Pimonidazole binding and oxygen regulated protein expression
The current state of affairs with respect to correlations between pimonidazole binding and the expression of endogenous, hypoxia inducible proteins is summarized in the table. Areas of spatial co-localization are often seen but overall correlations, while in some cases statistically significant, are generally weak for squamous cell carcinomas. The strongest correlations occur in carcinomas derived from simple epithelia (e.g., bladder and breast) indicating, perhaps, that a difference in biology exists between these tumors and squamous cell carcinomas.
Pimonidazole binding and endogenous “hypoxia marker” protein expression.
Endogenous Marker Correlation with pimonidazole Cancer Site Ref.
Carbonic anhydrase IX No correlation Liver mets; colorectal Ca (3)
No correlation Cervix SCC (4)
No correlation Colon AdenoCa (5)
0.27 (p<0.001) Cervix SCC (6)
0.36 (p=0.02) H&N SCC (7)
0.6 Cervix SCC (8)
0.74 (p<0.0001) Bladder Ca (9)
0.75 Cervix SCC (10)
EGFR No correlation Colon AdenoCa (5)
EPO 0.6 Breast Ca (11, 12)
0.74 (p=0.001) H&N SCC (13)
EPOR No correlation H&N SCC (13, 14)
0.63 (p=0.0001) Breast Ca (12)
Glut-1 No correlation Liver mets; colorectal Ca (3)
0.45 (p=0.003) Cervix SCC (4)
0.82 (p=0.0001) Bladder Ca (9, 15)
HIF-1a 0.24 (p=0.51) H&N SCC (16, 17)
0.34 (p=0.04) Cervix SCC (6)
Involucrin No correlation Cervix and H&N SCC (18-20)
Metallothionein No correlation Cervix and H&N SCC (18)
Thymidine phosphorylase No correlation Cervix SCC (21)
VEGF No correlation Cervix and H&N SCC (1, 22)
No correlation Colon AdenoCa (5)
Publications in which pimonidazole binding and ORP expression is studied.
1. Raleigh, J. A., Calkins-Adams, D. P., Rinker, L. H., Ballenger, C. A., Weissler, M. C., Fowler, W. C., Jr., Novotny, D. B., and Varia, M. A. Hypoxia and vascular endothelial growth factor expression in human squamous cell carcinomas using pimonidazole as a hypoxia marker. Cancer Res, 58: 3765-3768, 1998.
2. Wykoff, C. C., Beasley, N. J., Watson, P. H., Turner, K. J., Pastorek, J., Sibtain, A., Wilson, G. D., Turley, H., Talks, K. L., Maxwell, P. H., Pugh, C. W., Ratcliffe, P. J., and Harris, A. L. Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res, 60: 7075-7083, 2000.
3. Raleigh, J. A., Chou, S. C., Calkins-Adams, D. P., Ballenger, C. A., Novotny, D. B., and Varia, M. A. A clinical study of hypoxia and metallothionein protein expression in squamous cell carcinomas. Clin Cancer Res, 6: 855-862, 2000.
4. Olive, P. L., Aquino-Parsons, C., MacPhail, S. H., Liao, S. Y., Raleigh, J. A., Lerman, M. I., and Stanbridge, E. J. Carbonic anhydrase 9 as an endogenous marker for hypoxic cells in cervical cancer. Cancer Res, 61: 8924-8929, 2001.
5. Arcasoy, M. O., Amin, K., Karayal, A. F., Chou, S. C., Raleigh, J. A., Varia, M. A., and Haroon, Z. A. Functional significance of erythropoietin receptor expression in breast cancer. Lab Invest, 82: 911-918, 2002.
6. Janssen, H. L., Haustermans, K. M., Sprong, D., Blommestijn, G., Hofland, I., Hoebers, F. J., Blijweert, E., Raleigh, J. A., Semenza, G. L., Varia, M. A., Balm, A. J., van Velthuysen, M. L., Delaere, P., Sciot, R., and Begg, A. C. HIF-1alpha, pimonidazole, and iododeoxyuridine to estimate hypoxia and perfusion in human head-and-neck tumors. Int J Radiat Oncol Biol Phys, 54: 1537-1549, 2002.
