Tumor radiation response enhancement by acoustical stimulation of the vasculature

Czarnota, Gregory J.; Karshafian, Raffi; Burns, Peter N.; Wong, Shun; Mahrouki, Azza Al; Lee, Justin W.; Caissie, Amanda; Tran, William T.; Kim, Christina; Furukawa, M.; Wong, Emily Y.; Giles, Anoja

doi:10.1073/pnas.1200053109

Cited by 169 publications

(346 citation statements)

References 30 publications

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“…Following these mechanical changes, a range of biological effects on surrounding cells can be induced at physiological and tissue levels due to released energy. These biological effects include gene expression changes, as well as cell death and vascular shutdown [5,33]. Consistently, slightly increased vascular shutdown and tumor cell death were observed after USMB treatment in this study.…”

Section: Discussionsupporting

confidence: 72%

“…It has been shown that the growth of colon cancer in mice was effectively inhibited by USMBs, which was achieved by blood vessel disruption and tumor tissue damage [23]. Based on the susceptibility of endothelial cells to microbubbles, it was confirmed that USMBs can significantly enhance the radiosensitivity of a variety of tumors, such prostate, bladder, and breast cancers [5,24,25].…”

Section: Introductionmentioning

confidence: 74%

“…As blood vessels are critical for tumors, angiogenesis is promoted during tumor progression to ensure an abundant blood supply. Growing evidence indicates that death of the tumor-feeding vasculature is an important contributor to tumor killing and a primary determinant of overall response to radiotherapy [5,6]. However, radiotherapy often fails in NPC, especially for advanced-stage tumors [7], because resistance can be developed by tumors after radiotherapy.…”

Section: Introductionmentioning

confidence: 99%

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Ultrasound-Stimulated Microbubbles Enhance Radiosensitization of Nasopharyngeal Carcinoma

Deng

Cai

Feng

et al. 2018

Cell Physiol Biochem

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Background/Aims: Recent studies indicate that therapies targeting the vasculature can significantly sensitize tumors to radiation. Ultrasound-stimulated microbubbles (USMBs) are regarded as a promising radiosensitizer. In this study, we investigated the effect of USMBs on the sensitivity of nasopharyngeal carcinoma (NPC) to radiation. Methods: Human NPC (CNE-2) cells and human umbilical vein endothelial cells (HUVECs) were exposed to radiation (0, 2, and 8 Gy) alone or in combination with USMBs. Cell viability and apoptosis were measured with the MTT assay and flow cytometry, respectively. The angiogenic activity of HUVECs was detected using matrigel tubule formation. The in vitro effects induced by these treatments were confirmed in vivo with xenograft models of CNE-2 cells in nude mice by examining vascular integrity using color Doppler flow imaging and cell survival using immunohistochemistry. Additionally, the in vivo and in vitro expressions of angiotensin II (ANG II) and its receptor (AT1R) were detected by immunohistochemistry and western blotting, respectively. With CNE-2 cells and HUVECs transfected with control, ANG II, or AT1R, perindopril (an inhibitor of angiotensin-converting enzyme) and candesartan (an inhibitor of AT1R) were used to verify the role of ANG II and AT1R in the radiosensitivity of tumor and endothelial cells by USMBs, by determining cell viability and apoptosis and angiogenic activity. Results: In the NPC xenografts, USMBs slightly reduced blood flow and CD34 expression, increased tumor cell death and ANG II and AT1R expression, and significantly enhanced the effects of radiation. With CNE-2 cells and HUVECs, the USMBs further enhanced the inhibition of tumor cell viability and endothelial tubule formation and further enhanced the increase in ANG II and AT1R due to radiation. Furthermore, perindopril and candesartan significantly enhanced the inhibitory effect of radiation and USMBs on tumor cell growth and angiogenesis in vitro. Conclusions: We have demonstrated for the first time that USMB exposure can significantly enhance the destructive effect on NPC of radiation, and this effect might be further increased by ANG II and AT1R inhibition. Our findings suggest that USMBs can be used as a promising sensitizer of radiotherapy to treat NPC, and the clinical effect might be increased by ANG II and AT1R inhibition.

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Section: Discussionsupporting

confidence: 72%

Section: Introductionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

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Ultrasound-Stimulated Microbubbles Enhance Radiosensitization of Nasopharyngeal Carcinoma

Deng

Cai

Feng

et al. 2018

Cell Physiol Biochem

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“…Many studies have proved that low-frequency US combined with microbubbles could induce obvious microvessel damage in tumors mainly due to inertial cavitation, which can cause cell necrosis, apoptosis, and enhanced responses to radiation therapy. 18,19,22,29,30 However, these studies used a wide range of US parameters and radiation times. In this study, we evaluated the effect of LFUM on interrupting bleeding under the same conditions and with different radiation times.…”

Section: Discussionmentioning

confidence: 99%

Effect of low-frequency low-intensity ultrasound with microbubbles on prostate cancer hypoxia

Hou

et al. 2017

Tumour Biol.

