Skip to main content
Erschienen in: Strahlentherapie und Onkologie 7/2012

01.07.2012 | Original article

Intra- and intertumor heterogeneities in total, chronic, and acute hypoxia in xenografted squamous cell carcinomas

Detection and quantification using (immuno-)fluorescence techniques

verfasst von: C.-A. Maftei, C. Bayer, Ph.D., K. Shi, P. Vaupel

Erschienen in: Strahlentherapie und Onkologie | Ausgabe 7/2012

Einloggen, um Zugang zu erhalten

Abstract

Background

Heterogeneously distributed hypoxia is a major characteristic of solid tumors. (Immuno-)fluorescence detection of hypoxia in experimental tumors is frequently assessed in a single central section; however, this may not necessarily be representative of the whole tumor. In order to determine whether analysis of one central section is exemplary of the whole tumor and whether different volumes have an impact on tumor oxygenation, we assessed the fractions of total (TH), chronic (CH), and acute hypoxia (AH) throughout different layers of tumors of varying volumes.

Materials and methods

Xenografted FaDu human squamous cell carcinomas of different volumes were investigated for intra- and intertumor heterogeneities. Tissue blocks located at the apical, central, and basal layer were sliced from individual tumors. Four serial cryosections were analyzed from each tissue block. Vital tumor tissue was explored for the distribution of Hoechst 33342 (perfusion), pimonidazole (hypoxia), and CD31 (endothelium) to assess TH, CH, and AH.

Results

Fractions of TH, CH, and AH were consistently similar in the serial sections of individual tissue blocks. However, significant differences were found between the apical, central, and basal blocks that were even opposite depending on the tumor volume. Pooled data from all three tissue blocks revealed significantly higher fractions of hypoxia in the large tumors than in the small tumors.

