Enhanced cancer stem cell properties of a mitotically quiescent subpopulation of p75NTR-positive cells in esophageal squamous cell carcinoma

Autor: Takeshi Miwa, Takuya Nagata, Tetsuji Yamaguchi, Tomoyuki Okumura, Yutaka Shimada, Hirofumi Kojima
Rok vydání: 2017
Předmět:
0301 basic medicine
Male
Cancer Research
Esophageal Neoplasms
Cell
Apoptosis
Mice
0302 clinical medicine
Tumor Cells
Cultured
esophageal cancer
p75 neurotrophin receptor
Aged
80 and over
Mice
Inbred BALB C
Cell Cycle
Articles
Cell cycle
Cell sorting
Middle Aged
Prognosis
Survival Rate
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
Carcinoma
Squamous Cell
Neoplastic Stem Cells
Female
A431 cells
Homeobox protein NANOG
Adult
Mice
Nude
Mitosis
Antineoplastic Agents
Nerve Tissue Proteins
Receptors
Nerve Growth Factor
Biology
03 medical and health sciences
Cancer stem cell
medicine
Biomarkers
Tumor
Animals
Humans
Aged
Cell Proliferation
CD271
quiescent cancer stem cell
Cell growth
Xenograft Model Antitumor Assays
030104 developmental biology
Cell culture
Drug Resistance
Neoplasm
Cancer research
sense organs
Cisplatin
Follow-Up Studies
Zdroj: International Journal of Oncology
ISSN: 1791-2423
Popis: Mitotically quiescent cancer stem cells (CSCs) possess higher malignant potential than other CSCs, indicating their higher contribution to therapeutic resistance than that of other CSCs. In esophageal squamous cell carcinoma (ESCC), p75 neurotrophin receptor (p75NTR) is expressed in a candidate CSC population showing high tumorigenicity and chemoresistance. In the present study, we isolated and characterized quiescent CSCs population in ESCC based on p75NTR expression and cell cycle status. Expression of p75NTR and Ki-67 in ESCC cell lines (KYSE cells) and surgically resected ESCC specimens was detected by performing immunocytochemical analysis. p75NTR-positive KYSE cells were fractionated into quiescent and proliferating cells by performing flow cytometry with a fluorescent DNA-staining dye to determine their CSC phenotype. Immunocytochemical analysis showed that 21.8 and 36.5% of the p75NTR-positive cells were Ki-67-negative (G0), which accounted for 11.4 and 15.7% of cells in KYSE-30 and KYSE-140 cell lines, respectively. Flow cytometric cell sorting showed that p75NTR-positive cells in the G0-G1 phase (p75NTR-positive/G0-1 cells) but not in the S-G2-M phase (p75NTR-positive/S-G2-M cells) showed strong expression of stem cell-related genes Nanog, BMI-1, and p63; high colony formation ability; high tumorigenicity in a mouse xenograft model; and strong chemoresistance against cisplatin because of the expression of drug resistance genes ABCG2 and ERCC1. Label-retention assay showed that 3.4% p75NTR-positive cells retained fluorescent cell-tracing dye, but p75NTR-negative cells did not. Immunohistochemical analysis of ESCC specimens showed p75NTR expression in 39 of 95 (41.1%) patients, with a median of 13.2% (range, 3.0-80.1%) p75NTR-positive/Ki-67-negative cells, which were found to be associated with poorly differentiated histology. Our results suggest that p75NTR-positive/G0-1 cells represent quiescent CSCs in ESCC and indicate that these cells can be used as targets to investigate molecular processes regulating CSC phenotype and to develop novel therapeutic strategies.
Databáze: OpenAIRE
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