ANTIOXIDANTS & REDOX SIGNALING Volume 00, Number 00, 2014 ª Mary Ann Liebert, Inc. DOI: 10.1089/ars.2014.6155
LETTER
TO THE
EDITOR
The Clinical Importance of Assessing Tumor Hypoxia: Relationship of Tumor Hypoxia to Prognosis and Therapeutic Opportunities Peter Vaupel and Arnulf Mayer
which are surrounded by blood vessels, a typical constellation corresponding to the Hill-type model. According to Section II.A, ‘‘recurring tumors often exhibit a higher hypoxic fraction than primary tumors.’’ In fact, our group was the first to systematically measure and compare the oxygenation status of primary and recurrent tumors and, importantly, carried out these measurements in the same patients (2). This strategy enabled us to substantially support our hypothesis that hypoxia drives tumor progression and resistance to therapy since we unequivocally found a higher probability of more severely hypoxic primary cervix cancers to recur locally compared to less hypoxic tumors. In Section II.B.4, the authors depict an inadequate ‘‘blood supply that further worsens local hypoxia, ensuring a vicious cycle.’’ Regarding the idea of a vicious cycle in hypoxiaassociated pathophysiology, introduced into the oncologic field by our group in 2004, the readership may benefit from additional information regarding this complex concept given in the original articles (13, 19). In these sources, the role of the chaotic neovascularization on the efficacy of tumor blood flow and on the development of a hostile tumor microenvironment has been extensively discussed. In Section III, the authors delineate that the direct methods for detecting tissue hypoxia are ‘‘providing oxygen concentration data.’’ This only holds true when using bare electrodes, which are not suitable for in vivo measurements in tissues due to protein deposits on the cathode. The statement is not correct, however, considering membrane-covered oxygen electrodes. It is the latter type of microelectrodes that has been used in tumors in situ exclusively (according to a protocol which has been implemented in the clinical and preclinical settings using standard procedures under well-defined boundary conditions by our institution). These membrane-covered microelectrodes rather measure oxygen partial pressures (pO2 values, oxygen tensions). A conversion of pO2 values measured in tissues to oxygen concentrations using Henry’s law (pO2 = aO2 · cO2, where pO2 = oxygen partial pressure, cO2 = oxygen concentration, aO2 = Bunsen’s solubility coefficient) is not possible since Bunsen’s solubility coefficient is not known for living tissues.
To the Editor: e have read the comprehensive invited review of J.C. Walsh et al. in this Journal with great interest (20). The authors describe the clinical importance of assessing tumor hypoxia and its relationship to prognosis and therapeutic opportunities. We believe that this information is of utmost interest to experimental and clinical oncologists since tumor hypoxia is a hallmark feature of most locally advanced patient tumors, which promotes tumor progression and adversely impacts on the efficacy of different anticancer therapies (13, 14, 16, 17). Pretherapeutic hypoxia has been identified as a strong and independent adverse prognostic factor for patient outcome [e.g., hypoxic cancers of the uterine cervix, soft tissue sarcomas, and head and neck cancers (15)]. Our institution has contributed key information to the field of tumor hypoxia and its consequences in the clinical setting, which are partly referenced in the article of Dr. Walsh et al. However, we feel that this review may benefit from some additional information that might be of interest for the distinguished readership of this highly reputed journal. In Section II.A (Pathophysiology of Hypoxia), the authors state that tumor hypoxia can be the result of two general types of oxygen starvation: ‘‘Hypoxia can be perfusion limited (acute hypoxia).and can be diffusion limited (chronic hypoxia).’’ While this statement may serve as a working formulation for a first approach to the hypoxia problem, we would like to direct the readers’ attention to two recent articles, which address the scope of this topic in a more comprehensive manner (1, 18). As a case in point, there are at least two models of diffusion-limited oxygen supply, depending on the microvascular geometry (Krogh model vs. Hill model). Referring to the seminal work of Thomlinson and Gray (12) in Section II.A, the authors outline that ‘‘lung carcinoma rods were surrounded by a necrotic core caused by a tissue oxygen gradient,’’ which may easily be mistaken as an example of a Krogh-type diffusion situation. Conversely, the model described by Thomlinson and Gray (12) actually describes necrotic areas in the center of the tumor cell rods,
W
Department of Radiooncology and Radiotherapy, University Medical Center, Mainz, Germany.
