American Association for Cancer Research
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Figure S7 from Oxygen-Enhanced Optoacoustic Tomography Reveals the Effectiveness of Targeting Heme and Oxidative Phosphorylation at Normalizing Tumor Vascular Oxygenation

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journal contribution
posted on 2023-03-31, 03:24 authored by Poorva Ghosh, Yihang Guo, Adnin Ashrafi, Jingyu Chen, Sanchareeka Dey, Shigen Zhong, Jie Liu, James Campbell, Purna Chaitanya Konduri, Jeni Gerberich, Massoud Garrossian, Ralph P. Mason, Li Zhang, Li Liu

Fig. S7. The effect of HSP2 on oxygenation of subcutaneous NSCLC A549-luc tumor xenografts after 3 weeks of treatment (same tumors as shown in Fig. S1). (A) Representative tumor images of spatial distribution of oxygen saturation [sO2 (O2)] after the oxygen challenge and the amplitude of signal change (Î"sO2) for each treatment group from breathing air to breathing 100% oxygen. The change in sO2 (Î"sO2) is calculated by subtracting the average tumor sO2 while breathing air from the average tumor sO2 while breathing oxygen. The sizes of the shown tumors were: Control: 111 mm3; HSP2: 51.9 mm3. (B & C) Quantification of sO2 (O2) and Î"sO2 for each treatment group. For statistical analysis, the levels in treated tumors were compared to the levels in control tumors with a Welch 2-sample t-test. ***, P < 0.001. Box is between 25th and 75th percentile, line at median.


Cancer Prevention and Research Institute of Texas grants





Multispectral optoacoustic tomography (MSOT) is an emerging noninvasive imaging modality that can detect real-time dynamic information about the tumor microenvironment in humans and animals. Oxygen enhanced (OE)-MSOT can monitor tumor vasculature and oxygenation during disease development or therapy. Here, we used MSOT and OE-MSOT to examine in mice the response of human non–small cell lung cancer (NSCLC) xenografts to a new class of antitumor drugs, heme-targeting agents heme-sequestering peptide 2 (HSP2) and cyclopamine tartrate (CycT). HSP2 inhibits heme uptake, while CycT inhibits heme synthesis in NSCLC cells, where heme is essential for ATP generation via oxidative phosphorylation. HSP2 and CycT can inhibit ATP generation and thereby suppress NSCLC cell tumorigenic functions. MSOT showed that treatment of NSCLC tumors with HSP2 or CycT reduced total hemoglobin, increased oxygen saturation, and enhanced the amplitude of response to oxygen gas breathing challenge. HSP2 and CycT normalized tumor vasculature and improved tumor oxygenation, where levels of several hypoxia markers in NSCLC tumors were reduced by treatment with HSP2 or CycT. Furthermore, treatment with HSP2 or CycT reduced levels of angiogenic factor VEGFA, its receptor VEGFR1, and vascular marker CD34. Together, our data show that heme-targeting drugs HSP2 and CycT elicit multiple tumor-suppressing functions, such as inhibiting angiogenic function, normalizing tumor vasculature, alleviating tumor hypoxia, and inhibiting oxygen consumption and ATP generation. Heme-targeting agents HSP2 and CycT effectively normalize tumor vasculature and alleviate tumor hypoxia, raising the possibility of their combination with chemo-, radio-, and immunotherapies to improve antitumor efficacy.See related commentary by Tomaszewski, p. 3461

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