Immunohistochemical Evaluation of Cathepsin B, L, and S Expression in Breast Cancer Patients.
Activatable fluorescent imaging agents
Breast cancer
Cysteine cathepsins
Fluorescence-guided surgery
Optical surgical navigation
Target expression
Journal
Molecular imaging and biology
ISSN: 1860-2002
Titre abrégé: Mol Imaging Biol
Pays: United States
ID NLM: 101125610
Informations de publication
Date de publication:
27 Sep 2024
27 Sep 2024
Historique:
received:
01
07
2024
accepted:
16
09
2024
revised:
12
08
2024
medline:
27
9
2024
pubmed:
27
9
2024
entrez:
27
9
2024
Statut:
aheadofprint
Résumé
Cysteine cathepsins are proteases that play a role in normal cellular physiology and neoplastic transformation. Elevated expression and enzymatic activity of cathepsins in breast cancer (BCa) indicates their potential as a target for tumor imaging. In particular cathepsin B (CTSB), L (CTSL), and S (CTSS) are used as targets for near-infrared (NIR) fluorescence imaging (FI), a technique that allows real-time intraoperative tumor visualization and resection margin assessment. Therefore, this immunohistochemical study explores CTSB, CTSL, and CTSS expression levels in a large breast cancer patient cohort, to investigate in which BCa patients the use of cathepsin-targeted NIR FI may have added value. Protein expression was analyzed in tumor tissue microarrays (TMA) of BCa patients using immunohistochemistry and quantified as a total immunostaining score (TIS), ranging from 0-12. In total, the tissues of 557 BCa patients were included in the TMA. CTSB, CTSL, and CTSS were successfully scored in respectively 340, 373 and 252 tumors. All tumors showed CTSB, CTSL, and/or CTSS expression to some extent (TIS > 0). CTSB, CTSL, and CTSS expression was scored as high (TIS > 6) in respectively 28%, 80%, and 18% of tumors. In 89% of the tumors scored for all three cathepsins, the expression level of one or more of these proteases was scored as high (TIS > 6). Tumors showed significantly higher cathepsin expression levels with advancing Bloom-Richardson grade (p < 0.05). Cathepsin expression was highest in estrogen receptor (ER)-negative, human epidermal growth factor receptor 2(HER2)-positive and triple-negative (TN) tumors. There was no significant difference in cathepsin expression between tumors that were treated with neoadjuvant systemic therapy and tumors that were not. The expression of at least one of the cysteine cathepsins B, L and S in all breast tumor tissues tested suggests that cathepsin-activatable imaging agents with broad reactivity for these three proteases will likely be effective in the vast majority of breast cancer patients, regardless of molecular subtype and treatment status. Patients with high grade ER-negative, HER2-positive, or TN tumors might show higher imaging signals.
Identifiants
pubmed: 39331316
doi: 10.1007/s11307-024-01955-5
pii: 10.1007/s11307-024-01955-5
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Foundation for the National Institutes of Health
ID : 5R01CA246678
Informations de copyright
© 2024. The Author(s).
Références
Sung H, Ferlay J, Siegel RL et al (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 71:209–249
doi: 10.3322/caac.21660
pubmed: 33538338
Waks AG, Winer EP (2019) Breast Cancer Treatment: A Review. JAMA 321:288–300
doi: 10.1001/jama.2018.19323
pubmed: 30667505
Houssami N, Macaskill P, Marinovich ML et al (2010) Meta-analysis of the impact of surgical margins on local recurrence in women with early-stage invasive breast cancer treated with breast-conserving therapy. Eur J Cancer 46:3219–3232
doi: 10.1016/j.ejca.2010.07.043
pubmed: 20817513
McCahill LE, Single RM, Aiello Bowles EJ et al (2012) Variability in reexcision following breast conservation surgery. JAMA 307:467–475
doi: 10.1001/jama.2012.43
pubmed: 22298678
Brouwer de Koning SG, Vrancken Peeters M, Jozwiak K, Bhairosing PA, Ruers TJM (2018) Tumor Resection Margin Definitions in Breast-Conserving Surgery: Systematic Review and Meta-analysis of the Current Literature. Clin Breast Cancer 18:e595–e600
doi: 10.1016/j.clbc.2018.04.004
pubmed: 29731404
Bartelink H, Maingon P, Poortmans P et al (2015) Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial. Lancet Oncol 16:47–56
doi: 10.1016/S1470-2045(14)71156-8
pubmed: 25500422
Grant Y, Al-Khudairi R, St John E et al (2019) Patient-level costs in margin re-excision for breast-conserving surgery. Br J Surg 106:384–394
doi: 10.1002/bjs.11050
pubmed: 30566233
Maloney BW, McClatchy DM, Pogue BW, Paulsen KD, Wells WA, Barth RJ (2018) Review of methods for intraoperative margin detection for breast conserving surgery. J Biomed Opt 23:1–19
doi: 10.1117/1.JBO.23.10.100901
pubmed: 30369108
Vahrmeijer AL, Hutteman M, van der Vorst JR, van de Velde CJ, Frangioni JV (2013) Image-guided cancer surgery using near-infrared fluorescence. Nat Rev Clin Oncol 10:507–518
