Presence of a putative tumor-initiating progenitor cell population predicts poor prognosis in smokers with non-small cell lung cancer.
Smoking is the most important known risk factor for the development of lung cancer. Tobacco exposure results in chronic inflammation, tissue injury, and repair. A recent hypothesis argues for a stem/progenitor cell involved in airway epithelial repair that may be a tumor-initiating cell in lung cancer and which may be associated with recurrence and metastasis. We used immunostaining, quantitative real-time PCR, Western blots, and lung cancer tissue microarrays to identify subpopulations of airway epithelial stem/progenitor cells under steady-state conditions, normal repair, aberrant repair with premalignant lesions and lung cancer, and their correlation with injury and prognosis. We identified a population of keratin 14 (K14)-expressing progenitor epithelial cells that was involved in repair after injury. Dysregulated repair resulted in the persistence of K14+ cells in the airway epithelium in potentially premalignant lesions. The presence of K14+ progenitor airway epithelial cells in NSCLC predicted a poor prognosis, and this predictive value was strongest in smokers, in which it also correlated with metastasis. This suggests that reparative K14+ progenitor cells may be tumor-initiating cells in this subgroup of smokers with NSCLC.
Ooi
Aik T
AT
Department of Pediatrics, Division of Hematology Oncology, Mattel Children's Hospital, University of California at Los Angeles, David Geffen School of Medicine at the University of California, Los Angeles, California, USA.
Mah
Vei
V
Nickerson
Derek W
DW
Gilbert
Jennifer L
JL
Ha
Vi Luan
VL
Hegab
Ahmed E
AE
Horvath
Steve
S
Alavi
Mohammad
M
Maresh
Erin L
EL
Chia
David
D
Gower
Adam C
AC
Lenburg
Marc E
ME
Spira
Avrum
A
Solis
Luisa M
LM
Wistuba
Ignacio I
II
Walser
Tonya C
TC
Wallace
William D
WD
Dubinett
Steven M
SM
Goodglick
Lee
L
Gomperts
Brigitte N
BN
D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D053547:Keratin-14 / Q000096:biosynthesis; D053569:Keratin-15; D053555:Keratin-5 / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D020545:Respiratory Mucosa / Q000473:pathology; D012907:Smoking / Q000378:metabolism / Q000473:pathology*
C507540:KRT14 protein, human; C503940:KRT5 protein, human; D053547:Keratin-14; D053569:Keratin-15; D053555:Keratin-5; C507446:Krt14 protein, mouse; C492053:Krt15 protein, mouse