From Localized Mild Hyperthermia to Improved Tumor Oxygenation: Physiological Mechanisms Critically Involved in Oncologic Thermo-Radio-Immunotherapy
(1) Background: Mild hyperthermia (mHT, 39–42 °C) is a potent cancer treatment modality when delivered in conjunction with radiotherapy. mHT triggers a series of therapeutically relevant biological mechanisms, e.g., it can act as a radiosensitizer by improving tumor oxygenation, the latter generally...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-02-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/15/5/1394 |
| _version_ | 1797615674394148864 |
|---|---|
| author | Peter Vaupel Helmut Piazena Markus Notter Andreas R. Thomsen Anca-L. Grosu Felix Scholkmann Alan Graham Pockley Gabriele Multhoff |
| author_facet | Peter Vaupel Helmut Piazena Markus Notter Andreas R. Thomsen Anca-L. Grosu Felix Scholkmann Alan Graham Pockley Gabriele Multhoff |
| author_sort | Peter Vaupel |
| collection | DOAJ |
| description | (1) Background: Mild hyperthermia (mHT, 39–42 °C) is a potent cancer treatment modality when delivered in conjunction with radiotherapy. mHT triggers a series of therapeutically relevant biological mechanisms, e.g., it can act as a radiosensitizer by improving tumor oxygenation, the latter generally believed to be the commensurate result of increased blood flow, and it can positively modulate protective anticancer immune responses. However, the extent and kinetics of tumor blood flow (TBF) changes and tumor oxygenation are variable during and after the application of mHT. The interpretation of these spatiotemporal heterogeneities is currently not yet fully clarified. (2) Aim and methods: We have undertaken a systematic literature review and herein provide a comprehensive insight into the potential impact of mHT on the clinical benefits of therapeutic modalities such as radio- and immuno-therapy. (3) Results: mHT-induced increases in TBF are multifactorial and differ both spatially and with time. In the <i>short term</i>, changes are preferentially caused by vasodilation of co-opted vessels and of upstream normal tissue vessels as well as by improved hemorheology. <i>Sustained</i> TBF increases are thought to result from a drastic reduction of interstitial pressure, thus restoring adequate perfusion pressures and/or HIF-1α- and VEGF-mediated activation of angiogenesis. The enhanced oxygenation is not only the result of mHT-increased TBF and, thus, oxygen availability but also of heat-induced higher O<sub>2</sub> diffusivities, acidosis- and heat-related enhanced O<sub>2</sub> unloading from red blood cells. (4) Conclusions: Enhancement of tumor oxygenation achieved by mHT cannot be fully explained by TBF changes alone. Instead, a series of additional, complexly linked physiological mechanisms are crucial for enhancing tumor oxygenation, almost doubling the initial O<sub>2</sub> tensions in tumors. |
| first_indexed | 2024-03-11T07:30:03Z |
| format | Article |
| id | doaj.art-b08540027c654952b7a8e662b166872d |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T07:30:03Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-b08540027c654952b7a8e662b166872d2023-11-17T07:23:35ZengMDPI AGCancers2072-66942023-02-01155139410.3390/cancers15051394From Localized Mild Hyperthermia to Improved Tumor Oxygenation: Physiological Mechanisms Critically Involved in Oncologic Thermo-Radio-ImmunotherapyPeter Vaupel0Helmut Piazena1Markus Notter2Andreas R. Thomsen3Anca-L. Grosu4Felix Scholkmann5Alan Graham Pockley6Gabriele Multhoff7Department of Radiation Oncology, University Medical Center, University of Freiburg, 79106 Freiburg, GermanyDepartment of Anaesthesiology and Intensive Care Medicine, Charité-University Medicine, Cooperative Member of Freie Universität Berlin and Humboldt Universität zu Berlin, 10117 Berlin, GermanyDepartment of Radiation Oncology, Lindenhofspital Bern, 3012 Bern, SwitzerlandDepartment of Radiation Oncology, University Medical Center, University of Freiburg, 79106 Freiburg, GermanyDepartment of Radiation Oncology, University Medical Center, University of Freiburg, 79106 Freiburg, GermanyBiomedical Optics Research Laboratory, Department of Neonatology, University Hospital Zurich, University of Zurich, 8091 Zurich, SwitzerlandJohn van Geest Cancer Research Centre, Nottingham Trent University, Nottingham NG11 8NS, UKTranslaTUM—Central Institute for Translational Cancer Research, Technische Universität München (TUM), 81675 Munich, Germany(1) Background: Mild hyperthermia (mHT, 39–42 °C) is a potent cancer treatment modality when delivered in conjunction with radiotherapy. mHT triggers a series of therapeutically relevant biological mechanisms, e.g., it can act