Intratumoral spatial distribution of hypoxia and angiogenesis assessed by 18F-FAZA and 125I-Gluco-RGD autoradiography

Maria Picchio, Roswitha Beck, Roland Haubner, Stefan Seidl, Hans Jürgen Machulla, Timothy D. Johnson, Hans Jürgen Wester, Gerald Reischl, Markus Schwaiger, Morand Piert

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

The hypoxia-inducible factor-1α (HIF-1α) activates angiogenesis in response to cellular hypoxia, suggesting a spatial correlation between angiogenesis and tissue hypoxia. Methods: Using digital autoradiography of coinjected 18F-labeled azomycin arabinoside (8F-FAZA) (assessing regional hypoxia) and a glycosylated RGD-containing peptide ( 125I-3-iodo-DTyr4-cyclo(-Arg-Gly-Asp-DTyr-Lys(SAA)-), or 125I-Gluco-RGD) (assessing angiogenesis via binding to αvβ3 integrin receptors on endothelial cells) performed on 22 EMT6 tumor xenografts, we investigated the intratumoral spatial distribution of these tracers. We applied a Bayesian bivariate image analysis using the mean tumor-to-muscle ratio as a discriminator, resulting in 4 groups: FAZA high/RGD high (Q1), FAZA low/RGD high (Q2), FAZA low/RGD low (Q3), and FAZA high/RGD low (Q4). In an additional 18 xenografts, the immunohistochemically derived HIF-1α protein distribution was compared with 18F-FAZA autoradiography. Animals were divided into groups breathing either room air or carbogen (95% oxygen, 5% CO2) for 4 h until sacrifice. Results: Under room air conditions, roughly 60% of the tumor surface displayed a spatial coupling of 18F-FAZA and 125I-Gluco-RGD uptake: either high (Q1) or low (Q3) uptake for both tracers, with Q1 indicating spatial association of hypoxia and angiogenesis and Q3 indicating adequate oxygenation without active angiogenesis. However, the remaining approximately 40% of the tumor surface showed discordant 18F-FAZA and 125I-Gluco-RGD uptake, indicating that hypoxia and angiogenesis are not necessarily spatially linked to each other and highlighting substantial intratumoral heterogeneity of the 18F-FAZA and 125I-Gluco-RGD uptake. Although carbogen breathing conditions significantly decreased the mean 18F-FAZA tumor-to-muscle ratio, no significant changes were observed for 125I-Gluco-RGD, indicating that an acute increase in tumor oxygenation did not influence αvβ3 integrin receptor expression. The HIF-1α-positive (HIFpos) tumor cell fraction was not significantly influenced by breathing conditions and covered between 0% and 35% of the total tumor section surface. However, the HIFpos tumor section surface was much smaller than the tumor section surface of increased 18F-FAZA uptake, suggesting that both markers are identifying distinctly different biologic processes associated with hypoxia. Conclusion: The study revealed a substantial spatial discordance of the 18F-FAZA and 125I-Gluco-RGD tumor distribution suggesting that hypoxia and angiogenesis are not necessarily spatially linked in malignancies. These results may prove essential in developing advanced targeted systemic chemotherapeutic approaches (such as combinations of hypoxia-activated cytotoxins and antiangiogenic drugs) for hypoxic tumors. COPYRIGHT

Original languageEnglish
Pages (from-to)597-605
Number of pages9
JournalJournal of Nuclear Medicine
Volume49
Issue number4
DOIs
Publication statusPublished - Apr 1 2008

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Autoradiography
Neoplasms
Hypoxia-Inducible Factor 1
Respiration
Heterografts
Integrins
Hypoxia
fluoroazomycin arabinoside
Air
Cell Hypoxia
Muscles
Cytotoxins
Endothelial Cells
Oxygen

Keywords

  • I-Gluco-RGD
  • F-FAZA
  • Angiogenesis
  • HIF-1α
  • Tumor hypoxia

ASJC Scopus subject areas

  • Radiological and Ultrasound Technology

Cite this

Intratumoral spatial distribution of hypoxia and angiogenesis assessed by 18F-FAZA and 125I-Gluco-RGD autoradiography. / Picchio, Maria; Beck, Roswitha; Haubner, Roland; Seidl, Stefan; Machulla, Hans Jürgen; Johnson, Timothy D.; Wester, Hans Jürgen; Reischl, Gerald; Schwaiger, Markus; Piert, Morand.

In: Journal of Nuclear Medicine, Vol. 49, No. 4, 01.04.2008, p. 597-605.