Conclusion

FaDu tumors exhibit a heterogeneous and volume-dependent oxygenation status. Assessing the average fractions of TH, CH, and AH from central blocks corresponds best to the average of the entire tumor. However, information on intratumor heterogeneities is lost, especially when considering tumors of substantially different volumes.
Literatur
1.
Zurück zum Zitat Arabi M, Piert M (2010) Hypoxia PET/CT imaging: implications for radiation oncology. QJ Nucl Med Mol Imaging 54:500–509 Arabi M, Piert M (2010) Hypoxia PET/CT imaging: implications for radiation oncology. QJ Nucl Med Mol Imaging 54:500–509
2.
Zurück zum Zitat Arteel GE, Thurman RG, Yates JM, Raleigh JA (1995) Evidence that hypoxia markers detect oxygen gradients in liver: pimonidazole and retrograde perfusion of rat liver. Br J Cancer 72:889–895PubMedCrossRef Arteel GE, Thurman RG, Yates JM, Raleigh JA (1995) Evidence that hypoxia markers detect oxygen gradients in liver: pimonidazole and retrograde perfusion of rat liver. Br J Cancer 72:889–895PubMedCrossRef
3.
Zurück zum Zitat Astner ST, Shi K, Vaupel P, Molls M (2010) Imaging of tumor physiology: impacts on clinical radiation oncology. Exp Oncol 32:149–152PubMed Astner ST, Shi K, Vaupel P, Molls M (2010) Imaging of tumor physiology: impacts on clinical radiation oncology. Exp Oncol 32:149–152PubMed
4.
Zurück zum Zitat Bache M, Kappler M, Said HM et al (2008) Detection and specific targeting of hypoxic regions within solid tumors: current preclinical and clinical strategies. Curr Med Chem 15:322–338PubMedCrossRef Bache M, Kappler M, Said HM et al (2008) Detection and specific targeting of hypoxic regions within solid tumors: current preclinical and clinical strategies. Curr Med Chem 15:322–338PubMedCrossRef
5.
Zurück zum Zitat Bayer C, Maftei CA, Astner ST et al (2010) Subtypes of chronic and acute hypoxia in tumors according to different causative mechanisms. Strahlenther Onkol 186(Suppl 1):66 Bayer C, Maftei CA, Astner ST et al (2010) Subtypes of chronic and acute hypoxia in tumors according to different causative mechanisms. Strahlenther Onkol 186(Suppl 1):66
6.
Zurück zum Zitat Bayer C, Shi K, Astner ST et al (2011) Acute versus chronic hypoxia: why a simplified classification is simply not enough. Int J Radiat Oncol Biol Phys 80:965–968PubMedCrossRef Bayer C, Shi K, Astner ST et al (2011) Acute versus chronic hypoxia: why a simplified classification is simply not enough. Int J Radiat Oncol Biol Phys 80:965–968PubMedCrossRef
7.
Zurück zum Zitat Bayer C, Shi K, Maftei C et al (2011) Assessment of chronic and acute hypoxia in head and neck cancer using microscopic and macroscopic imaging approaches. Strahlenther Onkol 187:602 Bayer C, Shi K, Maftei C et al (2011) Assessment of chronic and acute hypoxia in head and neck cancer using microscopic and macroscopic imaging approaches. Strahlenther Onkol 187:602
8.
Zurück zum Zitat Brown JM (1979) Evidence for acutely hypoxic cells in mouse tumours, and a possible mechanism of reoxygenation. Br J Radiol 52:650–656PubMedCrossRef Brown JM (1979) Evidence for acutely hypoxic cells in mouse tumours, and a possible mechanism of reoxygenation. Br J Radiol 52:650–656PubMedCrossRef
9.
Zurück zum Zitat Busk M, Horsman MR, Jakobsen S et al (2009) Can hypoxia-PET map hypoxic cell density heterogeneity accurately in an animal tumor model at a clinically obtainable image contrast? Radiother Oncol 92:429–436PubMedCrossRef Busk M, Horsman MR, Jakobsen S et al (2009) Can hypoxia-PET map hypoxic cell density heterogeneity accurately in an animal tumor model at a clinically obtainable image contrast? Radiother Oncol 92:429–436PubMedCrossRef
10.
Zurück zum Zitat Chaplin DJ, Durand RE, Olive PL (1986) Acute hypoxia in tumors: implications for modifiers of radiation effects. Int J Radiat Oncol Biol Phys 12:1279–1282PubMedCrossRef Chaplin DJ, Durand RE, Olive PL (1986) Acute hypoxia in tumors: implications for modifiers of radiation effects. Int J Radiat Oncol Biol Phys 12:1279–1282PubMedCrossRef
11.
Zurück zum Zitat Chitneni SK, Palmer GM, Zalutsky MR, Dewhirst MW (2011) Molecular imaging of hypoxia. J Nucl Med 52:165–168PubMedCrossRef Chitneni SK, Palmer GM, Zalutsky MR, Dewhirst MW (2011) Molecular imaging of hypoxia. J Nucl Med 52:165–168PubMedCrossRef
12.
