Expression of epithelial-mesenchymal transition and cancer stem cell markers in colorectal adenocarcinoma: Clinicopathological significance

Choi, Ji Eun; Bae, Jong Seok; Kang, Myoung Jae; Chung, Myoung Ja; Jang, Kyu Yun; Park, Ho Sung; Moon, Woo Sung

doi:10.3892/or.2017.5790

Cited by 42 publications

(40 citation statements)

References 30 publications

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“…Some researchers have indicated that CSCs might be generated through processes that are related to activation of the EMT [3, 4]. Thus, CSC biology and the EMT are thought to be mechanistically correlated and key components of cancer migration, invasion, and metastasis [5, 52-54]. Accordingly, in-depth research into the crosstalk between cancer stemness and the EMT is essential for a better understanding of tumor progression.…”

Section: Discussionmentioning

confidence: 99%

Lgr5+CD44+EpCAM+ Strictly Defines Cancer Stem Cells in Human Colorectal Cancer

Leng

Xia

Chen

et al. 2018

Cell Physiol Biochem

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Background/Aims: Although EpCAM+CD44+ cells exhibit more stem-like properties than did EpCAM-CD44- cells, the specificity of EpCAM combined with CD44 in defining CSCs needs further improvement. Lgr5 is used as a biomarker to isolate cancer stem cells (CSCs) in colorectal cancer. However, it remains unclear whether Lgr5, along with EpCAM and CD44, can further identify and define CSCs in colorectal cancer. Methods: Lgr5+CD44+EpCAM+, Lgr5+CD44+EpCAM-, Lgr5+CD44-EpCAM+, Lgr5-CD44+EpCAM+, and Lgr5-CD44-EpCAM-cells were separately isolated using fluorescence-activated cell sorting (FACS). Colony formation, self-renewal, differentiation, and tumorigenic properties of these cells were investigated through in vitro experiments and in vivo tumor xenograft models. The expression of stemness genes and CSC- and epithelial-mesenchymal transition (EMT)-related genes, such as KLF4, Oct4, Sox2, Nanog, CD133, CD44, CD166, ALDH1, Lgr5, E-cadherin, ZO-1, Vimentin, Snail, Slug, and Twist, was examined using real-time PCR. Results: Lgr5-positive subpopulations exhibited higher capacities for colony formation, self-renewal, differentiation, and tumorigenicity as well as higher expression of stemness genes and mesenchymal genes and lower expression of epithelial genes than did Lgr5-negative subpopulations. Conclusion: Our data revealed that tumorigenic cells were highly restricted to Lgr5-positive subpopulations. Most importantly, Lgr5+CD44+EpCAM+ cells exhibited more pronounced CSC-like traits than did any other subpopulation, indicating that Lgr5 combined with CD44 and EpCAM can further improve the stem-like traits of CSCs in colorectal cancer.

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Section: Discussionmentioning

confidence: 99%

Lgr5+CD44+EpCAM+ Strictly Defines Cancer Stem Cells in Human Colorectal Cancer

Leng

Xia

Chen

et al. 2018

Cell Physiol Biochem

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“…Thus, an immunohistochemical loss of E-cadherin was associated with shorter cancer-free (p = 0.002) and overall survival (p = 0.007) in 286 cases of colorectal cancer. 80 In contrast, E-cadherin positivity in colorectal cancer stem cells is associated with a higher growth potential in vivo than seen in the E-cadherin negative subpopulation of cancer stem cells. 81 Combined assessment of E-cadherin and CD44 in colorectal cancer has been shown to have a higher prognostic value than isolated evaluation of single markers.…”

Section: Discussionmentioning

confidence: 97%

<p>The Association Between Inflammation, Epithelial Mesenchymal Transition and Stemness in Colorectal Carcinoma</p>