Research output: Contribution to journalArticle

Picchio, M, Beck, R, Haubner, R, Seidl, S, Machulla, HJ, Johnson, TD, Wester, HJ, Reischl, G, Schwaiger, M & Piert, M 2008, 'Intratumoral spatial distribution of hypoxia and angiogenesis assessed by 18F-FAZA and 125I-Gluco-RGD autoradiography', Journal of Nuclear Medicine, vol. 49, no. 4, pp. 597-605. https://doi.org/10.2967/jnumed.107.046870
Picchio, Maria ; Beck, Roswitha ; Haubner, Roland ; Seidl, Stefan ; Machulla, Hans Jürgen ; Johnson, Timothy D. ; Wester, Hans Jürgen ; Reischl, Gerald ; Schwaiger, Markus ; Piert, Morand. / Intratumoral spatial distribution of hypoxia and angiogenesis assessed by 18F-FAZA and 125I-Gluco-RGD autoradiography. In: Journal of Nuclear Medicine. 2008 ; Vol. 49, No. 4. pp. 597-605.
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abstract = "The hypoxia-inducible factor-1α (HIF-1α) activates angiogenesis in response to cellular hypoxia, suggesting a spatial correlation between angiogenesis and tissue hypoxia. Methods: Using digital autoradiography of coinjected 18F-labeled azomycin arabinoside (8F-FAZA) (assessing regional hypoxia) and a glycosylated RGD-containing peptide ( 125I-3-iodo-DTyr4-cyclo(-Arg-Gly-Asp-DTyr-Lys(SAA)-), or 125I-Gluco-RGD) (assessing angiogenesis via binding to αvβ3 integrin receptors on endothelial cells) performed on 22 EMT6 tumor xenografts, we investigated the intratumoral spatial distribution of these tracers. We applied a Bayesian bivariate image analysis using the mean tumor-to-muscle ratio as a discriminator, resulting in 4 groups: FAZA high/RGD high (Q1), FAZA low/RGD high (Q2), FAZA low/RGD low (Q3), and FAZA high/RGD low (Q4). In an additional 18 xenografts, the immunohistochemically derived HIF-1α protein distribution was compared with 18F-FAZA autoradiography. Animals were divided into groups breathing either room air or carbogen (95{\%} oxygen, 5{\%} CO2) for 4 h until sacrifice. Results: Under room air conditions, roughly 60{\%} of the tumor surface displayed a spatial coupling of 18F-FAZA and 125I-Gluco-RGD uptake: either high (Q1) or low (Q3) uptake for both tracers, with Q1 indicating spatial association of hypoxia and angiogenesis and Q3 indicating adequate oxygenation without active angiogenesis. However, the remaining approximately 40{\%} of the tumor surface showed discordant 18F-FAZA and 125I-Gluco-RGD uptake, indicating that hypoxia and angiogenesis are not necessarily spatially linked to each other and highlighting substantial intratumoral heterogeneity of the 18F-FAZA and 125I-Gluco-RGD uptake. Although carbogen breathing conditions significantly decreased the mean 18F-FAZA tumor-to-muscle ratio, no significant changes were observed for 125I-Gluco-RGD, indicating that an acute increase in tumor oxygenation did not influence αvβ3 integrin receptor expression. The HIF-1α-positive (HIFpos) tumor cell fraction was not significantly influenced by breathing conditions and covered between 0{\%} and 35{\%} of the total tumor section surface. However, the HIFpos tumor section surface was much smaller than the tumor section surface of increased 18F-FAZA uptake, suggesting that both markers are identifying distinctly different biologic processes associated with hypoxia. Conclusion: The study revealed a substantial spatial discordance of the 18F-FAZA and 125I-Gluco-RGD tumor distribution suggesting that hypoxia and angiogenesis are not necessarily spatially linked in malignancies. These results may prove essential in developing advanced targeted systemic chemotherapeutic approaches (such as combinations of hypoxia-activated cytotoxins and antiangiogenic drugs) for hypoxic tumors. COPYRIGHT",
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T1 - Intratumoral spatial distribution of hypoxia and angiogenesis assessed by 18F-FAZA and 125I-Gluco-RGD autoradiography

AU - Picchio, Maria

AU - Beck, Roswitha

AU - Haubner, Roland

AU - Seidl, Stefan

AU - Machulla, Hans Jürgen

AU - Johnson, Timothy D.

