Basal stem cells contribute to squamous cell carcinomas in the oral cavity.
The cells of origin of oral cavity squamous cell carcinoma (OCSCC) are unknown. We used a cell lineage tracing approach (adult K14-CreER(TAM); ROSA26 mice transiently treated with tamoxifen) to identify and track normal epithelial stem cells (SCs) in mouse tongues by X-gal staining and to determine if these cells become neoplastically transformed by treatment with a carcinogen, 4-nitroquinoline 1-oxide (4-NQO). Here, we show that in normal tongue epithelia, X-gal(+) cells formed thin columns throughout the entire epithelium 12 weeks after tamoxifen treatment, indicating that the basal layer contains long-lived SCs that produce progeny by asymmetric division to maintain homeostasis. Carcinogen treatment results in a ~10-fold reduction in the total number of X-gal(+) clonal cell populations and horizontal expansion of X-gal(+) clonal cell columns, a pattern consistent with symmetric division of some SCs. Finally, X-gal(+) SCs are present in papillomas and invasive OCSCCs, and these long-lived X-gal(+) SCs are the cells of origin of these tumors. Moreover, the resulting 4-NQO-induced tumors are multiclonal. These findings provide insights into the identity of the initiating cells of oral cancer.
Department of Pharmacology, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
Xiao-Han
XH
Tang
Theresa
T
Scognamiglio
Lorraine J
LJ
Gudas
D015112:4-Nitroquinoline-1-oxide / Q000009:adverse effects; D000818:Animals; D002273:Carcinogens; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D007763:Lac Operon; D051379:Mice; D008822:Mice, Transgenic; D009055:Mouth / Q000378:metabolism / Q000473:pathology*; D009062:Mouth Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015363:Quinolones / Q000009:adverse effects; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology*; D014062:Tongue Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
C120195:4-nitroquinolone-1-oxide; D002273:Carcinogens; D015363:Quinolones; D015112:4-Nitroquinoline-1-oxide