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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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METOXIA CourseTumor hypoxia
- detection and prognostic significanceHeidi Lyng
Thursday 11 October 2012
This course is funded with the support of the METOXIA project under the FP7 Programme.
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.
Tumor development
This course is funded with the support of the METOXIA project under the FP7 Programme.
Metastases
SpreadingInvasive growth
Therapy
Normal cell
Transformation
Cancer cell
Gene defectsSteps in carcinogenesis
Angiogenesis
Tumor
Hypoxia
Angiogenesis: growth of blood vessels
Uncontrolled cell growthAnti-apoptosis
Cell population
Apoptosis: programmed cell death
This course is funded with the support of the METOXIA project under the FP7 Programme.
Thomlinson & Gray, 1955
Vascularizedstroma
Tumor cells
Necrosis
Pioneer work from 1955Thomlinson and Gray describe corded structures in tumors
Hypothesis: cells bordering necrosis were viable, but hypoxic
Hypoxia
Oxygen concentrations
• 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.
Air: 21% O2 (160 mmHg)Normal tissue: 5-9% O2 (40 - 75mmHg)Hypoxia: < 3% O2 (0 - 20 mmHg)
Why does hypoxia arise in tumors?
This course is funded with the support of the METOXIA project under the FP7 Programme.
Tumors: imbalance between oxygen supply and demand
Oxygen supply Oxygen demand
Normal tissue
Tumor
Oxygen imbalance in tumors
• Poor oxygen supply - Inefficient vascular network - Low oxygen saturation of hemoglobin (HbO2)
• High oxygen demand - High metabolic activity
This course is funded with the support of the METOXIA project under the FP7 Programme.
Oxygen
Tumor vascular network
This course is funded with the support of the METOXIA project under the FP7 Programme.
Tumor grown in a window chamber
Dewhirst et al. Radiother Oncol 2007
Microscopy of living tissue
Irregular vascular network in tumors
Oxygen saturation of hemoglobin
This course is funded with the support of the METOXIA project under the FP7 Programme.
Hardee et al, Curr Mol Med 2009
Tumor grown in a window chamber
Heterogeneous and often low oxygen saturation in tumors
Cycling (acute, transient) hypoxia
This course is funded with the support of the METOXIA project under the FP7 Programme.
Hardee et al., Curr Mol Med 2009
Fluctuations in red cell flux and oxygen saturation in tumor vessels
Hemoglobin oxygen saturation (%)
Time (min)
Why is hypoxia an adverse factor?
This course is funded with the support of the METOXIA project under the FP7 Programme.
TUMOR HYPOXIA
Genomicinstability
Radioresistance
Metastasis, treatment resistance, malignant progression
Chemoresistance
Selection pressure by apoptosis
Poor clinical outcome
InvasionAngiogenesis
This course is funded with the support of the METOXIA project under the FP7 Programme.
Hypoxia-induced radioresistance
Oxygen: more damage, damage fixation
Hypoxia increases the radioresistance of tumor cells
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.
PO2 electrodes
This course is funded with the support of the METOXIA project under the FP7 Programme.
PO2 oxygen concentration ”Gold standard”Invasive
This course is funded with the support of the METOXIA project under the FP7 Programme.
Lyng et al. Radiother Oncol 1997
PO2 in human tumors: lower than in normal tissues varies within the tumor varies from tumor to tumor
PO2 measurements50
This course is funded with the support of the METOXIA project under the FP7 Programme.
PO2 measurementsMulti-center study of 397 head and neck tumors
Nordsmark et al. Radiother Oncol 2005
P = 0.006
Less hypoxic
More hypoxic
Poor outcome of patients with hypoxic head and neck tumor
Immunohistochemistry markers
• Pimonidazole, EF5
• Hypoxia-inducible proteins
This course is funded with the support of the METOXIA project under the FP7 Programme.
Cell type and compartment informationInvasive
Pimonidazole
This course is funded with the support of the METOXIA project under the FP7 Programme.
Mod from Varia et al. Gyn Oncol 1998
HYPOXIA
Requires administration of pimonidazole
Pimonidazole
This course is funded with the support of the METOXIA project under the FP7 Programme.
Lyng , unpublished
Pimonidazole staining of melanoma xenograft
Necrosis
Hypoxia-inducible proteins
This course is funded with the support of the METOXIA project under the FP7 Programme.
Proteins upregulated under hypoxia are potential immunohistochemistry markers
VEGF (angiogenesis) CA9 (pH)
GLUT1 (metabolism)
Key transcription factor:Hypoxia-inducible factor HIF1
HIF1 regulation
HIF1α staining
This course is funded with the support of the METOXIA project under the FP7 Programme.
Lyng, unpublished
HIF1α staining of cervical carcinoma
Necrosis
Multimarker staining
This course is funded with the support of the METOXIA project under the FP7 Programme.
Rademakers et al. BMC Cancer 2011PimoHIF1CA9
Staining of head and neck carcinoma
Gene signatures
This course is funded with the support of the METOXIA project under the FP7 Programme.
Tumor
DNA
mRNA
Protein
Whole genome screening of mRNAs
(gene expressions)
Can include genes from several pathwaysInvasive
Gene signature
Gene signatures
This course is funded with the support of the METOXIA project under the FP7 Programme.
High gene expression
Low gene expression
Poor outcome of patients with high expression of signature genes
Hypoxia gene signature of cervical tumors
Halle et al. Cancer Research 2012
31 hypoxia inducible genes in:
MetabolismCell cycle regulationProliferation
Imaging
• Dynamic contrast enhanced (DCE) MR imaging
This course is funded with the support of the METOXIA project under the FP7 Programme.
Information on the entire tumor and its heterogeneityNon-invasive but requires administration of contrast agent
Halle et al. Cancer Research 2012
DCE-MR imaging of tumor hypoxia
This course is funded with the support of the METOXIA project under the FP7 Programme.
HIF1
Less hypoxic cervical tumor
HIF1
Hypoxic cervical tumor
Halle et al. Cancer Research 2012
Prognostic significance
• 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.
Some cancer types and methods
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.