1
2
In Section III.A.1, the authors discuss several descriptive parameters of the pO2 histogram. The use of hypoxic fractions, mean, and median pO2 values have been suggested by Thews and Vaupel (11) for the clinical setting based on practical features of the Eppendorf histography system and hypoxic cutoff values for cellular and tissue functions as published in a comprehensive review later (3). In this section, Dr. Walsh et al. correctly argue that ‘‘the construction of three-dimensional (3D) oxygen maps is difficult.’’ Despite the fact that 3D oxygen tension maps have been published by Thews et al. (10) utilizing systematic pO2 measurements within numerous electrode tracks and tissue planes, this approach is indeed unlikely to leave the field of experimental tumors in the near future. In Section III.B.1–3, the authors acknowledge the fact that negative studies regarding the role of CA IX as a hypoxia marker exist (owing to its lack of correlation with both invasive pO2 measurements and pimonidazole staining). However, the overall message these paragraphs convey seems to be that HIF-1a, CA IX, and GLUT-1 are established endogenous markers of tumor hypoxia. Unfortunately, several studies from our (6, 8, 9) and other laboratories (4, 5) have proven that this expectation will not be met. Although the aforementioned proteins often show an association with the local tissue oxygenation status, this association is not of a quantitative type. Possible explanations for these findings have been summarized in a review (7). In Section III.C.8, Dr. Walsh et al. describe the use of noninvasive positron emission tomography (PET) imaging for hypoxia detection. In general, we agree with their statements. However, there is a pivotal problem when using these techniques due to the fact that very steep pO2 gradients exist (e.g., from 40 mmHg down to 0 mmHg within a distance in the order of 100 lm) causing hypoxic or even anoxic tumor microareas (‘‘hypoxic niches’’), which cannot be adequately sampled by current PET technologies because of spatial resolution limitations. Importantly, hypoxic microregions in tumors, not detectable in PET imaging, greatly contribute to tumor progression and acquired treatment resistance to anticancer therapies. We agree with the authors that the assessment of (at least) pretherapeutic oxygenation status of individual tumors in the clinical setting would be desirable (i) to assign patients with hypoxic tumors to individualized treatment protocols in the setting of clinical trials, (ii) to develop and validate hypoxia modification therapies, and (iii) to intensify the post-therapeutic follow-up of patients with hypoxic tumors on a regular basis. Finally, we congratulate Dr. Walsh et al. on an excellent and comprehensive review on the clinical importance of tumor hypoxia and unequivocally agree that the lack of hypoxia assessment in formerly conducted clinical trials ‘‘has made it difficult to extract the maximal benefit of hypoxia modification therapies for patients.’’ References
1. Bayer C, Shi K, Astner ST, Maftei CA, and Vaupel P. Acute versus chronic hypoxia: why a simplified classification is simply not enough. Int J Radiat Oncol Biol Phys 80: 965–968, 2011. 2. Ho¨ckel M, Schlenger K, Ho¨ckel S, Aral B, Scha¨ffer U, and Vaupel P. Tumor hypoxia in pelvic recurrences of cervical cancer. Int J Cancer 79: 365–369, 1998.
