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  • br a promising platform for fabricating


    a promising platform for fabricating effective co-delivery systems and potentially promote the combined application of biopharmaceuticals in the future.
    Conflict of interest
    No financial conflict of interest was reported by the authors of this paper.
    Appendix A. Supplementary data
    Y. Huang, Targeting death receptors for drug-resistant cancer therapy: codelivery of pTRAIL and monensin using dual-targeting and stimuli-responsive self-assembling nanocomposites, Biomaterials 158 (2018) 56–73, biomaterials.2017.12.018.
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    Original contribution
    Co-expression of cytokeratin and vimentin in colorectal cancer highlights a subset of tumor buds and an atypical cancer-associated stroma☆,☆☆,★
    Sara N. Meyer MD a,1, José A. Galván PhD a,1, Stefan Zahnd PhD a, Lena Sokol PhD a,b, Heather Dawson MD a, Alessandro Lugli MD a, Inti Zlobec PhD a,
    aInstitute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3008, Switzerland bSwiss Group for Clinical Cancer Research, Effingerstrasse 33, Bern, CH-3008, Switzerland
    Colorectal cancer; Tumor budding; Cancer-associated stroma; Epithelial-mesenchymal
    Summary Tumor buds in colorectal cancer are hypothesized to undergo a (partial) epithelial-mesenchymal transition (EMT). If so, cytokeratin (CK) and vimentin (VIM) co-expression is expected. CK+/VIM+ can also be found in some stromal cells; however, their origin remains unclear. Here, we determine the fre-quency of CK+/VIM+ tumor cells and characterize the CK+/VIM+ stroma in colorectal cancer. Three cell populations (CK+, VIM+, CK+/VIM+) were sorted using DepArray and fluorescence-activated cell sorting (FACS). Tumor areas were selected to include tumor center, stroma and tumor budding. Fluorescence microscopy was used to visualize co-expressing cells on whole slides. A next-generation tissue microarray (ngTMA) of matched Pan-CK–positive and -negative stroma was constructed and stained for E-cadherin, VIM, Snail1, Twist1, Zeb1 and Zeb2, COL11A1, SPARC, CD90, α-SMA, FAP and WT1. CK+/VIM+ co-expressing tumor cells were detected using all three methods. With DepArray, only tumor budding areas contained CK+/VIM+ cells. The proportion of CK+/VIM+ tumor cells was low (1.5%–22%). CK+ stroma was associated with aggressive tumor features like distant metastasis (P = .0003), lymphatic invasion (P =
    .0009) and tumor budding (P = .0084). CK+/VIM+ stroma was characterized by positive WT1 (P b .001), ZEB2 (P b .001), TWIST1 (P = .009), and FAP (P = .003). Our data suggest that CK+/VIM+ tumor cells exist, albeit in low numbers and could represent a subgroup of tumor buds in partial EMT. CK+/VIM+ stroma may be of mesothelial origin and shows features of mesenchymal cells and cancer-associated fibro-blasts. These results, together with the association with metastasis point to cells in mesothelial-mesenchymal transition (MMT). This atypical stroma may be a potential target for therapy. © 2019 Elsevier Inc. All rights reserved.
    ☆ Competing interests: the authors have no disclosures or conflicts of interest.
    ☆☆ Funding/Support: We thank the Werner und Hedy Berger Janser Stiftung, as well as the Mach-Gaensslen Stiftung and Johanna Dürmüller-Bol foundation for supporting this work.
    ★ Declaration of interest: none.
    Corresponding author at: University of Bern, Institute of Pathology, Murtenstrasse 31, Bern, CH-3008, Switzerland.
    E-mail address: [email protected] (I. Zlobec). 1 Authors contributed equally.
    1. Introduction
    Tumor budding in colorectal cancer is recognized as an important prognostic factor [1]. The presence of tumor buds, defined as single tumor cells or small tumor cell clusters (up to 4 cells), leads to worse overall and disease-free survival and is associated with advanced tumor stage, lymphatic and venous invasion as well as lymph node and distant metastasis.
    Co-expression of CK/VIM in tumor buds and stroma 19
    Tumor budding has often been referred to as a hallmark of epithelial-mesenchymal transition (EMT) but the morphology of tumor buds, as well as immunohistochemistry and RNA profiles do not suggest a full transition to a mesenchymal state [2,3]. A closer look at tumor budding in the literature suggests that only a subset of tumor buds shows nuclear expression of β-catenin and absence of membranous E-cadherin, which are considered “classic” signs of EMT, but this differs between tumor types (eg, more frequently found in colorectal cancers but almost never reported in pancreatic ductal adenocarcinoma) [3-7].