Endogenous markers of tumor hypoxia predictors of clinical radiation resistance?
BACKGROUND
Eppendorf electrode measurements of tumor oxygenation have defined an adverse effect of tumor hypoxia on prognosis after radiotherapy and other treatment modalities, in particular in head and neck and cervix carcinomas as well as soft tissue sarcomas. Recently, the immunohistochemical detection of proteins involved in the "hypoxic response" of tumor cells has been discussed as a method to estimate hypoxia in clinical tumor specimens.


METHODS
This review focuses on clinical and experimental data, regarding prognostic impact and comparability with other methods of hypoxia detection, for three proteins suggested as endogenous markers of tumor hypoxia: hypoxia-inducible factor-1alpha(HIF-1alpha), carbonic anhydrase 9 (CA 9), and glucose transporter 1 (GLUT1).


RESULTS
None of the three potential hypoxia markers is exclusively hypoxia-specific, and in each case protein can be detected under normoxic conditions in vitro. HIF-1alpha responds rapidly to hypoxia but also to reoxygenation, making this marker quite unstable in the context of clinical sample collection. The perinecrotic labeling pattern typical of chronic hypoxia and a reasonable agreement with injectable hypoxia markers such as pimonidazole have most consistently been described for CA 9. All three markers showed correlation with Eppendorf electrode measurements of tumor oxygenation in carcinoma of the cervix. In nine of 13 reports, among them all three that refer to curative radiotherapy for head and neck cancer, HIF-1alpha overexpression was associated with poor outcome. CA 9 was an adverse prognostic factor in cervix, head and neck and lung cancer, but not in two other head and neck cancer reports. GLUT1 predicted for poor survival in colorectal, cervix and lung cancer.


CONCLUSIONS
Endogenous markers have the potential to indicate therapeutically relevant levels of hypoxia within tumors. Clinical trials assessing a marker's ability to predict a benefit from specific hypoxia-directed treatment (e. g., tirapazamine, "ARCON" concept) are necessary to define the potential of individual markers.
Vordermark
Dirk
D
Department of Radiation Oncology, University of Würzburg, Germany. vordermark_d@klinik.uni-wuerzburg.de
Brown
J Martin
JM
D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D002256:Carbonic Anhydrases; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D005544:Forecasting; D051272:Glucose Transporter Type 1; D006367:HeLa Cells; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000401:mortality / Q000532:radiotherapy; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000378:metabolism / Q000401:mortality / Q000532:radiotherapy; D008297:Male; D009004:Monosaccharide Transport Proteins; D009369:Neoplasms / Q000378:metabolism* / Q000532:radiotherapy*; D010100:Oxygen / Q000378:metabolism*; D011379:Prognosis; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use; D000077704:Tirapazamine; D014157:Transcription Factors / Q000378:metabolism; D016896:Treatment Outcome; D014227:Triazines / Q000627:therapeutic use; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000401:mortality / Q000532:radiotherapy
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D051272:Glucose Transporter Type 1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009004:Monosaccharide Transport Proteins; D011838:Radiation-Sensitizing Agents; C495677:SLC2A1 protein, human; D014157:Transcription Factors; D014227:Triazines; D000077704:Tirapazamine; D002256:Carbonic Anhydrases; D010100:Oxygen