E‐cadherin‐Fc chimera protein matrix enhances cancer stem‐like properties and induces mesenchymal features in colon cancer cells

• Published in: Cancer science Vol. 110; no. 11; pp. 3520 - 3532
• Main Authors: Qian, Yamin, Wu, Xin, Yokoyama, Yuhki, Okuzaki, Daisuke, Taguchi, Mai, Hirose, Haruka, Wang, Jiaqi, Hata, Tsuyoshi, Inoue, Akira, Hiraki, Masayuki, Ohtsuka, Masahisa, Takahashi, Hidekazu, Haraguchi, Naotsugu, Mizushima, Tsunekazu, Tanaka, Shinji, Mori, Masaki, Yamamoto, Hirofumi
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.11.2019; John Wiley and Sons Inc
• Subjects: 1-Phosphatidylinositol 3-kinase; 5-Fluorouracil; AKT protein; Aldehyde dehydrogenase; Aldehyde Dehydrogenase - metabolism; Antineoplastic Agents - pharmacology; cancer stem cell; CD44 antigen; Cell adhesion & migration; Cell culture; Cell Line, Tumor; Chemoresistance; Colon cancer; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal cancer; Drug resistance; Drug Resistance, Neoplasm; Epidermal growth factor receptors; epithelial‐mesenchymal transition; ErbB Receptors; extracellular matrix; E‐cadherin‐Fc; Fc receptors; Fibroblast growth factor 2; Fluorouracil - pharmacology; Growth factors; Humans; Hyaluronan Receptors - metabolism; Immunoglobulin Fc Fragments; Limited partnerships; Medical prognosis; Medical research; Mesenchyme; Metastasis; Morphology; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Original; Ornithine; Ornithine Decarboxylase; Oxaliplatin; Oxaliplatin - pharmacology; Phosphorylation; Polycomb Repressive Complex 1 - metabolism; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Proteins; Receptors, G-Protein-Coupled - metabolism; Recombinant Fusion Proteins - metabolism; Sox9 protein; SOX9 Transcription Factor - metabolism; Spheroids, Cellular; Stem cells; Studies; TOR protein; Transcription factors; Tumor cells; Tumorigenesis; Tumorigenicity; United States > US; Japan; epithelial-mesenchymal transition; E-cadherin-Fc; cancer stem cell; colon cancer; extracellular matrix
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.14193

Cancer stem cells (CSC) are a subpopulation of tumor cells with properties of high tumorigenicity and drug resistance, which lead to recurrence and poor prognosis. Although a better understanding of CSC is essential for developing cancer therapies, scarcity of the CSC population has hindered such analyses. The aim of the present study was to elucidate whether the E‐cadherin‐Fc chimera protein (E‐cad‐Fc) enhances cancer stem‐like properties because studies show that soluble E‐cadherin stimulates human epithelial growth factor receptor (EGFR) and downstream signaling pathways that are reported to play a crucial role in CSC. For this purpose, we used ornithine decarboxylase (ODC)‐degron–transduced (Degron(+)) KM12SM cells as a CSC model that retains relatively low CSC properties. Compared to cultures without E‐cad‐Fc treatment, we found that E‐cad‐Fc treatment further suppressed proteasome activity and largely enhanced cancer stem‐like properties of ODC‐degron–transduced KM12SM cells. These results include increased expression of stem cell markers Lgr5, Bmi‐1, SOX9, CD44, and CD44v9, aldehyde dehydrogenase (ALDH), and enhancement of robust spheroid formation, and chemoresistance to 5‐fluorouracil (5‐FU) and oxaliplatin (L‐OHP). These effects could be attributed to activation of the EGFR pathway as identified by extensive phosphorylation of EGFR, ERK, PI3K, AKT, and mTOR. In SW480 cells, E‐cad‐Fc matrix induced some CSC markers such as CD44v9 and ALDH. We also found that E‐cad‐Fc matrix showed high efficiency of inducing mesenchymal changes in colon cancer cells. Our data suggest that the E‐cad‐Fc matrix may enhance CSC properties such as enhancement of chemoresistance and sphere formation. E‐cadherin matrix induces epithelial‐mesenchymal transition in colon cancer. It also facilitates cancer stem‐like properties in ODC‐degron–transduced cells.