AU - Wester, Hans Jürgen

AU - Reischl, Gerald

AU - Schwaiger, Markus

AU - Piert, Morand

PY - 2008/4/1

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N2 - The hypoxia-inducible factor-1α (HIF-1α) activates angiogenesis in response to cellular hypoxia, suggesting a spatial correlation between angiogenesis and tissue hypoxia. Methods: Using digital autoradiography of coinjected 18F-labeled azomycin arabinoside (8F-FAZA) (assessing regional hypoxia) and a glycosylated RGD-containing peptide ( 125I-3-iodo-DTyr4-cyclo(-Arg-Gly-Asp-DTyr-Lys(SAA)-), or 125I-Gluco-RGD) (assessing angiogenesis via binding to αvβ3 integrin receptors on endothelial cells) performed on 22 EMT6 tumor xenografts, we investigated the intratumoral spatial distribution of these tracers. We applied a Bayesian bivariate image analysis using the mean tumor-to-muscle ratio as a discriminator, resulting in 4 groups: FAZA high/RGD high (Q1), FAZA low/RGD high (Q2), FAZA low/RGD low (Q3), and FAZA high/RGD low (Q4). In an additional 18 xenografts, the immunohistochemically derived HIF-1α protein distribution was compared with 18F-FAZA autoradiography. Animals were divided into groups breathing either room air or carbogen (95% oxygen, 5% CO2) for 4 h until sacrifice. Results: Under room air conditions, roughly 60% of the tumor surface displayed a spatial coupling of 18F-FAZA and 125I-Gluco-RGD uptake: either high (Q1) or low (Q3) uptake for both tracers, with Q1 indicating spatial association of hypoxia and angiogenesis and Q3 indicating adequate oxygenation without active angiogenesis. However, the remaining approximately 40% of the tumor surface showed discordant 18F-FAZA and 125I-Gluco-RGD uptake, indicating that hypoxia and angiogenesis are not necessarily spatially linked to each other and highlighting substantial intratumoral heterogeneity of the 18F-FAZA and 125I-Gluco-RGD uptake. Although carbogen breathing conditions significantly decreased the mean 18F-FAZA tumor-to-muscle ratio, no significant changes were observed for 125I-Gluco-RGD, indicating that an acute increase in tumor oxygenation did not influence αvβ3 integrin receptor expression. The HIF-1α-positive (HIFpos) tumor cell fraction was not significantly influenced by breathing conditions and covered between 0% and 35% of the total tumor section surface. However, the HIFpos tumor section surface was much smaller than the tumor section surface of increased 18F-FAZA uptake, suggesting that both markers are identifying distinctly different biologic processes associated with hypoxia. Conclusion: The study revealed a substantial spatial discordance of the 18F-FAZA and 125I-Gluco-RGD tumor distribution suggesting that hypoxia and angiogenesis are not necessarily spatially linked in malignancies. These results may prove essential in developing advanced targeted systemic chemotherapeutic approaches (such as combinations of hypoxia-activated cytotoxins and antiangiogenic drugs) for hypoxic tumors. COPYRIGHT

AB - The hypoxia-inducible factor-1α (HIF-1α) activates angiogenesis in response to cellular hypoxia, suggesting a spatial correlation between angiogenesis and tissue hypoxia. Methods: Using digital autoradiography of coinjected 18F-labeled azomycin arabinoside (8F-FAZA) (assessing regional hypoxia) and a glycosylated RGD-containing peptide ( 125I-3-iodo-DTyr4-cyclo(-Arg-Gly-Asp-DTyr-Lys(SAA)-), or 125I-Gluco-RGD) (assessing angiogenesis via binding to αvβ3 integrin receptors on endothelial cells) performed on 22 EMT6 tumor xenografts, we investigated the intratumoral spatial distribution of these tracers. We applied a Bayesian bivariate image analysis using the mean tumor-to-muscle ratio as a discriminator, resulting in 4 groups: FAZA high/RGD high (Q1), FAZA low/RGD high (Q2), FAZA low/RGD low (Q3), and FAZA high/RGD low (Q4). In an additional 18 xenografts, the immunohistochemically derived HIF-1α protein distribution was compared with 18F-FAZA autoradiography. Animals were divided into groups breathing either room air or carbogen (95% oxygen, 5% CO2) for 4 h until sacrifice. Results: Under room air conditions, roughly 60% of the tumor surface displayed a spatial coupling of 18F-FAZA and 125I-Gluco-RGD uptake: either high (Q1) or low (Q3) uptake for both tracers, with Q1 indicating spatial association of hypoxia and angiogenesis and Q3 indicating adequate oxygenation without active angiogenesis. However, the remaining approximately 40% of the tumor surface showed discordant 18F-FAZA and 125I-Gluco-RGD uptake, indicating that hypoxia and angiogenesis are not necessarily spatially linked to each other and highlighting substantial intratumoral heterogeneity of the 18F-FAZA and 125I-Gluco-RGD uptake. Although carbogen breathing conditions significantly decreased the mean 18F-FAZA tumor-to-muscle ratio, no significant changes were observed for 125I-Gluco-RGD, indicating that an acute increase in tumor oxygenation did not influence αvβ3 integrin receptor expression. The HIF-1α-positive (HIFpos) tumor cell fraction was not significantly influenced by breathing conditions and covered between 0% and 35% of the total tumor section surface. However, the HIFpos tumor section surface was much smaller than the tumor section surface of increased 18F-FAZA uptake, suggesting that both markers are identifying distinctly different biologic processes associated with hypoxia. Conclusion: The study revealed a substantial spatial discordance of the 18F-FAZA and 125I-Gluco-RGD tumor distribution suggesting that hypoxia and angiogenesis are not necessarily spatially linked in malignancies. These results may prove essential in developing advanced targeted systemic chemotherapeutic approaches (such as combinations of hypoxia-activated cytotoxins and antiangiogenic drugs) for hypoxic tumors. COPYRIGHT

KW - I-Gluco-RGD

KW - F-FAZA

KW - Angiogenesis

KW - HIF-1α

KW - Tumor hypoxia

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