VAUPEL AND MAYER
3. Ho¨ckel M and Vaupel P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 93: 266–276, 2001. 4. Iakovlev VV, Pintilie M, Morrison A, Fyles AW, Hill RP, and Hedley DW. Effect of distributional heterogeneity on the analysis of tumor hypoxia based on carbonic anhydrase IX. Lab Invest 87: 1206–1217, 2007. 5. Janssen HL, Haustermans KM, Sprong D, Blommestijn G, Hofland I, Hoebers FJ, Blijweert E, Raleigh JA, Semenza GL, Varia MA, Balm AJ, van Velthuysen ML, Delaere P, Sciot R, and Begg AC. HIF-1a, pimonidazole, and iododeoxyuridine to estimate hypoxia and perfusion in human head-and-neck tumors. Int J Radiat Oncol Biol Phys 54: 1537–1549, 2002. 6. Mayer A, Ho¨ckel M, and Vaupel P. Carbonic anhydrase IX expression and tumor oxygenation status do not correlate at the microregional level in locally advanced cancers of the uterine cervix. Clin Cancer Res 11: 7220–7225, 2005. 7. Mayer A, Ho¨ckel M, and Vaupel P. Endogenous hypoxia markers in locally advanced cancers of the uterine cervix: reality or wishful thinking? Strahlenther Onkol 182: 501– 510, 2006. 8. Mayer A, Ho¨ckel M, Wree A, and Vaupel P. Microregional expression of glucose transporter-1 and oxygenation status: lack of correlation in locally advanced cervical cancers. Clin Cancer Res 11: 2768–2773, 2005. 9. Mayer A, Wree A, Ho¨ckel M, Leo C, Pilch H, and Vaupel P. Lack of correlation between expression of HIF-1a protein and oxygenation status in identical tissue areas of squamous cell carcinomas of the uterine cervix. Cancer Res 64: 5876–5881, 2004. 10. Thews O, Kelleher DK, and Vaupel PW. pO2-mapping of experimental rat tumors: visualization and statistical analysis. In: Tumor Oxygenation,edited by Vaupel PW, Kelleher DK, Gu¨nderoth M. Stuttgart, Jena, NY: Gustav Fischer Verlag, 1995, pp. 27–38. 11. Thews O and Vaupel P. Relevant parameters for describing the oxygenation status of solid tumors. Strahlenther Onkol 172: 239–243, 1996. 12. Thomlinson RH and Gray LH. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 9: 539–549, 1955. 13. Vaupel P. The role of hypoxia-induced factors in tumor progression. Oncologist 9 (Suppl 5): 10–17, 2004. 14. Vaupel P. Hypoxia and aggressive tumor phenotype: implications for therapy and prognosis. Oncologist 13 (Suppl 3): 21–26, 2008. 15. Vaupel P. Prognostic potential of the pre-therapeutic tumor oxygenation status. Adv Exp Med Biol 645: 241–246, 2009. 16. Vaupel P, Ho¨ckel M, and Mayer A. Detection and characterization of tumor hypoxia using pO2 histography. Antioxid Redox Signal 9: 1221–1235, 2007. 17. Vaupel P and Mayer A. Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 26: 225–239, 2007. 18. Vaupel P and Mayer A. Hypoxia in tumors: pathogenesisrelated classification, characterization of hypoxia subtypes, and associated biological and clinical implications. Adv Exp Med Biol 812: 19–24, 2014. 19. Vaupel P, Mayer A, and Ho¨ckel M. Tumor hypoxia and malignant progression. Methods Enzymol 381: 335–354, 2004. 20. Walsh JC, Lebedev A, Aten E, Madsen K, Marciano L, and Kolb HC. The clinical importance of assessing tumor hypoxia: relationship of tumor hypoxia to prognosis and therapeutic opportunities. Antioxid Redox Signal 21: 1516–1554, 2014.
TUMOR HYPOXIA
3
Address correspondence to: Dr. med. Peter Vaupel Department of Radiooncology and Radiotherapy University Medical Center Langenbeckstrasse 1 Mainz 55131 Germany E-mail: [email protected]
Date of first submission to ARS Central, October 6, 2014; date of final revised submission, October 23, 2014; date of acceptance, October 23, 2014. Abbreviations Used 3D ¼ three-dimensional PET ¼ positron emission tomography
Author Response Joseph C. Walsh
T
he Letter above helps to clarify key topics related to hypoxia characterization, detection, and assessment as described in a recent ARS article by Walsh et al. (20). Scientists must continue to refine the hypoxia paradigm as it relates to cancer initiation and progression, ultimately with an eye toward developing successful treatment strategies. I am thankful for the additional comments by Vaupel and Mayer as they help to further our understanding of tumor hypoxia and its complex role in oncology.
Address correspondence to: Dr. Joseph C. Walsh Siemens Molecular Imaging, Inc. 6140 Bristol Parkway Culver City, CA 90230 E-mail: [email protected] Date of first submission to ARS Central, October 6, 2014; date of final revised submission, October 23, 2014; date of acceptance, October 23, 2014.
