Tumour Hypoxia - detection and prognostic significance
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Tumour Hypoxia - detection and prognostic significance

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Lecture by Dr. Heidi Lyng in the context of the Course: "Tumour Hypoxia: From Biology to Therapy III".

Lecture by Dr. Heidi Lyng in the context of the Course: "Tumour Hypoxia: From Biology to Therapy III".
For the complete e-Course see http://www.myhaikuclass.com/MaastroClinic/metoxia

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  • What is hypoxia? Good evidences for adverse effect of hypoxia at levels as high as 10 mmHg.
  • The oxygen concentration is determined by the balance between the oxygen supply by the vasculature and the oxygen demand by the tumor cells.
  • Through a step of reactions, fo which he first one is totally inhibited at high oxygen concentrations. Stable adducts are made that can be detected with immunohistochemistry.
  • Also EF5

Tumour Hypoxia - detection and prognostic significance Presentation Transcript

  • 1. METOXIA Course Tumor hypoxia- detection and prognostic significance Heidi Lyng Thursday 11 October 2012 This course is funded with the support of the METOXIA project under the FP7 Programme.
  • 2. Learning objectives• Why does hypoxia arise in tumors?• How can we measure tumor hypoxia in patients?• What is the clinical importance of tumor hypoxia? This course is funded with the support of the METOXIA project under the FP7 Programme.
  • 3. Tumor development Steps in carcinogenesis Gene defects Metastases TumorNormal cell Cancer cell Cell populationTransformation Uncontrolled cell growth Angiogenesis Anti-apoptosis Hypoxia Apoptosis: programmed cell death Spreading Invasive growth Angiogenesis: growth of blood vessels Therapy This course is funded with the support of the METOXIA project under the FP7 Programme.
  • 4. Pioneer work from 1955 Thomlinson and Gray describe corded structures in tumorsVascularizedstromaTumor cellsNecrosis Hypoxia Thomlinson & Gray, 1955 Hypothesis: cells bordering necrosis were viable, but hypoxic This course is funded with the support of the METOXIA project under the FP7 Programme.
  • 5. Oxygen concentrations Air: 21% O2 (160 mmHg) Normal tissue: 5-9% O2 (40 - 75mmHg) Hypoxia: < 3% O2 (0 - 20 mmHg)• Radiobiological hypoxia: < 0.5% O2 (4 mmHg)• Activation of hypoxia inducible factor 1 (HIF1): < 1% O2 (7-8 mmHg)• Important clinically: < 1.5% O2 (10 mmHg) This course is funded with the support of the METOXIA project under the FP7 Programme.
  • 6. Why does hypoxia arise in tumors? Oxygen supply Oxygen demandNormal tissue Tumor Tumors: imbalance between oxygen supply and demand This course is funded with the support of the METOXIA project under the FP7 Programme.
  • 7. Oxygen imbalance in tumors• Poor oxygen supply - Inefficient vascular network - Low oxygen saturation of hemoglobin (HbO2)• High oxygen demand - High metabolic activity Oxygen This course is funded with the support of the METOXIA project under the FP7 Programme.
  • 8. Tumor vascular network Tumor grown in a window chamber Microscopy of living tissue Dewhirst et al. Radiother Oncol 2007Irregular vascular network in tumors This course is funded with the support of the METOXIA project under the FP7 Programme.
  • 9. Oxygen saturation of hemoglobin Tumor grown in a window chamber Hardee et al, Curr Mol Med 2009Heterogeneous and often low oxygen saturation in tumors This course is funded with the support of the METOXIA project under the FP7 Programme.
  • 10. Cycling (acute, transient) hypoxia Hemoglobin oxygen saturation (%) Time (min) Hardee et al., Curr Mol Med 2009Fluctuations in red cell flux and oxygen saturation in tumor vessels This course is funded with the support of the METOXIA project under the FP7 Programme.
  • 11. Why is hypoxia an adverse factor? TUMOR HYPOXIARadioresistance Chemoresistance Genomic Selection pressure Angiogenesis Invasion instability by apoptosis Metastasis, treatment resistance, malignant progression Poor clinical outcome This course is funded with the support of the METOXIA project under the FP7 Programme.
  • 12. Hypoxia-induced radioresistance Oxygen: more damage, damage fixationHypoxia increases the radioresistance of tumor cells This course is funded with the support of the METOXIA project under the FP7 Programme.