7. Kaanders, J. H., Wijffels, K. I., Marres, H. A., Ljungkvist, A. S., Pop, L. A., van den Hoogen, F. J., de Wilde, P. C., Bussink, J., Raleigh, J. A., and van der Kogel, A. J. Pimonidazole binding and tumor vascularity predict for treatment outcome in head and neck cancer. Cancer Res., 62: 7066-7074, 2002.
8. Airley, R. E., Loncaster, J., Raleigh, J. A., Harris, A. L., Davidson, S. E., Hunter, R. D., West, C. M., and Stratford, I. J. GLUT-1 and CAIX as intrinsic markers of hypoxia in carcinoma of the cervix: Relationship
to pimonidazole binding. Int. J. Cancer, 104: 85-91, 2003.
9. Azuma, Y., Chou, S. C., Lininger, R. A., Murphy, B. J., Varia, M. A., and Raleigh, J. A. Hypoxia and differentiation in squamous cell carcinomas of the uterine cervix: pimonidazole and involucrin. Clin Cancer Res, 9: 4944-4452, 2003.
10. Begg, A. C. Is HIF-1alpha a good marker for tumor hypoxia? Int. J. Radiat. Oncol. Biol. Phys., 56: 917-919, 2003.
11. Hoskin, P. J., Sibtain, A., Daley, F. M., and Wilson, G. D. GLUT1 and CAIX as intrinsic markers of hypoxia in bladder cancer: relationship with vascularity and proliferation as predictors of outcome of ARCON. Br J Cancer, 89: 1290-1297, 2003.
12. Chou, S. C., Azuma, Y., Varia, M. A., and Raleigh, J. A. Evidence that involucrin, a marker for differentiation, is oxygen regulated in human squamous cell carcinomas. Br. J. Cancer, 90: 728-735, 2004.
13. Hutchison, G. J., Valentine, H. R., Loncaster, J. A., Davidson, S. E., Hunter, R. D., Roberts, S. A., Harris, A. L., Stratford, I. J., Price, P. M., and West, C. M. Hypoxia-inducible factor 1alpha expression as an intrinsic marker of hypoxia: correlation with tumor oxygen, pimonidazole measurements, and outcome in locally advanced carcinoma of the cervix. Clin Cancer Res, 10: 8405-8412, 2004.
14. Arcasoy, M. O., Amin, K., Chou, S. C., Haroon, Z. A., Varia, M., and Raleigh, J. A. Erythropoietin and erythropoietin receptor expression in head and neck cancer: relationship to tumor hypoxia. Clin Cancer Res, 11: 20-27, 2005.
15. Hoogsteen, I. J., Peeters, W. J., Marres, H. A., Rijken, P. F., van den Hoogen, F. J., van der Kogel, A. J., and Kaanders, J. H. Erythropoietin receptor is not a surrogate marker for tumor hypoxia and does not correlate with survival in head and neck squamous cell carcinomas. Radiother Oncol, 76: 213-218, 2005.
16. Carnell, D. M., Smith, R. E., Daley, F. M., Saunders, M. I., Bentzen, S. M., and Hoskin, P. J. An immunohistochemical assessment of hypoxia in prostate carcinoma using pimonidazole: Implications for radioresistance. Int J Radiat Oncol Biol Phys, 65: 91-99, 2006.
17. Goethals, L., Debucquoy, A., Perneel, C., Geboes, K., Ectors, N., De Schutter, H., Penninckx, F., McBride, W. H., Begg, A. C., and Haustermans, K. M. Hypoxia in human colorectal adenocarcinoma: Comparison between extrinsic and potential intrinsic hypoxia markers. Int J Radiat Oncol Biol Phys, 65: 246-254, 2006.
18. Jankovic, B., Aquino-Parsons, C., Raleigh, J. A., Stanbridge, E. J., Durand, R. E., Banath, J. P., MacPhail, S. H., and Olive, P. L. Comparison between pimonidazole binding, oxygen electrode measurements, and expression of endogenous hypoxia markers in cancer of the uterine cervix. Cytometry B Clin Cytom, 70: 45-55, 2006.
19. Kabuubi, P., Loncaster, J. A., Davidson, S. E., Hunter, R. D., Kobylecki, C., Stratford, I. J., and West, C. M. No relationship between thymidine phosphorylase (TP, PD-ECGF) expression and hypoxia in carcinoma of the cervix. Br J Cancer, 94: 115-120, 2006.
