Abstract
In clinical trials, tumor hypoxia has consistently been associated with tumor aggressiveness. The evidence for an association between hypoxia and metastasis and more rapid tumor progression and death is seen in uterine cervical cancer, and sarcoma of soft tissue. Evidence is building in prostate, vulva, head and neck, and breast cancers. A major question is whether hypoxia precedes tumor aggressiveness or whether aggressive tumors incidentally are also hypoxic.
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References
M. Höckel, C. Knoop, B. Vorndran, E. Baussmann, M. Mitze, P. G. Knapstein, P. Vaupel, Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix, Radiother. Oncol. 26 45–50 (1993).
P. Vaupel, D. K. Kelleher, and M. Höckel, Oxygen status of malignant tumors: pathogenesis of hypoxia and significance for tumor therapy, Sem. Oncol. 28(2S8), 29–35 (2001).
D. M. Brizel, S.P. Scully, J.M. Harrelson, L. J. Layfield, J. M. Bean, L. R. Prosnitz, M. W. Dewhirst, Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma, Cancer Res. 56, 941–943 (1996).
B. Movsas, J. D. Chapman, R. E. Greenberg, A. L. Hanlon, E. M. Horwitz, W. H. Pinover, C. Stobbe, and G. E. Hanks, Increasing levels of hypoxia in prostate carcinoma correlate significantly with increasing clinical stage and patient age: an Eppendorf pO(2), Cancer. 89 2018–2024 (2000).
D. M. Brizel, G. S. Sibley, L. R. Prosnitz, R. L. Scher, M. W. Dewhirst, Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck, Int. J. Radial. Oncol. Biot Phys. 38 285–289 (1997).
P. Okunieff, J. de Bie, E. P. Dunphy, D. J. Terris, M. Höckel, Oxygen distributions partly explain the radiation response of human squamous cell carcinomas, Br. J. Cancer 74, S185–5190 (1996).
P. Okunieff, E. P. Dunphy, M. Höckel, D. J. Terris, P. Vaupel, The role of oxygen tension distribution on the radiation response of human breast carcinoma, Adv. Exp. Med. Biol. 345 485–492 (1994).
P. Okunieff, M. Höckel, E. P. Dunphy, K. Schienger, C. Knoop, P. Vaupel, Oxygen tension distributors are sufficient to explain the local response of human breast tumors treated with radiation alone, Int. J. Radial. Oncol. Biol. Phys. 26, 631–636 (1993).
J. W. Arends, Molecular interactions in the Vogelstein model of colorectal carcinoma, J. Pachol. 190 412416 (2000).
N. M. Mazure, E. Y. Chen, P. Yeh, Oncogenic transformation and hypoxia synergistically act to modulate vascular endothelial growth factor expression, Cancer Res. 56, 3436–3440 (1996).
A. J. Giacca, Hypoxic stress proteins: survival of the fittest, Semin. Radial. Oncol. 6, 46–58 (1996).
T. G. Graeber, C. Osmanian, T. Jacks, D. E. Housman, C. J. Koch, S. W. Lowe, A. J. Giaccia, Hypoxiamediated selection of cells with diminished apoptotic potential in solid tumours, Nature 379, 88–91 (1996).
R.H. Ackerman, R. Subramanyam, 1. A. Correia, N. M. Alpert, J. M. Taveras, Positron imaging of cerebral blood flow during continuous inhalation of C15O2, Stroke 11, 45–49 (1980).
E. Berra, J. Milanini, and D. E. Richard, Signaling angiogenesis via p42/p44 MAP kinase and hypoxia, Biochem. Pharmacol. 60, 1171–1178 (2000).
E. Berra, G. Pages, and J. Pouyssegur, MAP kinases and hypoxia in the control of VEGF expression, Cancer Metastasis Rev. 19 139–145 (2000).
F. G. Kern, S. W. McLeskey, L. Zhang, J. Kurebayashi, Y. Liu, I. Ding, S. Kharbanda, D. Chen, D. Miller, K. Cullen, S. Paik, R. B. Dickson, Transfected MCF-7 cells as a model for breast cancer progression, Breast Cancer Res. Treat. 31 153–165 (1994).
M. Nguyen, H. Watanabe, A. E. Budson, J. P. Richie, J. Folkman, Elevated levels of the angiogenic peptide basic fibroblast growth factor in urine of bladder cancer patients, J. Natl. Cancer Inst. 85 241–242 (1993).
J. Folkman, Angiogenesis and breast cancer, J. Clin. Oncol. 12 441–444 (1994).
P. Okunieff, M. Mester, 1. Wang, T. Maddox, X. Gong, D. Tang, M. Coffee, I. Ding, In vivo radioprotective effects of angiogenic factors on the small bowel of C3H mice, Radial. Res. 150 204–211 (1998).
C. Koumenis, R. Alarcon, E. Hammond, P. Sutphin, W. Hoffman, M. Murphy, J. Derr, Y. Tava, S. W. Lowe, M. Kastan, and A. Giacca, Regulation of p53 by hypoxia: Dissociation of transcriptional repression and apoptosis from p53-dependent transactivation, Mol. Cell. Biol. 21 1297–1310 (2001).
L. Hlatky, P. Hahnfeldt, C. Tsionou, and C. N. Coleman, Vascular endothelial growth factor: environmental controls and effects in angiogenesis, Br. J. Cancer. 27 S151–156 (1996).