  • 13. Detection of tumor hypoxia in patients• Oxygen tension (pO2) electrodes• Immunohistochemistry markers• Gene signatures• Imaging This course is funded with the support of the METOXIA project under the FP7 Programme.
  • 14. PO2 electrodesPO2 oxygen concentration ”Gold standard” Invasive This course is funded with the support of the METOXIA project under the FP7 Programme.
  • 15. PO2 measurements 50 Lyng et al. Radiother Oncol 1997PO2 in human tumors: lower than in normal tissues varies within the tumor varies from tumor to tumor This course is funded with the support of the METOXIA project under the FP7 Programme.
  • 16. PO2 measurementsMulti-center study of 397 head and neck tumors Less hypoxic More hypoxic P = 0.006 Nordsmark et al. Radiother Oncol 2005 Poor outcome of patients with hypoxic head and neck tumor This course is funded with the support of the METOXIA project under the FP7 Programme.
  • 17. Immunohistochemistry markers• Pimonidazole, EF5• Hypoxia-inducible proteins Cell type and compartment information Invasive This course is funded with the support of the METOXIA project under the FP7 Programme.
  • 18. Pimonidazole HYPOXIA Mod from Varia et al. Gyn Oncol 1998Requires administration of pimonidazole This course is funded with the support of the METOXIA project under the FP7 Programme.
  • 19. PimonidazolePimonidazole staining of melanoma xenograft Necrosis Lyng , unpublished This course is funded with the support of the METOXIA project under the FP7 Programme.
  • 20. Hypoxia-inducible proteinsHIF1 regulation Key transcription factor: Hypoxia-inducible factor HIF1 VEGF (angiogenesis) CA9 (pH) GLUT1 (metabolism) Proteins upregulated under hypoxia are potential immunohistochemistry markers This course is funded with the support of the METOXIA project under the FP7 Programme.
  • 21. HIF1α stainingHIF1α staining of cervical carcinoma Necrosis Lyng, unpublished This course is funded with the support of the METOXIA project under the FP7 Programme.
  • 22. Multimarker staining Staining of head and neck carcinomaPimo Rademakers et al. BMC Cancer 2011HIF1CA9 This course is funded with the support of the METOXIA project under the FP7 Programme.
  • 23. Gene signatures Tumor DNAmRNA Whole genome screening of mRNAs (gene expressions)Protein Gene signature Can include genes from several pathways Invasive This course is funded with the support of the METOXIA project under the FP7 Programme.
  • 24. Gene signaturesHypoxia gene signature of cervical tumors 31 hypoxia inducible genes in: Low gene expression Metabolism Cell cycle regulation Proliferation High gene expression Halle et al. Cancer Research 2012Poor outcome of patients with high expression of signature genes This course is funded with the support of the METOXIA project under the FP7 Programme.
  • 25. Imaging• Dynamic contrast enhanced (DCE) MR imaging Halle et al. Cancer Research 2012 Information on the entire tumor and its heterogeneityNon-invasive but requires administration of contrast agent This course is funded with the support of the METOXIA project under the FP7 Programme.
  • 26. DCE-MR imaging of tumor hypoxia Hypoxic cervical tumor HIF1 Less hypoxic cervical tumor HIF1 This course is funded with the support of the METOXIA project Halle et al. Cancer Research 2012 under the FP7 Programme.
  • 27. Prognostic significanceSome cancer types and methods• Head and neck cancer, cervical cancer: - pO2 electrodes, pimonidazole, hypoxia-inducible proteins, hypoxia gene signature, imaging• Prostate cancer, soft tissue sarcomas: - pO2 electrodes• Breast cancer, ovarian cancer: - hypoxia-inducible proteins, hypoxia gene signature This course is funded with the support of the METOXIA project under the FP7 Programme.
  • 28. Tumor hypoxia – key points• Arises due to a higher oxygen demand than supply• Can be chronic or cycling (acute, transient)• Promotes metastasis, treatment resistance and malignant progression• Has been studied extensively in patients by complementary methods with different strengths and weaknesses• Is related to poor clinical outcome of many cancer diseases This course is funded with the support of the METOXIA project under the FP7 Programme.