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Evaluating the Accuracy of FUCCI Cell Cycle In Vivo Fluorescent Imaging to Assess Tumor Proliferation in Preclinical Oncology Models

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Abstract

Purpose

The primary goal of this study is to evaluate the accuracy of the fluorescence ubiquitination cell cycle indicator (FUCCI) system with fluorescence in vivo imaging compared to 3′-deoxy-3′-[18F]fluorothymidine ([18F]-FLT) positron emission tomography (PET)/computed tomography (CT) and biological validation through histology. Imaging with [18F]-FLT PET/CT can be used to noninvasively assess cancer cell proliferation and has been utilized in both preclinical and clinical studies. However, a cost-effective and straightforward method for in vivo, cell cycle targeted cancer drug screening is needed prior to moving towards translational imaging methods such as PET/CT.

Procedures

In this study, fluorescent MDA-MB-231-FUCCI tumor growth was monitored weekly with caliper measurements and fluorescent imaging. Seven weeks post-injection, [18F]-FLT PET/CT was performed with a preclinical PET/CT, and tumors samples were harvested for histological analysis.

Results

RFP fluorescent signal significantly correlated with tumor volume (r = 0.8153, p < 0.0001). Cell proliferation measured by GFP fluorescent imaging was correlated with tumor growth rate (r = 0.6497, p < 0.001). Also, GFP+ cells and [18F]-FLT regions of high uptake were both spatially located in the tumor borders, indicating that the FUCCI-IVIS method may provide an accurate assessment of tumor heterogeneity of cell proliferation. The quantification of total GFP signal was correlated with the sum of tumor [18F]-FLT standard uptake value (SUV) (r = 0.5361, p = 0.0724). Finally, histological analysis confirmed viable cells in the tumor and the correlation of GFP + and Ki67 + cells (r = 0.6368, p = 0.0477).

Conclusion

Fluorescent imaging of the cell cycle provides a noninvasive accurate depiction of tumor progression and response to therapy, which may benefit in vivo testing of novel cancer therapeutics that target the cell cycle.

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Acknowledgements

We acknowledge grant support from the American Cancer Society (RSG-18-006-01-CCE) and National Cancer Institute (R01CA24058) and the O’Neal Comprehensive Cancer Center at UAB’s preclinical shared imaging facility (NIH P30CA013148).

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Authors and Affiliations

  1. Department of Radiology, University of Alabama at Birmingham, Volker Hall G082, 1670 University Boulevard, Birmingham, AL, 35233, USA

    Yun Lu, Adriana V. F. Massicano & Anna G. Sorace

  2. Graduate Biomedical Sciences, University of Alabama at Birmingham, Birmingham, AL, 35233, USA

    Yun Lu & Anna G. Sorace

  3. Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL, 35233, USA

    Carlos A. Gallegos, Katherine A. Heinzman, Sean W. Parish & Anna G. Sorace

  4. O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, 35233, USA

    Jason M. Warram & Anna G. Sorace

  5. Department of Otolaryngology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA

    Jason M. Warram

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Contributions

Conceptualization, A.G.S., J.M.W., and Y.L.; methodology, A.V.F.M.; image analysis, Y.L.; histological staining, Y.L.; histological analysis, C.A.G., K.A.H., and S.W.P.; writing—original draft preparation, Y.L.; writing—review and editing, Y.L., A.V.F.M., C.A.G., K.A.H., S.W.P., J.M.W, and A.G.S.; funding acquisition, A.G.S. All authors have read and agreed to the published version of the manuscript and accountable for all aspects of the work.

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Correspondence to Anna G. Sorace.

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Lu, Y., Massicano, A.V.F., Gallegos, C.A. et al. Evaluating the Accuracy of FUCCI Cell Cycle In Vivo Fluorescent Imaging to Assess Tumor Proliferation in Preclinical Oncology Models. Mol Imaging Biol 24, 898–908 (2022). https://doi.org/10.1007/s11307-022-01739-9

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