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Clinical Investigations |
CRC Experimental Radiation Oncology Group, Paterson Institute [J. A. L., C. M. L. W.] and Department of Clinical Oncology [S. E. D., J. P. L., R. D. H.], Christie Hospital NHS Trust, Manchester M20 4BX, United Kingdom; Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom [A. L. H., C. C. W.]; School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PL, United Kingdom [I. J. S.]; Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, United Kingdom [P. J. R.]; and Institute of Virology, Slovak Academy of Sciences, 84246 Bratislava, Slovak Republic [J. P.]
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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CAs catalyze the reversible hydration of carbon dioxide to carbonic acid (2) and, therefore, play a role in pH regulation. To date, 14 human isoforms (11 active and 3 CA-related proteins; Ref. 3 ) have been reported, but it is the CA IX protein that is strongly induced by hypoxia in a broad range of cell types (1) . CA IX, initially described as a tumor-associated MN, was originally detected in HeLa cells where its expression was found to be cell density dependent (4) . It is a transmembrane glycoprotein, the extracellular domain of which contains the essential features and activity of CAs. Evidence supporting the role of the CA IX protein in neoplastic progression includes its association with tumorigenic phenotypes in human cell hybrids and neoplastic transformation of mouse 3T3 cells after transfection with MN cDNA (4) . The gene product is expressed in many types of human cancer and is usually absent from their normal tissue counterparts. Its role as a biomarker of malignancy has been demonstrated in renal cell, cervical, lung, and colorectal tumors (5, 6, 7) . CA IX protein was found to be expressed in 90% of cervical squamous cell carcinomas (6) . In colonic lesions, a progressive increase in CA IX expression has been noted from hyperplastic polyps through adenomas to carcinomas (8) . Little is known about the role of CA IX in malignancy. Its site on the plasma membrane suggests a role in cell-cell and cell-matrix interactions (9) . It has also been implicated in cellular proliferation (4 , 8) and more recently hypoxia (1) .
In view of the tight regulation of the CA 9 gene by an HIF-1-dependent hypoxia-responsive element, it was suggested that CA IX may be a useful endogenous marker of tumor hypoxia (1) . Interest in the latter stems from the need to find an alternative to the current Eppendorf pO2 histograph method for assessing tumor hypoxia. Although the Eppendorf method provides prognostic information in a variety of tumor types, it is limited to tumors accessible for microneedle insertion. A method based on the immunohistochemical expression of a hypoxia marker would be attractive. In this study, therefore, we have explored the role of CA IX as a marker of hypoxia and prognosis in cancer. Two hypotheses were generated: (a) there is a relationship between tumor hypoxia and CA IX expression in human tumors; and (b) the extent of CA IX expression is prognostic for patient outcome. The hypotheses were tested in carcinoma of the cervix by comparing CA IX expression with oxygen electrode measurements of tumor hypoxia and by examining the relationship between expression and outcome after radiation therapy.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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5 years after treatment, using a
standard follow-up protocol. Additional follow-up information was
obtained from questionnaires to general practitioners. For surviving
patients, the median follow-up was 60 months (range 27–115 months).
The sites of any disease relapse were identified clinically and
radiologically and, where appropriate, were confirmed on biopsy. The
recurrences were then classified as being either local
(i.e., within the radiation field) or metastatic
(i.e., outside the radiation field). Data were also
available on the inherent radiosensitivity measured in vitro
as the surviving fraction at 2Gy (SF2; Ref. 11
) in 78 of
the tumors in the retrospective series. Information about tumor
differentiation was obtained from the hospital pathology department.
CA IX Immunohistochemistry.
Formalin-fixed, paraffin-embedded, 4-µm sections were prepared from
the pretreatment biopsy specimens. After dewaxing and rehydration,
an endogenous peroxidase block (DAKO Envision) was applied for 5 min.
The samples were then washed and incubated with 10% casein (Vector) in
Tris-buffered saline (blocking buffer) for 10 min. A mouse monoclonal
antihuman antibody (M75) raised to the external domain of
CA9 (12)
was applied at a 1/50 dilution for 30
min at room temperature. Secondary polymer from the Envision kit (DAKO)
was applied for 30 min at room temperature. Visualization of CA IX was
by diaminobenzidine substrate. After rinsing in water, slides were
lightly counterstained with hematoxylin, dehydrated, and mounted.