Zurück zum Zitat Grosu AL, Souvatzoglou M, Röper B et al (2007) Hypoxia imaging with FAZA-PET and theoretical considerations with regard to dose painting for individualization of radiotherapy in patients with head and neck cancer. Int J Radiat Oncol Biol Phys 69:541–551PubMedCrossRef Grosu AL, Souvatzoglou M, Röper B et al (2007) Hypoxia imaging with FAZA-PET and theoretical considerations with regard to dose painting for individualization of radiotherapy in patients with head and neck cancer. Int J Radiat Oncol Biol Phys 69:541–551PubMedCrossRef
13.
Zurück zum Zitat Höckel M, Schlenger K, Knoop C, Vaupel P (1991) Oxygenation of carcinomas of the uterine cervix: evaluation by computerized O2 tension measurements. Cancer Res 51:6098–6102PubMed Höckel M, Schlenger K, Knoop C, Vaupel P (1991) Oxygenation of carcinomas of the uterine cervix: evaluation by computerized O2 tension measurements. Cancer Res 51:6098–6102PubMed
14.
Zurück zum Zitat Ljungkvist AS, Bussink J, Rijken PF et al (2002) Vascular architecture, hypoxia, and proliferation in first-generation xenografts of human head-and-neck squamous cell carcinomas. Int J Radiat Oncol Biol Phys 54:215–228PubMedCrossRef Ljungkvist AS, Bussink J, Rijken PF et al (2002) Vascular architecture, hypoxia, and proliferation in first-generation xenografts of human head-and-neck squamous cell carcinomas. Int J Radiat Oncol Biol Phys 54:215–228PubMedCrossRef
15.
Zurück zum Zitat Maftei CA, Bayer C, Astner ST et al (2011) Monitoring the fraction of total hypoxia and hypoxia subtypes in human squamous cell carcinomas during fractionated irradiation: evaluation using pattern recognition in microcirculatory supply units. Strahlenther Onkol 187(Suppl 1):25CrossRef Maftei CA, Bayer C, Astner ST et al (2011) Monitoring the fraction of total hypoxia and hypoxia subtypes in human squamous cell carcinomas during fractionated irradiation: evaluation using pattern recognition in microcirculatory supply units. Strahlenther Onkol 187(Suppl 1):25CrossRef
16.
Zurück zum Zitat Maftei CA, Bayer C, Shi K et al (2011) Quantitative assessment of hypoxia subtypes in microcirculatory supply units of malignant tumors using (immuno-)fluorescence techniques. Strahlenther Onkol 187:260–266PubMedCrossRef Maftei CA, Bayer C, Shi K et al (2011) Quantitative assessment of hypoxia subtypes in microcirculatory supply units of malignant tumors using (immuno-)fluorescence techniques. Strahlenther Onkol 187:260–266PubMedCrossRef
17.
Zurück zum Zitat Maftei CA, Bayer C, Shi K et al (2011) Changes in the fraction of total hypoxia and hypoxia subtypes in human squamous cell carcinomas upon fractionated irradiation: evaluation using pattern recognition in microcirculatory supply units. Radiother Oncol 101:209–216PubMedCrossRef Maftei CA, Bayer C, Shi K et al (2011) Changes in the fraction of total hypoxia and hypoxia subtypes in human squamous cell carcinomas upon fractionated irradiation: evaluation using pattern recognition in microcirculatory supply units. Radiother Oncol 101:209–216PubMedCrossRef
18.
Zurück zum Zitat Maftei CA, Shi K, Bayer C et al (2011) Comparison of (immuno-) fluorescence data with serial [18F]Fmiso PET/CT imaging for assessment of chronic and acute hypoxia in head and neck cancers. Radiother Oncol 99:412–417PubMedCrossRef Maftei CA, Shi K, Bayer C et al (2011) Comparison of (immuno-) fluorescence data with serial [18F]Fmiso PET/CT imaging for assessment of chronic and acute hypoxia in head and neck cancers. Radiother Oncol 99:412–417PubMedCrossRef
19.
Zurück zum Zitat Magat J, Jordan BF, Cron GO, Gallez B (2010) Noninvasive mapping of spontaneous fluctuations in tumor oxygenation using 19 F MRI. Med Phys 37:5434–5441PubMedCrossRef Magat J, Jordan BF, Cron GO, Gallez B (2010) Noninvasive mapping of spontaneous fluctuations in tumor oxygenation using 19 F MRI. Med Phys 37:5434–5441PubMedCrossRef
20.
Zurück zum Zitat Manz R, Otte J, Thews G, Vaupel P (1983) Relationship between size and oxygenation status of malignant tumors. Adv Exp Med Biol 159:391–398PubMed Manz R, Otte J, Thews G, Vaupel P (1983) Relationship between size and oxygenation status of malignant tumors. Adv Exp Med Biol 159:391–398PubMed
21.
Zurück zum Zitat Mueller-Klieser W, Vaupel P, Manz R, Schmidseder R (1981) Intracapillary oxyhemoglobin saturation of malignant tumors in humans. Int J Radiat Oncol Biol Phys 7:1397–404PubMedCrossRef Mueller-Klieser W, Vaupel P, Manz R, Schmidseder R (1981) Intracapillary oxyhemoglobin saturation of malignant tumors in humans. Int J Radiat Oncol Biol Phys 7:1397–404PubMedCrossRef
22.