Briede¹,

Štrumfa²,

Vanags³

et al. 2020

JIR

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Background: Inflammation plays an important albeit dual role in carcinogenesis. Survival studies have highlighted the prognostic significance of peritumorous inflammation. Currently, the theoretical background allows inflammation, epithelial mesenchymal transition (EMT) and the closely associated stem cell differentiation in colorectal carcinoma (CRC) to be linked. However, there is scarce direct morphological evidence. Purpose and methods: The aim of our study was to investigate the role of inflammation in cancer growth and invasion by analyzing the association between inflammation and known morphological prognostic features of colorectal cancer, EMT, stemness and mismatch repair (MMR) protein expression. The study was designed as a retrospective morphological and immunohistochemical assessment of 553 consecutive cases of surgically treated primary CRC. Results: There were statistically significant associations between high-grade inflammation and lower pT (p = 0.002), absence of lymph node metastases (p < 0.001) and less frequent lymphatic (p = 0.003), venous (p = 0.017), arterial (p = 0.012), perineural (p = 0.001) and intraneural (p = 0.01) invasion. In contrast, Crohn's like reaction (CLR) by density of lymphoid follicles in the invasive front lacked significant differences in regard to pT, pN, tumor invasion into surrounding structures (blood or lymphatic vessels, nerves), grade or necrosis (all p > 0.05). The expression of E-cadherin, CD44 and MMR proteins yielded no statistically significant associations with peritumorous inflammation by Klintrup-Mäkinen score or the density of lymphoid follicles. Nevertheless, E-cadherin levels were significantly associated with the density of eosinophils (p = 0.007). Conclusion: High-grade peritumorous inflammation is associated with beneficial morphologic CRC features, including less frequent manifestations of invasion, and is not secondary to tissue damage and necrosis. CLR is not associated with cancer spread by pTN; this finding indirectly suggests an independent role of CLR in carcinogenesis. Further, inflammation by Klintrup-Mäkinen grade and CLR is not dependent on epithelial-mesenchymal transition and stem cell differentiation. Our study highlights the complex associations between inflammation, tumor morphology, EMT, stemness and MMR protein expression in human CRC tissues.

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“…Selected EGFR‐positive cancer‐derived tumorspheres were investigated to identify driver genes for mediating PD‐L1 expression. Cancer stem cells (CSCs) exhibit high self‐renewal and pluripotency, thereby contributing to tumor recurrence . Moreover, CSCs have high drug resistance and antiapoptotic properties, which potentially enable them to survive clinical chemotherapies.…”

Section: Introductionmentioning

confidence: 99%

Epidermal growth factor induces STAT1 expression to exacerbate the IFNr‐mediated PD‐L1 axis in epidermal growth factor receptor‐positive cancers

Cheng¹,

Lin

Tsai³

et al. 2018

Molecular Carcinogenesis

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The epidermal growth factor (EGF) receptor (EGFR) overexpressed in many cancers, including lung and head and neck cancers, and is involved in cancer cell progression and survival. PD-L1, increases in tumor cells to evade and inhibit CD8+ T cells, is a clinical immunotherapeutic target. This study investigated the molecular mechanism of EGF on regulating PD-L1 in EGFR-positive cancers and determined potential agents to reduce PD-L1 expression. RNA sequencing (RNAseq) and bioinformatics analysis were performed to determine potential driver genes that regulate PD-L1 in tumor cells-derived tumorspheres which mimicking cancer stem cells. Then, the specific inhibitors targeting EGFR were applied to reduce the expression of PD-L1 in vitro and in vivo. We validated that EGF could induce PD-L1 expression in the selected EGFR-positive cancers. RNAseq results revealed that STAT1 increased as a driver gene in KOSC-3-derived tumorspheres; these data were analyzed using PANTHER followed by NetworkAnalyst. The blockade of EGFR by afatinib resulted in decreased STAT1 and IRF-1 levels, both are transcriptional factors of PD-L1, and disabled the IFNr-STAT1-mediated PD-L1 axis in vitro and in vivo. Moreover, STAT1 knockdown significantly reduced EGF-mediated PD-L1 expression, and ruxolitinib, a JAK1/JAK2 inhibitor, significantly inhibited STAT1 phosphorylation to reduce the IFNr-mediated PD-L1 axis. These results indicate that EGF exacerbates PD-L1 by increasing the protein levels of STAT1 to enforce the IFNr-JAK1/2-mediated signaling axis in selected EGFR-positive cancers. The inhibition of EGFR by afatinib significantly reduced PD-L1 and may be a potential strategy for enhancing immunotherapeutic efficacy.

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Expression of epithelial-mesenchymal transition and cancer stem cell markers in colorectal adenocarcinoma: Clinicopathological significance

Cited by 42 publications

References 30 publications

Lgr5+CD44+EpCAM+ Strictly Defines Cancer Stem Cells in Human Colorectal Cancer

Lgr5+CD44+EpCAM+ Strictly Defines Cancer Stem Cells in Human Colorectal Cancer

<p>The Association Between Inflammation, Epithelial Mesenchymal Transition and Stemness in Colorectal Carcinoma</p>

Epidermal growth factor induces STAT1 expression to exacerbate the IFNr‐mediated PD‐L1 axis in epidermal growth factor receptor‐positive cancers

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