L. Hlatky, C. Tsionou, P. Hahnfeldt, and C. N. Coleman, Mammary fibroblasts may influence breast tumor angiogenesis via hypoxia-induced vascular endothelial growth factor up-regulation and protein expression, Cancer Res. 54(23), 6083–6086 (1994).
A. C. Koong, E. Y. Chen, N. F. Mivechi, et al, Hypoxic activation of nuclear factor-kappa B is mediated by a Ras and Raf signaling pathway and does not involve MAP kinase (ERK1 or ERK2), Cancer Res. 54 5273–5279(1994).
Y. Seko, K. Tobe, N. Takahashi, et al, Hypoxia and hypoxia/reoxygenation activate Src family tyrosine kinases and p2lras in cultured rat cardiac myocytes, Biochem. Biophys. Res. Commun. 226, 530–535 (1996).
L. W. Lo, J. J. Cheng, and J. J. Chiu, Endothelial exposure to hypoxia induces Egr-I expression involving PKCalpha-mediated Ras/Raf-I/ERKI/2 pathway, J. Cell. Physio!. 188, 304–312 (2001).
C. J. Green, P. Lichtlen, and N. T. Huynh, Placenta growth factor gene expression is induced by hypoxia in fibroblasts: a central role for metal transcription factor-1, Cancer Res. 61, 2696–2703 (2001).
N. C. Denko, and A. J. Giacca, Tumor hypoxia, the physiological link between Trousseau’s syndrome (carcinoma-induced coagulopathy) and metastasis, Cancer Res. 61, 795–798 (2001).
K. S. Kim, K. Takeda, R. Sethi, et al, Protection from reoxygenation injury by inhibition of rac1, J. Clin. Invest. 101, 1821–1826 (1998).
J. Rak, J. L. Yu, and G. Klement, Oncogenes and angiogenesis: signaling three-dimensional tumor growth, J. Inveslig. Dermatol. Symp. Proc. 5, 24–33 (2000).
F. C. White, A. Benehacene, and J. S. Scheele, VEGF mRNA is stabilized by ras and tyrosine kinase oncogenes, as well as by UV radiation--evidence for divergent stabilization pathways, Growth Factors 14, 199–212 (1997).
S. W. Lowe, Activation of p53 by oncogenes, Endocr. Relat. Cancer 6, 45–48 (1999).
J. L. Arbiser, M. A. Moses, C. A. Fernandez, et al, Oncogenic H-ras stimulates tumor angiogenesis by two distinct pathways, Proc. Natl. Acad. Sci. USA 94, 861–866 (1997).
T. Konishi, C. L. Huang, M. Adachi, et al, The K-ras gene regulates vascular endothelial growth factor gene expression in non-small cell lung cancers, Int. J. Oncol. 16, 501–511 (2000).
F. Kallinowski, R. R. Friis, F. Van Roy, et al, Oxygenation of tumors derived from ras transformed cells, Adv. Exp. Med. Biol. 277, 907–916 (1990).
E. Cohen-Jonathan, S. M. Evans, C. J. Koch, et al, The farnesyltransferase inhibitor L744,832 reduces hypoxia in tumors expressing activated H-ras, Cancer Res. 61, 2289–2293 (2001).
B. Enholm, K. Paavonen, A. Ristimaki, et al, Comparison of VEGF, VEGF-B, VEGF-C and Ang-1 mRNA regulation by serum, growth factors, oncoproteins and hypoxia, Oncogene 14, 2475–2483 (1997).
A. Maity, N. Pore, J. Lee, et al, Epidermal growth factor receptor transcriptionally up-regulates vascular endothelial growth factor expression in human glioblastoma cells via a pathway involving phosphatidylinositol 3’-kinase and distinct from that induced by hypoxia, Cancer Res. 60, 5879–5886 (2000).
K. R. Laderoute, R. M. Alarcon, M. D. Brody, et al, Opposing effects of hypoxia on expression of the angiogenic inhibitor thrombospondin 1 and the angiogenic inducer vascular endothelial growth factor, Clin. Cancer Res. 6, 2941–2950 (2000).
C. Chen, N. Pore, A. Behrooz, et al, Regulation of glutl mRNA by hypoxia-inducible factor-1. Interaction between H-ras and hypoxia, J. Biot Chem. 276, 9519–9525 (2001).
D. R. Premkumar, G. Adhikary, J. L. Overholt, et al, Intracellular pathways linking hypoxia to activation of c-fos and AP-1, Adv. Exp. Med. Biol. 475, 101–109 (2000).
M. Höckel, K. Schlenger, C. Knoop; P. Vaupel, Oxygenation of carcinomas of the uterine cervix: evaluation by computerized 02 tension measurements. Cancer Res. 51:6098–102 (1991).
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Okunieff, P., Ding, I., Vaupel, P., Höckel, M. (2003). Evidence for and Against Hypoxia as the Primary Cause of Tumor Aggressiveness. In: Wilson, D.F., Evans, S.M., Biaglow, J., Pastuszko, A. (eds) Oxygen Transport To Tissue XXIII. Advances in Experimental Medicine and Biology, vol 510. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0205-0_12
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DOI: https://doi.org/10.1007/978-1-4615-0205-0_12
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