An evaluation of tumor oxygenation and gene expression in patients with early stage non-small cell lung cancers.
BACKGROUND
To directly assess tumor oxygenation in resectable non-small cell lung cancers (NSCLC) and to correlate tumor pO2 and the selected gene and protein expression to treatment outcomes.


METHODS
Twenty patients with resectable NSCLC were enrolled. Intraoperative measurements of normal lung and tumor pO2 were done with the Eppendorf polarographic electrode. All patients had plasma osteopontin measurements by ELISA. Carbonic anhydrase-IX (CA IX) staining of tumor sections was done in the majority of patients (n = 16), as was gene expression profiling (n = 12) using cDNA microarrays. Tumor pO2 was correlated with CA IX staining, osteopontin levels, and treatment outcomes.


RESULTS
The median tumor pO2 ranged from 0.7 to 46 mm Hg (median, 16.6) and was lower than normal lung pO2 in all but one patient. Because both variables were affected by the completeness of lung deflation during measurement, we used the ratio of tumor/normal lung (T/L) pO2 as a reflection of tumor oxygenation. The median T/L pO2 was 0.13. T/L pO2 correlated significantly with plasma osteopontin levels (r = 0.53, P = 0.02) and CA IX expression (P = 0.006). Gene expression profiling showed that high CD44 expression was a predictor for relapse, which was confirmed by tissue staining of CD44 variant 6 protein. Other variables associated with the risk of relapse were T stage (P = 0.02), T/L pO2 (P = 0.04), and osteopontin levels (P = 0.001).


CONCLUSIONS
Tumor hypoxia exists in resectable NSCLC and is associated with elevated expression of osteopontin and CA IX. Tumor hypoxia and elevated osteopontin levels and CD44 expression correlated with poor prognosis. A larger study is needed to confirm the prognostic significance of these factors.
Department of Radiation Oncology, Stanford University Medical Center, Stanford, California 94305-5847, USA.
Quynh-Thu
QT
Le
Eunice
E
Chen
Ali
A
Salim
Hongbin
H
Cao
Christina S
CS
Kong
Richard
R
Whyte
Jessica
J
Donington
Walter
W
Cannon
Heather
H
Wakelee
Robert
R
Tibshirani
John D
JD
Mitchell
Donna
D
Richardson
Ken J
KJ
O'Byrne
Albert C
AC
Koong
Amato J
AJ
Giaccia
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D053495:Osteopontin; D010100:Oxygen / Q000378:metabolism*; D011379:Prognosis; D012795:Sialoglycoproteins / Q000097:blood*; D015996:Survival Rate
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; D053495:Osteopontin; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; D010100:Oxygen