Expression of stem cell markers as useful complementary factors in the early detection of urinary bladder carcinogens by
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GENOTOXICITY AND CARCINOGENICITY
Expression of stem cell markers as useful complementary factors in the early detection of urinary bladder carcinogens by immunohistochemistry for γ‑H2AX Takanori Yamada1,2 · Takeshi Toyoda1 · Kohei Matsushita1 · Young‑Man Cho1 · Jun‑ichi Akagi1 · Tomomi Morikawa1 · Yasuko Mizuta1 · Kumiko Ogawa1 Received: 21 September 2020 / Accepted: 5 November 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract We previously demonstrated that immunohistochemistry for γ-H2AX, a biomarker of DNA damage, is useful for early detection of urinary bladder carcinogens in rats. In a 28-day repeated-dose study, γ-H2AX was shown to have high sensitivity for detection of bladder carcinogens. However, no reports have evaluated whether a combination of multiple biomarkers may further improve sensitivity. Accordingly, in this study, we aimed to evaluate the applicability of bladder tissue and cancer stem cell markers, including cytokeratin 14 (KRT14), aldehyde dehydrogenase 1A1 (ALDH1A1), and cluster of differentiation 44 (CD44), as complementary markers for early detection of bladder carcinogens. Bladder samples obtained from male F344 rats orally treated with 14 bladder carcinogens and five nonbladder carcinogens for 28 days were used for immunohistochemical analysis of stem cell markers. In the bladder carcinogen-treated rats, increases in KRT14, ALDH1A1, and CD44 expression were observed in 9, 10, and 10 out of 14 groups, respectively, whereas the five nonbladder carcinogens did not cause upregulation of these markers. Although most epithelial cells with KRT14 or ALDH1A1 expression were also positive for CD44, KRT14 and ALDH1A1 expression were mutually exclusive. Twelve bladder carcinogens showed increases in at least one of the three markers, indicating that the combined evaluation showed higher sensitivity than the use of individual markers alone. Importantly, two of three bladder carcinogens that did not induce γ-H2AX immunostaining showed stem cell marker expression. Our results demonstrated that these stem cell markers may be useful as complementary markers for γ-H2AX in evaluation of bladder carcinogens. Keywords Urinary bladder · Stem cell marker · Cytokeratin 14 · Aldehyde dehydrogenase 1A1 · Cluster of differentiation 44 · γ-H2AX
Introduction Urinary bladder cancer is the sixth most common cancer in men worldwide, and smoking and occupational exposure are considered major risk factors for its development (Bray et al. 2018). Several epidemiological and experimental studies have suggested that various chemicals are closely associated * Takeshi Toyoda t‑[email protected] 1
Division of Pathology, National Institute of Health Sciences, 3‑25‑26 Tonomachi, Kawasaki‑ku, Kawasaki 210‑9501, Japan
Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3‑5‑8 Saiwai‑cho, Fuchu, Tokyo 183‑8509, Japan
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with the risk of bladder carcinogenesis (Cumberbatch et al. 2015). Therefore, the development of an effective shortterm method for detecting blad
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