Substitution of the primary antibody with Tris-buffered saline was used
as a negative control.
Analysis of CA IX Staining.
The extent and distribution of the CA IX staining was evaluated under
low magnification, without the observer’s knowledge of outcome data or
oxygen measurements. The sections were scored in a semiquantitative
fashion by estimating the percentage area of tumor cells that had been
stained: 0 for <1%, 1 for 1–10%, 2 for 10–30%, and 3 for >30%
immunostaining. These values were chosen to achieve similar patient
numbers in each group. Regions of necrosis were excluded from the
analysis. Batch-to-batch variation was taken into account by including
a high and low scoring section from each batch in the following batch.
All of the retrospective series were scored independently by two
observers (J. A. L. and C. M. L. W.). Where more than one biopsy
was available for assessment, the average of the scores was used to
represent the tumor.
Eppendorf Measurements.
In the prospective series of patients, measurements of tumor
oxygenation were made using a sterile polarographic needle electrode.
The methods are described in detail elsewhere (13)
.
Briefly, measurements were made with patients in the lithotomy position
and under general anesthetic maintained using propofol infusion and
nitric oxide. Measurements were made at the 12 and 6 o’clock
positions, starting at a depth of 
4 mm and taken every 0.7 mm. A
distance of 
5 mm separated measurement tracks. Data were stored in
the Eppendorf computer system and subsequently processed using the
pO2 pool program (Eppendorf-Netheler-Hinz
GmbH, Hamburg, Germany). The individual patients’ tumor
oxygenation results were expressed as the median
pO2 and as the percentage of values <5-mm Hg
(HP5).
Statistical Analysis.
Survival was analyzed using the Kaplan-Meier method, and prognostic
factors were assessed by Log-rank analysis. Univariate and bivariate
analyses were made of disease-specific survival (based on the number of
patients who did not die from cervical cancer), metastasis-free
survival, and local recurrence-free survival. CA IX score, and other
putative prognostic factors (age, stage, tumor differentiation, and
SF2), were used to stratify patients. A stepwise multivariate Cox
regression analysis was also performed to further test the independence
of CA IX expression from other parameters. The distribution of the CA
IX score in relation to tumor and patient characteristics was
investigated using the 
2 test. Correlations
between variables were obtained using Spearman’s rank correlation. All
tests were two-sided, and a significance level of 0.05 was used
throughout.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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CA IX Expression.
Staining was predominantly on the plasma membrane. The intensity of the
staining, where present, was usually strong, with minimal intra- and
inter-tumor variation. There was clear demarcation between stained and
nonstained areas. For this reason, the extent, rather than the
intensity, of the expression was scored. Very weak cytoplasmic staining
was considered negative because of the lack of specificity
(14)
. The distribution of staining was focal and intense
around, but not in, areas of necrosis. There was an absence of staining
close to blood vessels, consistent with diffusion-limited hypoxia.
Stromal staining was rare. Examples of typical CA IX immunostaining are
shown in Fig. 1
. Definite CA IX expression was seen in 64 of 68 (94%) and 92 of 130
(71%) of tumors in the prospective and retrospective series,
respectively.
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. There was also a significant correlation between CA IX expression and
the fraction of values <10-mm Hg (r = 0.45,
P < 0.001), <2.5-mm Hg
(r = 0.43, P <
0.001), and the median pO2
(r = -0.44, P <
0.001).
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summarizes the distribution of tumor CA IX expression in relation to
patient characteristics in the retrospective series of 130 patients.
Information on tumor differentiation was available for only 114 of the
patients. For 78 patients, data were also available for inherent tumor
radiosensitivity measured in vitro as surviving fraction at
2 Gy (SF2). Using Fisher’s exact test, CA IX expression was
independent of tumor cell differentiation and radiosensitivity. There
were borderline significant trends for a higher level of tumor
expression in older women and more advanced disease stage.