20. Rosenberger C, Rosen S, Shina A, et al. Hypoxia-inducible factors and tubular cell survival in isolated perfused kidneys. Kidney Int 2006; 70: 60-70.
21. Tanaka T, Kato H, Kojima I, et al. Hypoxia and expression of hypoxia-inducible factor in the aging kidney. J Gerontol A Biol Sci Med Sci 2006; 61: 795-805.
22. Tanaka H, Yamamoto M, Hashimoto N, et al. Hypoxia-independent overexpression of hypoxia-inducible factor 1alpha as an early change in mouse hepatocarcinogenesis. Cancer Res 2006; 66: 11263-70.
23. van Laarhoven, H. W., Kaanders, J. H., Lok, J., Peeters, W. J., Rijken, P. F., Wiering, B., Ruers, T. J., Punt, C. J., Heerschap, A., and van der Kogel, A. J. Hypoxia in relation to vasculature and proliferation in liver metastases in patients with colorectal cancer. Int J Radiat Oncol Biol Phys, 64: 473-482, 2006.
24. Amarilio R, Viukov SV, Sharir A, Eshkar-Oren I, Johnson RS, Zelzer E. HIF1alpha regulation of Sox9 is necessary to maintain differentiation of hypoxic prechondrogenic cells during early skeletogenesis. Development 2007; 134: 3917-28.
25. Burgu B, Medina Ortiz WE, Pitera JE, Woolf AS, Wilcox DT. Vascular endothelial growth factor mediates hypoxic stimulated embryonic bladder growth in organ culture. J Urol 2007; 177: 1552-7.
26. Echevarria M, Munoz-Cabello AM, Sanchez-Silva R, Toledo-Aral JJ, Lopez-Barneo J. Development of cytosolic hypoxia and hypoxia-inducible factor stabilization are facilitated by aquaporin-1 expression. J Biol Chem 2007; 282: 30207-15.
27. Hoogsteen IJ, Marres HA, Bussink J, van der Kogel AJ, Kaanders JH. Tumor microenvironment in head and neck squamous cell carcinomas: predictive value and clinical relevance of hypoxic markers. A review. Head Neck 2007; 29: 591-604.
28. Hoogsteen IJ, Marres HA, van der Kogel AJ, Kaanders JH. The hypoxic tumour microenvironment, patient selection and hypoxia-modifying treatments. Clin Oncol (R Coll Radiol) 2007; 19: 385-96.
29. Kim YJ, Kang HH, Ahn JH, Chung JW. Hypoxic changes in the central nervous system of noise-exposed mice. Acta Otolaryngol Suppl 2007: 73-7.
30. Le QT. Identifying and targeting hypoxia in head and neck cancer: a brief overview of current approaches. Int J Radiat Oncol Biol Phys 2007; 69: S56-8.
31. Pringle KG, Kind KL, Thompson JG, Roberts CT. Complex interactions between hypoxia inducible factors, insulin-like growth factor-II and oxygen in early murine trophoblasts. Placenta 2007; 28: 1147-57.
32. Shin KH, Diaz-Gonzalez JA, Russell J, et al. Detecting changes in tumor hypoxia with carbonic anhydrase IX and pimonidazole. Cancer Biol Ther 2007; 6: 70-5.
33. Busk M, Horsman MR, Kristjansen PE, van der Kogel AJ, Bussink J, Overgaard J. Aerobic glycolysis in cancers: implications for the usability of oxygen-responsive genes and fluorodeoxyglucose-PET as markers of tissue hypoxia. Int J Cancer 2008; 122: 2726-34.
34. Bussink J, van der Kogel AJ, Kaanders JH. Patterns and levels of hypoxia in head and neck squamous cell carcinomas and their relationship to patient outcome: in regard to Evans et al. (Int J Radiat Oncol Biol Phys 2007;69:1024-1031). Int J Radiat Oncol Biol Phys 2008; 70: 1616.
35. Fujita N, Imai J, Suzuki T, et al. Vascular endothelial growth factor-A is a survival factor for nucleus pulposus cells in the intervertebral disc. Biochem Biophys Res Commun 2008; 372: 367-72.
