Cysteine Cathepsins in Breast Cancer: Promising Targets for Fluorescence-Guided Surgery

Daan Linders*, Okker D Bijlstra, Laura Fallert, Denise Hilling, Ethan Walker, Brian Straight, Taryn March, Rob Valentijn, Martin Pool, Jacobus Burggraaf, James Basilion, Alexander Vahrmeijer, Peter J.K. Kuppen

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Scopus)


The majority of breast cancer patients is treated with breast-conserving surgery (BCS) combined with adjuvant radiation therapy. Up to 40% of patients has a tumor-positive resection margin after BCS, which necessitates re-resection or additional boost radiation. Cathepsin-targeted near-infrared fluorescence imaging during BCS could be used to detect residual cancer in the surgical cavity and guide additional resection, thereby preventing tumor-positive resection margins and associated mutilating treatments. The cysteine cathepsins are a family of proteases that play a major role in normal cellular physiology and neoplastic transformation. In breast cancer, the increased enzymatic activity and aberrant localization of many of the cysteine cathepsins drive tumor progression, proliferation, invasion, and metastasis. The upregulation of cysteine cathepsins in breast cancer cells indicates their potential as a target for intraoperative fluorescence imaging. This review provides a summary of the current knowledge on the role and expression of the most important cysteine cathepsins in breast cancer to better understand their potential as a target for fluorescence-guided surgery (FGS). In addition, it gives an overview of the cathepsin-targeted fluorescent probes that have been investigated preclinically and in breast cancer patients. The current review underscores that cysteine cathepsins are highly suitable molecular targets for FGS because of favorable expression and activity patterns in virtually all breast cancer subtypes. This is confirmed by cathepsin-targeted fluorescent probes that have been shown to facilitate in vivo breast cancer visualization and tumor resection in mouse models and breast cancer patients. These findings indicate that cathepsin-targeted FGS has potential to improve treatment outcomes in breast cancer patients.

Original languageEnglish
Pages (from-to)58-73
Number of pages16
JournalMolecular Imaging and Biology
Issue number1
Publication statusPublished - Feb 2023
Externally publishedYes

Bibliographical note

Funding Information:
This research was funded by The National Institutes of Health (NIH), grant number 5R01CA246678.

Publisher Copyright:
© 2022, The Author(s).


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