as a radiosensitizer by improving tumor oxygenation, the latter generally believed to be the commensurate result of increased blood flow, and it can positively modulate protective anticancer immune responses. However, the extent and kinetics of tumor blood flow (TBF) changes and tumor oxygenation are variable during and after the application of mHT. The interpretation of these spatiotemporal heterogeneities is currently not yet fully clarified. (2) Aim and methods: We have undertaken a systematic literature review and herein provide a comprehensive insight into the potential impact of mHT on the clinical benefits of therapeutic modalities such as radio- and immuno-therapy. (3) Results: mHT-induced increases in TBF are multifactorial and differ both spatially and with time. In the <i>short term</i>, changes are preferentially caused by vasodilation of co-opted vessels and of upstream normal tissue vessels as well as by improved hemorheology. <i>Sustained</i> TBF increases are thought to result from a drastic reduction of interstitial pressure, thus restoring adequate perfusion pressures and/or HIF-1α- and VEGF-mediated activation of angiogenesis. The enhanced oxygenation is not only the result of mHT-increased TBF and, thus, oxygen availability but also of heat-induced higher O<sub>2</sub> diffusivities, acidosis- and heat-related enhanced O<sub>2</sub> unloading from red blood cells. (4) Conclusions: Enhancement of tumor oxygenation achieved by mHT cannot be fully explained by TBF changes alone. Instead, a series of additional, complexly linked physiological mechanisms are crucial for enhancing tumor oxygenation, almost doubling the initial O<sub>2</sub> tensions in tumors.https://www.mdpi.com/2072-6694/15/5/1394radio-oncologymild hyperthermiaimmuno-oncologyenhanced tumor blood flowimproved tumor oxygenationphysiological responses |
| spellingShingle | Peter Vaupel Helmut Piazena Markus Notter Andreas R. Thomsen Anca-L. Grosu Felix Scholkmann Alan Graham Pockley Gabriele Multhoff From Localized Mild Hyperthermia to Improved Tumor Oxygenation: Physiological Mechanisms Critically Involved in Oncologic Thermo-Radio-Immunotherapy Cancers radio-oncology mild hyperthermia immuno-oncology enhanced tumor blood flow improved tumor oxygenation physiological responses |
| title | From Localized Mild Hyperthermia to Improved Tumor Oxygenation: Physiological Mechanisms Critically Involved in Oncologic Thermo-Radio-Immunotherapy |
| title_full | From Localized Mild Hyperthermia to Improved Tumor Oxygenation: Physiological Mechanisms Critically Involved in Oncologic Thermo-Radio-Immunotherapy |
| title_fullStr | From Localized Mild Hyperthermia to Improved Tumor Oxygenation: Physiological Mechanisms Critically Involved in Oncologic Thermo-Radio-Immunotherapy |
| title_full_unstemmed | From Localized Mild Hyperthermia to Improved Tumor Oxygenation: Physiological Mechanisms Critically Involved in Oncologic Thermo-Radio-Immunotherapy |
| title_short | From Localized Mild Hyperthermia to Improved Tumor Oxygenation: Physiological Mechanisms Critically Involved in Oncologic Thermo-Radio-Immunotherapy |
| title_sort | from localized mild hyperthermia to improved tumor oxygenation physiological mechanisms critically involved in oncologic thermo radio immunotherapy |
| topic | radio-oncology mild hyperthermia immuno-oncology enhanced tumor blood flow improved tumor oxygenation physiological responses |
| url | https://www.mdpi.com/2072-6694/15/5/1394 |
| work_keys_str_mv | AT petervaupel fromlocalizedmildhyperthermiatoimprovedtumoroxygenationphysiologicalmechanismscriticallyinvolvedinoncologicthermoradioimmunotherapy AT helmutpiazena fromlocalizedmildhyperthermiatoimprovedtumoroxygenationphysiologicalmechanismscriticallyinvolvedinoncologicthermoradioimmunotherapy AT markusnotter fromlocalizedmildhyperthermiatoimprovedtumoroxygenationphysiologicalmechanismscriticallyinvolvedinoncologicthermoradioimmunotherapy AT andreasrthomsen fromlocalizedmildhyperthermiatoimprovedtumoroxygenationphysiologicalmechanismscriticallyinvolvedinoncologicthermoradioimmunotherapy AT ancalgrosu fromlocalizedmildhyperthermiatoimprovedtumoroxygenationphysiologicalmechanismscriticallyinvolvedinoncologicthermoradioimmunotherapy AT felixscholkmann fromlocalizedmildhyperthermiatoimprovedtumoroxygenationphysiologicalmechanismscriticallyinvolvedinoncologicthermoradioimmunotherapy AT alangrahampockley fromlocalizedmildhyperthermiatoimprovedtumoroxygenationphysiologicalmechanismscriticallyinvolvedinoncologicthermoradioimmunotherapy AT gabrielemulthoff fromlocalizedmildhyperthermiatoimprovedtumoroxygenationphysiologicalmechanismscriticallyinvolvedinoncologicthermoradioimmunotherapy |