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Angiogenesis plays an important role in tumor growth, invasiveness, and metastasis. It is well established that prostate cancer is exposed to fluctuating oxygen tensions and both acute and chronic hypoxia exist, and these conditions can upregulate angiogenesis-associated proteins such as hypoxia-inducible factor 1 alpha and vascular endothelial growth factor A. Low-frequency low-intensity ultrasound with microbubbles can induce obvious microvessel damage in tumors, cause cell necrosis or apoptosis. However, there is no information about whether the blocking blood effect of lowfrequency low-intensity ultrasound with microbubbles has an influence on hypoxia environment of prostate cancer. Therefore, we investigated the impact of different low-frequency low-intensity ultrasound with microbubbles radiation times on prostate tumors, observed the change in the hypoxia-inducible factor 1 alpha and vascular endothelial growth factor A protein levels, as well as cell proliferation, apoptosis, and tumor volume. The results indicated that as the radiation was repeated four times on each treatment day, the effects of interruption were durable, the cell proliferation was inhibited, and apoptosis was promoted, and the hypoxia-inducible factor 1 alpha and vascular endothelial growth factor A expression levels were lower in the treatment group than in the control group. When the radiation was carried out once per treatment day, the hypoxia response was stimulated, the hypoxia-inducible factor 1 alpha and vascular endothelial growth factor A expression levels were higher compared with the control group, and cell proliferation was promoted. In addition, the tumor volume increased obviously in the hypoxia-stimulated group, whereas tumors grew slowly in the hypoxia-suppressed group. The results of this work demonstrated that under the same conditions, different radiation times of low-frequency low-intensity ultrasound with microbubbles affect the hypoxia response differently, and the effect at least partly stimulates or inhibits tumor growth. KeywordsLow-frequency low-intensity ultrasound, prostate cancer, acute hypoxia, hypoxia-inducible factor 1 alpha, angiogenesis Date

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“…Molecular imaging has been shown to detect changes in angiogenic and inflammation endothelial biomarkers, such as vascular endothelial growth factor and P-selectin, that may predict response to therapy [16,24,25]. Perfusion imaging techniques, such as power Doppler and destruction reperfusion, have also demonstrated that tumor blood flow changes caused by RT by itself or in combination with adjuvant chemotherapy can be detected within days after treatment [18,[26][27][28][29].…”

Section: Introductionmentioning

confidence: 99%

Early Assessment of Tumor Response to Radiation Therapy Using High-Resolution Quantitative Microvascular Ultrasound Imaging

Chang

Kasoji

Rivera

et al. 2017

International Journal of Radiation Oncology*Biology*Physics

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Measuring changes in tumor volume using anatomical imaging weeks to months post radiation therapy (RT) is currently the clinical standard for indicating treatment response to RT. For patients whose tumors do not respond successfully to treatment, this approach is suboptimal as timely modification of the treatment approach may lead to better clinical outcomes. We propose to use tumor microvasculature as a biomarker for early assessment of tumor response to RT. Acoustic angiography is a novel contrast ultrasound imaging technique that enables high-resolution microvascular imaging and has been shown to detect changes in microvascular structure due to cancer growth. Data suggest that acoustic angiography can detect longitudinal changes in the tumor microvascular environment that correlate with RT response. Methods: Three cohorts of Fisher 344 rats were implanted with rat fibrosarcoma tumors and were treated with a single fraction of RT at three dose levels (15 Gy, 20 Gy, and 25 Gy) at a dose rate of 300 MU/min. A simple treatment condition was chosen for testing the feasibility of our imaging technique. All tumors were longitudinally imaged immediately prior to and after treatment and then every 3 days after treatment for a total of 30 days. Both acoustic angiography (using in-house produced microbubble contrast agents) and standard b-mode imaging was performed at each imaging time point using a pre-clinical Vevo770 scanner and a custom modified dual-frequency transducer. Results: Results show that all treated tumors in each dose group initially responded to treatment between days 3-15 as indicated by decreased tumor growth accompanied with decreased vascular density. Untreated tumors continued to increase in both volume and vascular density until they reached the maximum allowable size of 2 cm in diameter. Tumors that displayed complete control (no tumor recurrence) continued to decrease in size and vascular density, while tumors that progressed after the initial response presented an increase in tumor volume and volumetric vascular density. The increase in tumor volumetric vascular density in recurring tumors can be detected 10.25 ± 1.5 days, 6 ± 0 days, and 4 ± 1.4 days earlier than the measurable increase in tumor volume in the 15, 20, and 25 Gy dose groups, respectively. A dose-dependent growth rate for tumor recurrence was also observed. Conclusions: In this feasibility study we have demonstrated the ability of acoustic angiography to detect longitudinal changes in vascular density, which was shown to be a potential biomarker for tumor response to RT.

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Tumor radiation response enhancement by acoustical stimulation of the vasculature

Cited by 169 publications

References 30 publications

Ultrasound-Stimulated Microbubbles Enhance Radiosensitization of Nasopharyngeal Carcinoma

Ultrasound-Stimulated Microbubbles Enhance Radiosensitization of Nasopharyngeal Carcinoma

Effect of low-frequency low-intensity ultrasound with microbubbles on prostate cancer hypoxia

Early Assessment of Tumor Response to Radiation Therapy Using High-Resolution Quantitative Microvascular Ultrasound Imaging

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