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illustrates the relationship between CA IX expression and treatment
outcome. The level of expression was a significant prognostic factor
for disease-specific (P = 0.018) and
metastasis-free (P = 0.022) survival but not
local control (P = 0. 73). The significance
of CA IX expression as a predictor of outcome increased slightly when
stage IV tumors were excluded from the analysis
[P = 0.013, P =
0.015, and P = 0.80, respectively (results
not illustrated)]. The analyses were repeated stratifying patients by
the absence (<1%) or presence (>1%) of immunostaining. The
prognostic significance of CA IX expression increased for both
disease-specific (P = 0.0041) and
metastasis-free (P = 0.0049) survival (Fig. 4)
. The sensitivity of CA IX staining to predict poor outcome was 85 and
86% for disease-specific and metastasis-free survival,
respectively. Table 2
summarizes the results of univariate Log-rank analyses of outcome after
radiation therapy. Tumor stage and CA IX expression were the strongest
prognostic factors for disease-specific and metastasis-free survival.
Radiosensitivity (SF2) was the strongest prognostic factor for
local control.
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. Expression remained a significant predictor of disease-specific and
metastasis-free survival after allowing for stage, age, and tumor
grade. Finally, a Cox multiple regression analysis was performed. This
included CA IX (absence/presence) and the conventional prognostic
indicators: stage, age, and grade. There were 114 patients available
for this analysis. For survival, stage (P <
0.0010) and CA IX (P = 0.050) were
statistically significant independent prognostic indicators. Stage
(P = 0.002), CA IX (P
= 0.021), and age (P = 0.047) were
significant independent prognostic factors for metastasis-free
survival. Only stage (P = 0.007) was a
significant independent prognostic factor for local control.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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However, although there was a high P for the correlation
between CA IX expression and hypoxia, the correlation coefficient was
only 0.5, and there are a number of possible reasons for this. First,
like VEGF, CA IX may also be up-regulated by other nonhypoxic stimuli.
Second, p53 may exert a repressive effect on CA IX expression via its
inhibition of HIF-1 transcription (17)
and degradation of
HIF-1
(18)
. Although the cervix tumors studied are
likely to have diminished levels of wild-type p53 because of
degradation by the human papillomavirus E6 protein, hypoxia may induce
accumulation of p53 by uncoupling its interaction with E6
(19)
. Third, oxygen electrode measurements are likely to
be dominated by the level of acute (perfusion limited) rather than
chronic (diffusion limited) hypoxia. In contrast, CA IX expression
probably reflects chronic hypoxia (1)
. Although the exact
level and duration of exposure to hypoxia required to up-regulate CA IX
expression is unknown, tissue culture experiments showed the protein to
be stable and accumulate after a period of 4-h hypoxia with maximum
up-regulation at 16 h (1)
. Finally, sampling is
heterogeneous, and the two methods are not comparing the same part of a
tumor. Despite these factors possibly influencing the correlation
between the two methods of estimating the extent of tumor hypoxia,
there was nevertheless a substantial relationship between the two end
points.
Prognostic Role of CA IX Expression.
The prognostic value of needle electrode measurements has been
demonstrated in many studies but is not predictive of outcome in
30% of cases (20)
. This may, in part, reflect the
technical limitations of needle electrodes, sampling errors, and other
clinical/biological confounding factors. In addition, the relative
prognostic importance of acute versus chronic hypoxia has
still to be determined. A method of detecting chronic hypoxia alone may
not necessarily provide the same prognostic information as an Eppendorf
pO2 histograph. We found CA IX expression to be a
significant and independent prognostic factor for disease-specific and
metastasis-free survival after radiation therapy in locally advanced
cervical carcinoma. Its independence from disease stage implies that
information about CA IX expression together with stage could highlight
large differences in patient outcome. However, if CA IX expression is
reflecting tumor hypoxia, which is known to limit radioresponsiveness,
it might also be expected to predict local recurrence. The lack of
relationship between CA IX expression and local control in this study
may again reflect the absence of information on acute hypoxia that is
likely to result in resistance to therapeutic agents. Our results
suggest that CA IX expression reflects the enhanced metastatic
potential of hypoxic tumors but not the relative radioresistance of
hypoxic cells. In support of this, no relationship was seen between CA
IX expression and intrinsic tumor cell radiosensitivity measured as
SF2.