LETTER
TO THE
EDITOR
The Clinical Importance of Assessing Tumor Hypoxia: Relationship of Tumor Hypoxia to Prognosis and Therapeutic Opportunities Peter Vaupel and Arnulf Mayer
which are surrounded by blood vessels, a typical constellation corresponding to the Hill-type model. According to Section II.A, ‘‘recurring tumors often exhibit a higher hypoxic fraction than primary tumors.’’ In fact, our group was the first to systematically measure and compare the oxygenation status of primary and recurrent tumors and, importantly, carried out these measurements in the same patients (2). This strategy enabled us to substantially support our hypothesis that hypoxia drives tumor progression and resistance to therapy since we unequivocally found a higher probability of more severely hypoxic primary cervix cancers to recur locally compared to less hypoxic tumors. In Section II.B.4, the authors depict an inadequate ‘‘blood supply that further worsens local hypoxia, ensuring a vicious cycle.’’ Regarding the idea of a vicious cycle in hypoxiaassociated pathophysiology, introduced into the oncologic field by our group in 2004, the readership may benefit from additional information regarding this complex concept given in the original articles (13, 19). In these sources, the role of the chaotic neovascularization on the efficacy of tumor blood flow and on the development of a hostile tumor microenvironment has been extensively discussed. In Section III, the authors delineate that the direct methods for detecting tissue hypoxia are ‘‘providing oxygen concentration data.’’ This only holds true when using bare electrodes, which are not suitable for in vivo measurements in tissues due to protein deposits on the cathode. The statement is not correct, however, considering membrane-covered oxygen electrodes. It is the latter type of microelectrodes that has been used in tumors in situ exclusively (according to a protocol which has been implemented in the clinical and preclinical settings using standard procedures under well-defined boundary conditions by our institution). These membrane-covered microelectrodes rather measure oxygen partial pressures (pO2 values, oxygen tensions). A conversion of pO2 values measured in tissues to oxygen concentrations using Henry’s law (pO2 = aO2 · cO2, where pO2 = oxygen partial pressure, cO2 = oxygen concentration, aO2 = Bunsen’s solubility coefficient) is not possible since Bunsen’s solubility coefficient is not known for living tissues.
To the Editor: e have read the comprehensive invited review of J.C. Walsh et al. in this Journal with great interest (20). The authors describe the clinical importance of assessing tumor hypoxia and its relationship to prognosis and therapeutic opportunities. We believe that this information is of utmost interest to experimental and clinical oncologists since tumor hypoxia is a hallmark feature of most locally advanced patient tumors, which promotes tumor progression and adversely impacts on the efficacy of different anticancer therapies (13, 14, 16, 17). Pretherapeutic hypoxia has been identified as a strong and independent adverse prognostic factor for patient outcome [e.g., hypoxic cancers of the uterine cervix, soft tissue sarcomas, and head and neck cancers (15)]. Our institution has contributed key information to the field of tumor hypoxia and its consequences in the clinical setting, which are partly referenced in the article of Dr. Walsh et al. However, we feel that this review may benefit from some additional information that might be of interest for the distinguished readership of this highly reputed journal. In Section II.A (Pathophysiology of Hypoxia), the authors state that tumor hypoxia can be the result of two general types of oxygen starvation: ‘‘Hypoxia can be perfusion limited (acute hypoxia).and can be diffusion limited (chronic hypoxia).’’ While this statement may serve as a working formulation for a first approach to the hypoxia problem, we would like to direct the readers’ attention to two recent articles, which address the scope of this topic in a more comprehensive manner (1, 18). As a case in point, there are at least two models of diffusion-limited oxygen supply, depending on the microvascular geometry (Krogh model vs. Hill model). Referring to the seminal work of Thomlinson and Gray (12) in Section II.A, the authors outline that ‘‘lung carcinoma rods were surrounded by a necrotic core caused by a tissue oxygen gradient,’’ which may easily be mistaken as an example of a Krogh-type diffusion situation. Conversely, the model described by Thomlinson and Gray (12) actually describes necrotic areas in the center of the tumor cell rods,
W
Department of Radiooncology and Radiotherapy, University Medical Center, Mainz, Germany.
