TY - JOUR
T1 - Activity-Based NIR Bioluminescence Probe Enables Discovery of Diet-Induced Modulation of the Tumor Microenvironment via Nitric Oxide
AU - Yadav, Anuj K.
AU - Lee, Michael C.
AU - Lucero, Melissa Y.
AU - Su, Shengzhang
AU - Reinhardt, Christopher J.
AU - Chan, Jefferson
N1 - A.K.Y. thanks the Department of Chemistry at UIUC for a C.S. Marvel Travel Award. M.C.L. thanks the National Science Foundation for a Graduate Fellowship. M.Y.L. acknowledges the Alfred P. Sloan Foundation and the Seemon Pines Graduate Fellowship for financial support. C.J.R. thanks the Chemistry-Biology Interface Training Grant (T32 GM070421) and the Seemon Pines Graduate Fellowship for support. Major funding for the 500 MHz Bruker CryoProbe was provided by the Roy J. Carver Charitable Trust (Muscatine, Iowa; Grant 15-4521) to the School of Chemical Sciences NMR Lab. The Q-Tof Ultima mass spectrometer was purchased in part with a grant from the National Science Foundation, Division of Biological Infrastructure (DBI-0100085). We also acknowledge Dr. Iwona Dobrucka and the Molecular Imaging Laboratory at the Beckman Institute for use of the IVIS imaging system. We thank Professor Benita Katzenellenbogen (Molecular and Integrative Physiology, UIUC) for providing 4T1-Luc mammary carcinoma cells. We also thank Mr. Joseph Reid McClure of the Division of Animal Resources for administering the research diets and Drs. Nicole Herndon and Jessica Xu for helping to generate the heterotopic lung cancer model. We also acknowledge Karen Frances Doty of the Veterinary Medicine Histology Laboratory for immunohistochemical staining.
This work was supported by the National Institutes of Health (R35GM133581).
PY - 2022/4/27
Y1 - 2022/4/27
N2 - Nitric oxide (NO) plays a critical role in acute and chronic inflammation. NO's contributions to cancer are of particular interest due to its context-dependent bioactivities. For example, immune cells initially produce cytotoxic quantities of NO in response to the nascent tumor. However, it is believed that this fades over time and reaches a concentration that supports the tumor microenvironment (TME). These complex dynamics are further complicated by other factors, such as diet and oxygenation, making it challenging to establish a complete picture of NO's impact on tumor progression. Although many activity-based sensing (ABS) probes for NO have been developed, only a small fraction have been employed in vivo, and fewer yet are practical in cancer models where the NO concentration is <200 nM. To overcome this outstanding challenge, we have developed BL660-NO, the first ABS probe for NIR bioluminescence imaging of NO in cancer. Owing to the low intrinsic background, high sensitivity, and deep tissue imaging capabilities of our design, BL660-NO was successfully employed to visualize endogenous NO in cellular systems, a human liver metastasis model, and a murine breast cancer model. Importantly, its exceptional performance facilitated two dietary studies which examine the impact of fat intake on NO and the TME. BL660-NO provides the first direct molecular evidence that intratumoral NO becomes elevated in mice fed a high-fat diet, which became obese with larger tumors, compared to control animals on a low-fat diet. These results indicate that an inflammatory diet can increase NO production via recruitment of macrophages and overexpression of inducible nitric oxide synthase which in turn can drive tumor progression.
AB - Nitric oxide (NO) plays a critical role in acute and chronic inflammation. NO's contributions to cancer are of particular interest due to its context-dependent bioactivities. For example, immune cells initially produce cytotoxic quantities of NO in response to the nascent tumor. However, it is believed that this fades over time and reaches a concentration that supports the tumor microenvironment (TME). These complex dynamics are further complicated by other factors, such as diet and oxygenation, making it challenging to establish a complete picture of NO's impact on tumor progression. Although many activity-based sensing (ABS) probes for NO have been developed, only a small fraction have been employed in vivo, and fewer yet are practical in cancer models where the NO concentration is <200 nM. To overcome this outstanding challenge, we have developed BL660-NO, the first ABS probe for NIR bioluminescence imaging of NO in cancer. Owing to the low intrinsic background, high sensitivity, and deep tissue imaging capabilities of our design, BL660-NO was successfully employed to visualize endogenous NO in cellular systems, a human liver metastasis model, and a murine breast cancer model. Importantly, its exceptional performance facilitated two dietary studies which examine the impact of fat intake on NO and the TME. BL660-NO provides the first direct molecular evidence that intratumoral NO becomes elevated in mice fed a high-fat diet, which became obese with larger tumors, compared to control animals on a low-fat diet. These results indicate that an inflammatory diet can increase NO production via recruitment of macrophages and overexpression of inducible nitric oxide synthase which in turn can drive tumor progression.
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U2 - 10.1021/acscentsci.1c00317
DO - 10.1021/acscentsci.1c00317
M3 - Article
C2 - 35505872
AN - SCOPUS:85127407943
SN - 2374-7943
VL - 8
SP - 461
EP - 472
JO - ACS Central Science
JF - ACS Central Science
IS - 4
ER -