The molecular basis for the involvement of CA9 in carcinogenesis remains unclear. There is some evidence for a role in aberrant cell-cell and cell-matrix interactions that facilitate loss of contact inhibition and anchorage independence of cancer cells (21) . It has also been suggested that the role of the CA domain in regulating acid-base balance may optimize conditions in the tumor microenvironment in favor of tumor invasion (22) . Alternatively, our findings may simply reflect global HIF-regulated up-regulated gene expression, rather than a direct influence on tumor behavior.
Implications for Patient Management.
Our results have a number of implications for cancer patient
management. First, the rapid identification of hypoxic tumors before
treatment remains a goal for many of those involved in the management
of solid tumors. Of the various methods explored to date, most have
limited value in the routine clinical setting. Any potential intrinsic
marker of hypoxia has the advantage of being assessable on routine
clinical biopsies without the need for specialist equipment or
administration of exogenous hypoxia markers. Once hypoxic tumors can be
quickly and reliably identified, it will be possible to select patients
who not only have a poorer prognosis but also are most likely to
benefit from hypoxia-modifying therapy or bio-reductive drugs. Second,
the findings provide a potential link between tumor hypoxia, pH
regulation, and treatment outcome, which could be exploited
therapeutically. CA inhibitors have already been shown in tumor models
to inhibit the invasion of renal cell carcinoma lines (22)
and to have synergistic effects with other chemotherapeutic agents in
animal models (23)
. Third, the MN/CA IX antigen has been
shown to be a strong biomarker of malignancy and may be a good target
for immunotherapy (24
, 25) . Finally, the induction of CA
IX in hypoxic conditions may be used in the refinement of gene therapy
vectors seeking to target therapeutic gene expression to hypoxic
regions of tumors.
In conclusion, we have identified a potential intrinsic marker of hypoxia validated by oxygen electrode measurements. Scoring CA IX expression was rapid, reproducible, and simple to perform, yielding significant independent prognostic information on treatment outcome. The level of CA IX expression may have potential to aid selection of patients who might benefit most from hypoxia-modification therapies or bio-reductive drugs.
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FOOTNOTES |
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1 Supported by the Cancer Research Campaign (to
C. M. L. W.), Imperial Cancer Research Fund (to A. H. and
C. C. W.), the Marchall Fund (to C. C. W.), and the Wellcome Trust
(to P. J. R.). 
2 To whom requests for reprints should be
addressed, at Experimental Radiation Oncology Group, Paterson Institute
for Cancer Research, Christie Hospital, Wilmslow Road, Withington,
Manchester M20 4BX, United Kingdom.
3 The abbreviations used are: HIF,
hypoxia-inducible factor; VEGF, vascular endothelial growth factor; CA,
carbonic anhydrase; MN, membrane antigen.
Received 9/29/00. Accepted 6/21/01.
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.. Genes Dev., 14: 34-44, 2000.This article has been cited by other articles:
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A. Bhattacharya, K. Toth, R. Mazurchuk, J. A. Spernyak, H. K. Slocum, L. Pendyala, R. Azrak, S. Cao, F. A. Durrani, and Y. M. Rustum Lack of Microvessels in Well-Differentiated Regions of Human Head and Neck Squamous Cell Carcinoma A253 Associated with Functional Magnetic Resonance Imaging Detectable Hypoxia, Limited Drug Delivery, and Resistance to Irinotecan Therapy Clin. Cancer Res., December 1, 2004; 10(23): 8005 - 8017. [Abstract] [Full Text] [PDF]