Zurück zum Zitat Nordsmark M, Bentzen SM, Rudat V et al (2005) Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study. Radiother Oncol 77:18–24PubMedCrossRef Nordsmark M, Bentzen SM, Rudat V et al (2005) Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study. Radiother Oncol 77:18–24PubMedCrossRef
23.
Zurück zum Zitat Reinhold HS, Blachiwiecz B, Blok A (1977) Oxygenation and reoxygenation in “sandwich” tumours. Bibl Anat 15:270–272PubMed Reinhold HS, Blachiwiecz B, Blok A (1977) Oxygenation and reoxygenation in “sandwich” tumours. Bibl Anat 15:270–272PubMed
24.
Zurück zum Zitat Rofstad EK, Maseide K (1999) Radiobiological and immunohistochemical assessment of hypoxia in human melanoma xenografts: acute and chronic hypoxia in individual tumors. Int J Radiat Biol 75:1377–1393PubMedCrossRef Rofstad EK, Maseide K (1999) Radiobiological and immunohistochemical assessment of hypoxia in human melanoma xenografts: acute and chronic hypoxia in individual tumors. Int J Radiat Biol 75:1377–1393PubMedCrossRef
25.
Zurück zum Zitat Stadler P, Becker A, Feldmann HJ et al (1999) Influence of the hypoxic subvolume on the survival of patients with head and neck cancer. Int J Radiat Oncol Biol Phys 44:749–754PubMedCrossRef Stadler P, Becker A, Feldmann HJ et al (1999) Influence of the hypoxic subvolume on the survival of patients with head and neck cancer. Int J Radiat Oncol Biol Phys 44:749–754PubMedCrossRef
26.
Zurück zum Zitat Tatum J, Kelloff GJ, Gillies RJ et al (2006) Hypoxia: Importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy. Int J Radiat Biol 82:699–757PubMedCrossRef Tatum J, Kelloff GJ, Gillies RJ et al (2006) Hypoxia: Importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy. Int J Radiat Biol 82:699–757PubMedCrossRef
27.
Zurück zum Zitat Thomlinson RH, Gray l (1955) The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 9:539–549PubMedCrossRef Thomlinson RH, Gray l (1955) The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 9:539–549PubMedCrossRef
29.
Zurück zum Zitat Vaupel P (2004) The role of hypoxia-induced factors in tumor progression. Oncologist 9(Suppl 5):10–17PubMedCrossRef Vaupel P (2004) The role of hypoxia-induced factors in tumor progression. Oncologist 9(Suppl 5):10–17PubMedCrossRef
30.
Zurück zum Zitat Vaupel P (2009) Physiological mechanisms of treatment resistance. In: Molls M, Vaupel P, Nieder C et al (eds) The impact of tumor biology on cancer treatment and multidisciplinary strategies. Springer, Berlin-Heidelberg, pp 273–290 Vaupel P (2009) Physiological mechanisms of treatment resistance. In: Molls M, Vaupel P, Nieder C et al (eds) The impact of tumor biology on cancer treatment and multidisciplinary strategies. Springer, Berlin-Heidelberg, pp 273–290
31.
Zurück zum Zitat Vaupel P (2011) Acute and chronic hypoxia in the clinical setting: merely an academic discussion or do we need to distinguish between the two? Strahlenther Onkol 187:601 Vaupel P (2011) Acute and chronic hypoxia in the clinical setting: merely an academic discussion or do we need to distinguish between the two? Strahlenther Onkol 187:601
32.
Zurück zum Zitat Vaupel P, Harrison L (2004) Tumor hypoxia: causative factors, compensatory mechanisms, and cellular response. Oncologist 9(Suppl 5):4–9PubMedCrossRef Vaupel P, Harrison L (2004) Tumor hypoxia: causative factors, compensatory mechanisms, and cellular response. Oncologist 9(Suppl 5):4–9PubMedCrossRef
33.
Zurück zum Zitat Vaupel P, Mayer A (2007) Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 26:225–239PubMedCrossRef Vaupel P, Mayer A (2007) Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 26:225–239PubMedCrossRef
34.
Zurück zum Zitat Vaupel P, Mueller-Klieser W (1986) Cell line and growth site as relevant parameters governing tumor tissue oxygenation. Adv Exp Med Biol 200:633–643PubMedCrossRef Vaupel P, Mueller-Klieser W (1986) Cell line and growth site as relevant parameters governing tumor tissue oxygenation. Adv Exp Med Biol 200:633–643PubMedCrossRef
35.
Zurück zum Zitat Vaupel PW, Frinak S, Bicher HI (1981) Heterogeneous oxygen partial pressure and pH distribution in C3H mouse mammary adenocarcinoma. Cancer Res 41:2008–2013PubMed Vaupel PW, Frinak S, Bicher HI (1981) Heterogeneous oxygen partial pressure and pH distribution in C3H mouse mammary adenocarcinoma. Cancer Res 41:2008–2013PubMed
36.
