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". 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.

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