1
2
In Section III.A.1, the authors discuss several descriptive parameters of the pO2 histogram. The use of hypoxic fractions, mean, and median pO2 values have been suggested by Thews and Vaupel (11) for the clinical setting based on practical features of the Eppendorf histography system and hypoxic cutoff values for cellular and tissue functions as published in a comprehensive review later (3). In this section, Dr. Walsh et al. correctly argue that ‘‘the construction of three-dimensional (3D) oxygen maps is difficult.’’ Despite the fact that 3D oxygen tension maps have been published by Thews et al. (10) utilizing systematic pO2 measurements within numerous electrode tracks and tissue planes, this approach is indeed unlikely to leave the field of experimental tumors in the near future. In Section III.B.1–3, the authors acknowledge the fact that negative studies regarding the role of CA IX as a hypoxia marker exist (owing to its lack of correlation with both invasive pO2 measurements and pimonidazole staining). However, the overall message these paragraphs convey seems to be that HIF-1a, CA IX, and GLUT-1 are established endogenous markers of tumor hypoxia. Unfortunately, several studies from our (6, 8, 9) and other laboratories (4, 5) have proven that this expectation will not be met. Although the aforementioned proteins often show an association with the local tissue oxygenation status, this association is not of a quantitative type. Possible explanations for these findings have been summarized in a review (7). In Section III.C.8, Dr. Walsh et al. describe the use of noninvasive positron emission tomography (PET) imaging for hypoxia detection. In general, we agree with their statements. However, there is a pivotal problem when using these techniques due to the fact that very steep pO2 gradients exist (e.g., from 40 mmHg down to 0 mmHg within a distance in the order of 100 lm) causing hypoxic or even anoxic tumor microareas (‘‘hypoxic niches’’), which cannot be adequately sampled by current PET technologies because of spatial resolution limitations. Importantly, hypoxic microregions in tumors, not detectable in PET imaging, greatly contribute to tumor progression and acquired treatment resistance to anticancer therapies. We agree with the authors that the assessment of (at least) pretherapeutic oxygenation status of individual tumors in the clinical setting would be desirable (i) to assign patients with hypoxic tumors to individualized treatment protocols in the setting of clinical trials, (ii) to develop and validate hypoxia modification therapies, and (iii) to intensify the post-therapeutic follow-up of patients with hypoxic tumors on a regular basis. Finally, we congratulate Dr. Walsh et al. on an excellent and comprehensive review on the clinical importance of tumor hypoxia and unequivocally agree that the lack of hypoxia assessment in formerly conducted clinical trials ‘‘has made it difficult to extract the maximal benefit of hypoxia modification therapies for patients.’’ References
1. Bayer C, Shi K, Astner ST, Maftei CA, and Vaupel P. Acute versus chronic hypoxia: why a simplified classification is simply not enough. Int J Radiat Oncol Biol Phys 80: 965–968, 2011. 2. Ho¨ckel M, Schlenger K, Ho¨ckel S, Aral B, Scha¨ffer U, and Vaupel P. Tumor hypoxia in pelvic recurrences of cervical cancer. Int J Cancer 79: 365–369, 1998.