Zurück zum Zitat Vaupel P, Höckel M, Mayer A (2007) Detection and characterization of tumor hypoxia using pO2 histography. Antioxid Redox Signal 9:1221–1235PubMedCrossRef Vaupel P, Höckel M, Mayer A (2007) Detection and characterization of tumor hypoxia using pO2 histography. Antioxid Redox Signal 9:1221–1235PubMedCrossRef
37.
Zurück zum Zitat Vaupel P, Kluge M, Ambroz MC (1988) Laser Doppler flowmetry in subepidermal tumours and in normal skin of rats during localized ultrasound hyperthermia. Int J Hyperthermia 4:307–321PubMedCrossRef Vaupel P, Kluge M, Ambroz MC (1988) Laser Doppler flowmetry in subepidermal tumours and in normal skin of rats during localized ultrasound hyperthermia. Int J Hyperthermia 4:307–321PubMedCrossRef
38.
Zurück zum Zitat Vaupel P, Fortmeyer HP, Runkel S, Kallinowski F (1987) Blood flow, oxygen consumption, and tissue oxygenation of human breast cancer xenografts in nude rats. Cancer Res 47:3496–503PubMed Vaupel P, Fortmeyer HP, Runkel S, Kallinowski F (1987) Blood flow, oxygen consumption, and tissue oxygenation of human breast cancer xenografts in nude rats. Cancer Res 47:3496–503PubMed
39.
Zurück zum Zitat Vaupel P, Schlenger K, Knoop C, Höckel M (1991) Oxygenation of human tumors: evaluation of tissue oxygen distribution in breast cancers by computerized O2 tension measurements. Cancer Res 51:3316–3322PubMed Vaupel P, Schlenger K, Knoop C, Höckel M (1991) Oxygenation of human tumors: evaluation of tissue oxygen distribution in breast cancers by computerized O2 tension measurements. Cancer Res 51:3316–3322PubMed
40.
Zurück zum Zitat Wendling P, Manz R, Thews G, Vaupel P (1984) Heterogeneous oxygenation of rectal carcinomas in humans: a critical parameter for preoperative irradiation? Adv Exp Med Biol 180:293–300PubMed Wendling P, Manz R, Thews G, Vaupel P (1984) Heterogeneous oxygenation of rectal carcinomas in humans: a critical parameter for preoperative irradiation? Adv Exp Med Biol 180:293–300PubMed
41.
Zurück zum Zitat Yaromina A, Hölscher T, Eicheler W et al (2005) Does heterogeneity of pimonidazole labelling correspond to the heterogeneity of radiation-response of FaDu human squamous cell carcinoma? Radiother Oncol 76:206–212PubMedCrossRef Yaromina A, Hölscher T, Eicheler W et al (2005) Does heterogeneity of pimonidazole labelling correspond to the heterogeneity of radiation-response of FaDu human squamous cell carcinoma? Radiother Oncol 76:206–212PubMedCrossRef
42.
Zurück zum Zitat Yaromina A, Zips D, Thames HD et al (2006) Pimonidazole labelling and response to fractionated irradiation of five human squamous cell carcinoma (hSCC) lines in nude mice: the need for a multivariate approach in biomarker studies. Radiother Oncol 81:122–129PubMedCrossRef Yaromina A, Zips D, Thames HD et al (2006) Pimonidazole labelling and response to fractionated irradiation of five human squamous cell carcinoma (hSCC) lines in nude mice: the need for a multivariate approach in biomarker studies. Radiother Oncol 81:122–129PubMedCrossRef
43.
Zurück zum Zitat Yasui H, Matsumoto S, Devasahayam N et al (2010) Low-field magnetic resonance imaging to visualize chronic and cycling hypoxia in tumor-bearing mice. Cancer Res 70:6427–6436PubMedCrossRef Yasui H, Matsumoto S, Devasahayam N et al (2010) Low-field magnetic resonance imaging to visualize chronic and cycling hypoxia in tumor-bearing mice. Cancer Res 70:6427–6436PubMedCrossRef
44.
Zurück zum Zitat Wang K, Yorke E, Nehmeh SA et al (2009) Modeling acute and chronic hypoxia using serial images of 18 F-FMISO PET. Med Phys 36:4400–4408PubMedCrossRef Wang K, Yorke E, Nehmeh SA et al (2009) Modeling acute and chronic hypoxia using serial images of 18 F-FMISO PET. Med Phys 36:4400–4408PubMedCrossRef
45.
Zurück zum Zitat Zoula S, Rijken PF, Peters JP et al (2003) Pimonidazole binding in C6 rat brain glioma: relation with lipid droplet detection. Br J Cancer 88:1439–1444PubMedCrossRef Zoula S, Rijken PF, Peters JP et al (2003) Pimonidazole binding in C6 rat brain glioma: relation with lipid droplet detection. Br J Cancer 88:1439–1444PubMedCrossRef
Metadaten
Titel
Intra- and intertumor heterogeneities in total, chronic, and acute hypoxia in xenografted squamous cell carcinomas
Detection and quantification using (immuno-)fluorescence techniques
verfasst von
C.-A. Maftei
C. Bayer, Ph.D.
K. Shi
P. Vaupel
Publikationsdatum
01.07.2012
Verlag
Springer-Verlag
Erschienen in
Strahlentherapie und Onkologie / Ausgabe 7/2012
Print ISSN: 0179-7158
Elektronische ISSN: 1439-099X
DOI
https://doi.org/10.1007/s00066-012-0105-4