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 M. Hilvo, M. Rafajova, S. Pastorekova, J. Pastorek, and S. Parkkila Expression of Carbonic Anhydrase IX in Mouse Tissues J. Histochem. Cytochem., October 1, 2004; 52(10): 1313 - 1322. [Abstract] [Full Text] [PDF]
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N. Robertson, C. Potter, and A. L. Harris Role of Carbonic Anhydrase IX in Human Tumor Cell Growth, Survival, and Invasion Cancer Res., September 1, 2004; 64(17): 6160 - 6165. [Abstract] [Full Text] [PDF]
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M. Kaluzova, S. Kaluz, M. I. Lerman, and E. J. Stanbridge DNA Damage Is a Prerequisite for p53-Mediated Proteasomal Degradation of HIF-1{alpha} in Hypoxic Cells and Downregulation of the Hypoxia Marker Carbonic Anhydrase IX Mol. Cell. Biol., July 1, 2004; 24(13): 5757 - 5766. [Abstract] [Full Text] [PDF]
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K. Maseide, R. A. Kandel, R. S. Bell, C. N. Catton, B. O'Sullivan, J. S. Wunder, M. Pintilie, D. Hedley, and R. P. Hill Carbonic Anhydrase IX as a Marker for Poor Prognosis in Soft Tissue Sarcoma Clin. Cancer Res., July 1, 2004; 10(13): 4464 - 4471. [Abstract] [Full Text] [PDF]
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A M Jubb, T Q Pham, A M Hanby, G D Frantz, F V Peale, T D Wu, H W Koeppen, and K J Hillan Expression of vascular endothelial growth factor, hypoxia inducible factor 1{alpha}, and carbonic anhydrase IX in human tumours J. Clin. Pathol., May 1, 2004; 57(5): 504 - 512. [Abstract] [Full Text] [PDF]
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 G. Hopfl, O. Ogunshola, and M. Gassmann HIFs and tumors--causes and consequences Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2004; 286(4): R608 - R623. [Abstract] [Full Text] [PDF]
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 D. Hedley, M. Pintilie, J. Woo, T. Nicklee, A. Morrison, D. Birle, A. Fyles, M. Milosevic, and R. Hill Up-Regulation of the Redox Mediators Thioredoxin and Apurinic/Apyrimidinic Excision (APE)/Ref-1 in Hypoxic Microregions of Invasive Cervical Carcinomas, Mapped Using Multispectral, Wide-Field Fluorescence Image Analysis Am. J. Pathol., February 1, 2004; 164(2): 557 - 565. [Abstract] [Full Text] [PDF]
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D. Hedley, M. Pintilie, J. Woo, A. Morrison, D. Birle, A. Fyles, M. Milosevic, and R. Hill Carbonic Anhydrase IX Expression, Hypoxia, and Prognosis in Patients with Uterine Cervical Carcinomas Clin. Cancer Res., November 15, 2003; 9(15): 5666 - 5674. [Abstract] [Full Text] [PDF]
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A. J. Pantuck, G. Zeng, A. S. Belldegrun, and R. A. Figlin Pathobiology, Prognosis, and Targeted Therapy for Renal Cell Carcinoma: Exploiting the Hypoxia-Induced Pathway Clin. Cancer Res., October 15, 2003; 9(13): 4641 - 4652. [Abstract] [Full Text] [PDF]
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K. L. Blackwell, J. P. Kirkpatrick, S. A. Snyder, G. Broadwater, F. Farrell, L. Jolliffe, D. M. Brizel, and M. W. Dewhirst Human Recombinant Erythropoietin Significantly Improves Tumor Oxygenation Independent of Its Effects on Hemoglobin Cancer Res., October 1, 2003; 63(19): 6162 - 6165. [Abstract] [Full Text] [PDF]
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C. N. Coleman Linking Radiation Oncology and Imaging through Molecular Biology (or Now That Therapy and Diagnosis Have Separated, It's Time to Get Together Again!) Radiology, July 1, 2003; 228(1): 29 - 35. [Abstract] [Full Text] [PDF]
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Y. Chen, C. Miller, R. Mosher, X. Zhao, J. Deeds, M. Morrissey, B. Bryant, D. Yang, R. Meyer, F. Cronin, et al. Identification of Cervical Cancer Markers by cDNA and Tissue Microarrays Cancer Res., April 15, 2003; 63(8): 1927 - 1935. [Abstract] [Full Text] [PDF]