VAUPEL AND MAYER
3. Ho¨ckel M and Vaupel P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 93: 266–276, 2001. 4. Iakovlev VV, Pintilie M, Morrison A, Fyles AW, Hill RP, and Hedley DW. Effect of distributional heterogeneity on the analysis of tumor hypoxia based on carbonic anhydrase IX. Lab Invest 87: 1206–1217, 2007. 5. Janssen HL, Haustermans KM, Sprong D, Blommestijn G, Hofland I, Hoebers FJ, Blijweert E, Raleigh JA, Semenza GL, Varia MA, Balm AJ, van Velthuysen ML, Delaere P, Sciot R, and Begg AC. HIF-1a, pimonidazole, and iododeoxyuridine to estimate hypoxia and perfusion in human head-and-neck tumors. Int J Radiat Oncol Biol Phys 54: 1537–1549, 2002. 6. Mayer A, Ho¨ckel M, and Vaupel P. Carbonic anhydrase IX expression and tumor oxygenation status do not correlate at the microregional level in locally advanced cancers of the uterine cervix. Clin Cancer Res 11: 7220–7225, 2005. 7. Mayer A, Ho¨ckel M, and Vaupel P. Endogenous hypoxia markers in locally advanced cancers of the uterine cervix: reality or wishful thinking? Strahlenther Onkol 182: 501– 510, 2006. 8. Mayer A, Ho¨ckel M, Wree A, and Vaupel P. Microregional expression of glucose transporter-1 and oxygenation status: lack of correlation in locally advanced cervical cancers. Clin Cancer Res 11: 2768–2773, 2005. 9. Mayer A, Wree A, Ho¨ckel M, Leo C, Pilch H, and Vaupel P. Lack of correlation between expression of HIF-1a protein and oxygenation status in identical tissue areas of squamous cell carcinomas of the uterine cervix. Cancer Res 64: 5876–5881, 2004. 10. Thews O, Kelleher DK, and Vaupel PW. pO2-mapping of experimental rat tumors: visualization and statistical analysis. In: Tumor Oxygenation,edited by Vaupel PW, Kelleher DK, Gu¨nderoth M. Stuttgart, Jena, NY: Gustav Fischer Verlag, 1995, pp. 27–38. 11. Thews O and Vaupel P. Relevant parameters for describing the oxygenation status of solid tumors. Strahlenther Onkol 172: 239–243, 1996. 12. Thomlinson RH and Gray LH. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 9: 539–549, 1955. 13. Vaupel P. The role of hypoxia-induced factors in tumor progression. Oncologist 9 (Suppl 5): 10–17, 2004. 14. Vaupel P. Hypoxia and aggressive tumor phenotype: implications for therapy and prognosis. Oncologist 13 (Suppl 3): 21–26, 2008. 15. Vaupel P. Prognostic potential of the pre-therapeutic tumor oxygenation status. Adv Exp Med Biol 645: 241–246, 2009. 16. Vaupel P, Ho¨ckel M, and Mayer A. Detection and characterization of tumor hypoxia using pO2 histography. Antioxid Redox Signal 9: 1221–1235, 2007. 17. Vaupel P and Mayer A. Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 26: 225–239, 2007. 18. Vaupel P and Mayer A. Hypoxia in tumors: pathogenesisrelated classification, characterization of hypoxia subtypes, and associated biological and clinical implications. Adv Exp Med Biol 812: 19–24, 2014. 19. Vaupel P, Mayer A, and Ho¨ckel M. Tumor hypoxia and malignant progression. Methods Enzymol 381: 335–354, 2004. 20. Walsh JC, Lebedev A, Aten E, Madsen K, Marciano L, and Kolb HC. The clinical importance of assessing tumor hypoxia: relationship of tumor hypoxia to prognosis and therapeutic opportunities. Antioxid Redox Signal 21: 1516–1554, 2014.
TUMOR HYPOXIA
3
Address correspondence to: Dr. med. Peter Vaupel Department of Radiooncology and Radiotherapy University Medical Center Langenbeckstrasse 1 Mainz 55131 Germany E-mail: [email protected]
Date of first submission to ARS Central, October 6, 2014; date of final revised submission, October 23, 2014; date of acceptance, October 23, 2014. Abbreviations Used 3D ¼ three-dimensional PET ¼ positron emission tomography
Author Response Joseph C. Walsh
T
he Letter above helps to clarify key topics related to hypoxia characterization, detection, and assessment as described in a recent ARS article by Walsh et al. (20). Scientists must continue to refine the hypoxia paradigm as it relates to cancer initiation and progression, ultimately with an eye toward developing successful treatment strategies. I am thankful for the additional comments by Vaupel and Mayer as they help to further our understanding of tumor hypoxia and its complex role in oncology.
Address correspondence to: Dr. Joseph C. Walsh Siemens Molecular Imaging, Inc. 6140 Bristol Parkway Culver City, CA 90230 E-mail: [email protected] Date of first submission to ARS Central, October 6, 2014; date of final revised submission, October 23, 2014; date of acceptance, October 23, 2014.