36. Genin O, Hasdai A, Shinder D, Pines M. Hypoxia, hypoxia-inducible factor-1alpha (HIF-1alpha), and heat-shock proteins in tibial dyschondroplasia. Poult Sci 2008; 87: 1556-64.
37. Wijffels KI, Marres HA, Peters JP, Rijken PF, van der Kogel AJ, Kaanders JH. Tumour cell proliferation under hypoxic conditions in human head and neck squamous cell carcinomas. Oral Oncol 2008; 44: 335-44.
38. Yeom CJ, Chung JK, Kang JH, et al. Visualization of Hypoxia-Inducible Factor-1 Transcriptional Activation in C6 Glioma Using Luciferase and Sodium Iodide Symporter Genes. J Nucl Med 2008.
39. Ahlskog JK, Schliemann C, Marlind J, et al. Human monoclonal antibodies targeting carbonic anhydrase IX for the molecular imaging of hypoxic regions in solid tumours. Br J Cancer 2009; 101: 645-57.
40. Hoogsteen IJ, Lok J, Marres HA, et al. Hypoxia in larynx carcinomas assessed by pimonidazole binding and the value of CA-IX and vascularity as surrogate markers of hypoxia. Eur J Cancer 2009; 45: 2906-14.
41. Kim HK, Bian H, Aya-ay J, Garces A, Morgan EF, Gilbert SR. Hypoxia and HIF-1alpha expression in the epiphyseal cartilage following ischemic injury to the immature femoral head. Bone 2009; 45: 280-8.
42. Kizaka-Kondoh S, Konse-Nagasawa H. Significance of nitroimidazole compounds and hypoxia-inducible factor-1 for imaging tumor hypoxia. Cancer Sci 2009; 100: 1366-73.
43. Kudo T, Ueda M, Kuge Y, et al. Imaging of HIF-1-active tumor hypoxia using a protein effectively delivered to and specifically stabilized in HIF-1-active tumor cells. J Nucl Med 2009; 50: 942-9.
44. Araujo AP, Frezza TF, Allegretti SM, Giorgio S. Hypoxia, hypoxia-inducible factor-1alpha and vascular endothelial growth factor in a murine model of Schistosoma mansoni infection. Exp Mol Pathol 2010; 89: 327-33.
45. Mowat FM, Luhmann UF, Smith AJ, et al. HIF-1alpha and HIF-2alpha are differentially activated in distinct cell populations in retinal ischaemia. PLoS One 2010; 5: e11103.
46. Wright WS, McElhatten RM, Messina JE, Harris NR. Hypoxia and the expression of HIF-1alpha and HIF-2alpha in the retina of streptozotocin-injected mice and rats. Exp Eye Res 2010; 90: 405-12.
47. Young RJ, Moller A. Immunohistochemical detection of tumour hypoxia. Methods Mol Biol 2010; 611: 151-9.
48. Gillies RM, Robinson SP, McPhail LD, Carter ND, Murray JF. Immunohistochemical assessment of intrinsic and extrinsic markers of hypoxia in reproductive tissue: differential expression of HIF1alpha and HIF2alpha in rat oviduct and endometrium. J Mol Histol 2011; 42: 341-54.
49. Mees G, Vangestel C, Dierckx R, et al. Metabolic correlates of tumour hypoxia in malignant canine mammary carcinoma. Res Vet Sci 2011.
50. Rademakers SE, Lok J, van der Kogel AJ, Bussink J, Kaanders JH. Metabolic markers in relation to hypoxia; staining patterns and colocalization of pimonidazole, HIF-1alpha, CAIX, LDH-5, GLUT-1, MCT1 and MCT4. BMC Cancer 2011; 11: 167.
51. Baker LC, Boult JK, Walker-Samuel S, et al. The HIF-pathway inhibitor NSC-134754 induces metabolic changes and anti-tumour activity while maintaining vascular function. Br J Cancer 2012; 106: 1638-47.
52. Toustrup K, Sorensen BS, Alsner J, Overgaard J. Hypoxia Gene Expression Signatures as Prognostic and Predictive Markers in Head and Neck Radiotherapy. Semin Radiat Oncol 2012; 22: 119-27.
53. Verstraete M, Debucquoy A, Devos E, et al. Investigation of possible endogenous hypoxia markers in colorectal cancer. Int J Radiat Biol 2012.