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S. Kaluz, M. Kaluzova, and E. J. Stanbridge Expression of the Hypoxia Marker Carbonic Anhydrase IX Is Critically Dependent on SP1 Activity. Identification of a Novel Type of Hypoxia-responsive Enhancer Cancer Res., March 1, 2003; 63(5): 917 - 922. [Abstract] [Full Text] [PDF]
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D. E.B. Swinson, J. L. Jones, D. Richardson, C. Wykoff, H. Turley, J. Pastorek, N. Taub, A. L. Harris, and K. J. O'Byrne Carbonic Anhydrase IX Expression, a Novel Surrogate Marker of Tumor Hypoxia, Is Associated With a Poor Prognosis in Non-Small-Cell Lung Cancer J. Clin. Oncol., February 1, 2003; 21(3): 473 - 482. [Abstract] [Full Text] [PDF]
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M. H. T. Bui, D. Seligson, K.-r. Han, A. J. Pantuck, F. J. Dorey, Y. Huang, S. Horvath, B. C. Leibovich, S. Chopra, S.-Y. Liao, et al. Carbonic Anhydrase IX Is an Independent Predictor of Survival in Advanced Renal Clear Cell Carcinoma: Implications for Prognosis and Therapy Clin. Cancer Res., February 1, 2003; 9(2): 802 - 811. [Abstract] [Full Text] [PDF]
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Q.-T. Le, P. D. Sutphin, S. Raychaudhuri, S. C. T. Yu, D. J. Terris, H. S. Lin, B. Lum, H. A Pinto, A. C. Koong, and A. J. Giaccia Identification of Osteopontin as a Prognostic Plasma Marker for Head and Neck Squamous Cell Carcinomas Clin. Cancer Res., January 1, 2003; 9(1): 59 - 67. [Abstract] [Full Text] [PDF]
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J. H. A. M. Kaanders, K. I. E. M. Wijffels, H. A. M. Marres, A. S. E. Ljungkvist, L. A. M. Pop, F. J. A. van den Hoogen, P. C. M. de Wilde, J. Bussink, J. A. Raleigh, and A. J. van der Kogel Pimonidazole Binding and Tumor Vascularity Predict for Treatment Outcome in Head and Neck Cancer Cancer Res., December 1, 2002; 62(23): 7066 - 7074. [Abstract] [Full Text] [PDF]
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S. Kaluz, M. Kaluzova, A. Chrastina, P. L. Olive, S. Pastorekova, J. Pastorek, M. I. Lerman, and E. J. Stanbridge Lowered Oxygen Tension Induces Expression of the Hypoxia Marker MN/Carbonic Anhydrase IX in the Absence of Hypoxia-inducible Factor 1{alpha} Stabilization: A Role for Phosphatidylinositol 3'-Kinase Cancer Res., August 1, 2002; 62(15): 4469 - 4477. [Abstract] [Full Text] [PDF]
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E. P. Hui, A. T. C. Chan, F. Pezzella, H. Turley, K.-F. To, T. C. W. Poon, B. Zee, F. Mo, P. M. L. Teo, D. P. Huang, et al. Coexpression of Hypoxia-inducible Factors 1{alpha} and 2{alpha}, Carbonic Anhydrase IX, and Vascular Endothelial Growth Factor in Nasopharyngeal Carcinoma and Relationship to Survival Clin. Cancer Res., August 1, 2002; 8(8): 2595 - 2604. [Abstract] [Full Text] [PDF]
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C. J. Koch, P. R. Oprysko, A. L. Shuman, W. T. Jenkins, G. Brandt, and S. M. Evans Radiosensitization of Hypoxic Tumor Cells by Dodecafluoropentane: A Gas-Phase Perfluorochemical Emulsion Cancer Res., July 1, 2002; 62(13): 3626 - 3629. [Abstract] [Full Text] [PDF]
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M. Leppilampi, P. Koistinen, E.-R. Savolainen, J. Hannuksela, A.-K. Parkkila, O. Niemela, S. Pastorekova, J. Pastorek, A. Waheed, W. S. Sly, et al. The Expression of Carbonic Anhydrase II in Hematological Malignancies Clin. Cancer Res., July 1, 2002; 8(7): 2240 - 2245. [Abstract] [Full Text] [PDF]
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C. N. Coleman, J. B. Mitchell, and K. Camphausen Tumor Hypoxia: Chicken, Egg, or a Piece of the Farm? J. Clin. Oncol., February 1, 2002; 20(3): 610 - 615. [Full Text] [PDF]
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P. L. Olive, C. Aquino-Parsons, S. H. MacPhail, S.-Y. Liao, J. A. Raleigh, M. I. Lerman, and E. J. Stanbridge Carbonic Anhydrase 9 as an Endogenous Marker for Hypoxic Cells in Cervical Cancer Cancer Res., December 1, 2001; 61(24): 8924 - 8929. [Abstract] [Full Text] [PDF]
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