Weitere Artikel der Ausgabe 7/2012

Strahlentherapie und Onkologie 7/2012 Zur Ausgabe

Labor, CT-Anthropometrie zeigen Risiko für Pankreaskrebs

13.05.2024 Pankreaskarzinom Nachrichten

Gerade bei aggressiven Malignomen wie dem duktalen Adenokarzinom des Pankreas könnte Früherkennung die Therapiechancen verbessern. Noch jedoch klafft hier eine Lücke. Ein Studienteam hat einen Weg gesucht, sie zu schließen.

Viel pflanzliche Nahrung, seltener Prostata-Ca.-Progression

12.05.2024 Prostatakarzinom Nachrichten

Ein hoher Anteil pflanzlicher Nahrung trägt möglicherweise dazu bei, das Progressionsrisiko von Männern mit Prostatakarzinomen zu senken. In einer US-Studie war das Risiko bei ausgeprägter pflanzlicher Ernährung in etwa halbiert.

Alter verschlechtert Prognose bei Endometriumkarzinom

11.05.2024 Endometriumkarzinom Nachrichten

Ein höheres Alter bei der Diagnose eines Endometriumkarzinoms ist mit aggressiveren Tumorcharakteristika assoziiert, scheint aber auch unabhängig von bekannten Risikofaktoren die Prognose der Erkrankung zu verschlimmern.

Darf man die Behandlung eines Neonazis ablehnen?

08.05.2024 Gesellschaft Nachrichten

In einer Leseranfrage in der Zeitschrift Journal of the American Academy of Dermatology möchte ein anonymer Dermatologe bzw. eine anonyme Dermatologin wissen, ob er oder sie einen Patienten behandeln muss, der eine rassistische Tätowierung trägt.

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.