proof of concept, we applied our methodology to a series of about a hundred urothelial carcinomas and demonstrated that the presence of cancer cells with hybrid E/M phenotypes at the time of diagnosis is strongly associated with a poor prognostic value, independently of standard clinicopathological features. Although validation on a larger case series and other cancer types is required, our data support the hybrid E/M score as a promising prognostic biomarker for carcinoma patients.
Highlights
In the context of carcinoma pathogenesis and progression, the epithelial-to-mesenchymal transition (EMT) program can be regulated by many signaling pathways and transcription factors, as well as post-transcriptional, epigenetic and post-translational mechanisms [1,2,3]
It should be noted that cells that have undergone only partial EMT, giving them a hybrid E/M state combining both epithelial and mesenchymal features, are more likely to acquire stem-like properties
As E-cad is mainly expressed in the cell membrane, we aimed to identify the whole surface of cells expressing E-cad in order to be comparable to the quantified pan-CK+ area in epithelial cells
Summary
In the context of carcinoma pathogenesis and progression, the epithelial-to-mesenchymal transition (EMT) program can be regulated by many signaling pathways and transcription factors, as well as post-transcriptional, epigenetic and post-translational mechanisms [1,2,3]. It has been shown that the EMT program can be manifested in cells to various degrees, meaning that cells may transit through a series of states across the epithelial–mesenchymal spectrum. This suggests that carcinoma cells might adopt and reside in multiple intermediate phenotypic states and these states might be transmitted through multiple cell generations [4]. Increasing evidence shows that tumor progression and metastasis is favored by carcinoma cell residence in hybrid, partially epithelial, and partially mesenchymal states [2,3,4,5,6,7]. Characterization of the hybrid E/M status of tumors could provide useful biomarkers for diagnostic, prognostic, and theranostic purposes
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