doi: 10.1038/nrclinonc.2013.123
pubmed: 23881033
pmcid: 3755013
Hernot S, van Manen L, Debie P, Mieog JSD, Vahrmeijer AL (2019) Latest developments in molecular tracers for fluorescence image-guided cancer surgery. Lancet Oncol 20:e354–e367
doi: 10.1016/S1470-2045(19)30317-1
pubmed: 31267970
Linders DGJ, Bijlstra OD, Fallert LC et al (2023) Cysteine Cathepsins in Breast Cancer: Promising Targets for Fluorescence-Guided Surgery. Mol Imaging Biol 25:58–73
doi: 10.1007/s11307-022-01768-4
pubmed: 36002710
U.S. Food & Drug Administration (2024) FDA approves imaging drug to assist in detection of cancerous tissue following lumpectomy. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-imaging-drug-assist-detection-cancerous-tissue-following-lumpectomy . Accessed June 2024
Smith BL, Hunt KK, Carr D, et al. (2023) Intraoperative fluorescence guidance for breast cancer lumpectomy surgery. NEJM Evidence 2:EVIDoa2200333
Mohamed MM, Sloane BF (2006) Cysteine cathepsins: multifunctional enzymes in cancer. Nat Rev Cancer 6:764–775
doi: 10.1038/nrc1949
pubmed: 16990854
Sun T, Jiang D, Zhang L, Su Q, Mao W, Jiang C (2016) Expression profile of cathepsins indicates the potential of cathepsins B and D as prognostic factors in breast cancer patients. Oncol Lett 11:575–583
doi: 10.3892/ol.2015.3960
pubmed: 26870250
Thomssen C, Schmitt M, Goretzki L et al (1995) Prognostic value of the cysteine proteases cathepsins B and cathepsin L in human breast cancer. Clin Cancer Res 1:741–746
pubmed: 9816040
Lah TT, Kokalj-Kunovar M, Strukelj B et al (1992) Stefins and lysosomal cathepsins B, L and D in human breast carcinoma. Int J Cancer 50:36–44
doi: 10.1002/ijc.2910500109
pubmed: 1728611
Smith BL, Gadd MA, Lanahan CR et al (2018) Real-time, intraoperative detection of residual breast cancer in lumpectomy cavity walls using a novel cathepsin-activated fluorescent imaging system. Breast Cancer Res Treat 171:413–420
doi: 10.1007/s10549-018-4845-4
pubmed: 29948401
pmcid: 6193492
Whitley MJ, Cardona DM, Lazarides AL, et al. (2016) A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer. Sci Transl Med 8:320ra324
Lah TT, Kalman E, Najjar D et al (2000) Cells producing cathepsins D, B, and L in human breast carcinoma and their association with prognosis. Hum Pathol 31:149–160
doi: 10.1016/S0046-8177(00)80214-2
pubmed: 10685628
Lah TT, Cercek M, Blejec A et al (2000) Cathepsin B, a prognostic indicator in lymph node-negative breast carcinoma patients: comparison with cathepsin D, cathepsin L, and other clinical indicators. Clin Cancer Res 6:578–584
pubmed: 10690542
Chen B, Platt MO (2011) Multiplex zymography captures stage-specific activity profiles of cathepsins K, L, and S in human breast, lung, and cervical cancer. J Transl Med 9:109
doi: 10.1186/1479-5876-9-109
pubmed: 21756348
pmcid: 3146840
Wilkinson RDA, Burden RE, McDowell SH et al (2019) A Novel Role for Cathepsin S as a Potential Biomarker in Triple Negative Breast Cancer. J Oncol 2019:3980273
doi: 10.1155/2019/3980273
pubmed: 31346333
pmcid: 6620839
Blok EJ, van den Bulk J, Dekker-Ensink NG et al (2017) Combined evaluation of the FAS cell surface death receptor and CD8+ tumor infiltrating lymphocytes as a prognostic biomarker in breast cancer. Oncotarget 8:15610–15620
doi: 10.18632/oncotarget.14779
pubmed: 28121628
pmcid: 5362509
Bremer C, Tung CH, Bogdanov A Jr, Weissleder R (2002) Imaging of differential protease expression in breast cancers for detection of aggressive tumor phenotypes. Radiology 222:814–818
doi: 10.1148/radiol.2223010812
pubmed: 11867806
Zajc I, Sever N, Bervar A, Lah TT (2002) Expression of cysteine peptidase cathepsin L and its inhibitors stefins A and B in relation to tumorigenicity of breast cancer cell lines. Cancer Lett 187:185–190
doi: 10.1016/S0304-3835(02)00452-4
pubmed: 12359367
Zajc I, Frangež L, Lah T (2003) Expression of cathepsin B is related to tumorigenicity of breast cancer cell lines. Radiology and Oncology 37:233–240+270
Mougalian SS, Soulos PR, Killelea BK et al (2015) Use of neoadjuvant chemotherapy for patients with stage I to III breast cancer in the United States. Cancer 121:2544–2552
doi: 10.1002/cncr.29348
pubmed: 25902916
Killelea BK, Yang VQ, Mougalian S et al (2015) Neoadjuvant chemotherapy for breast cancer increases the rate of breast conservation: results from the National Cancer Database. J Am Coll Surg 220:1063–1069
doi: 10.1016/j.jamcollsurg.2015.02.011
pubmed: 25868410
Russnes HG, Navin N, Hicks J, Borresen-Dale AL (2011) Insight into the heterogeneity of breast cancer through next-generation sequencing. J Clin Invest 121:3810–3818
doi: 10.1172/JCI57088
pubmed: 21965338
pmcid: 3195464
Moore KM, Thomas GJ, Duffy SW, et al. (2014) Therapeutic targeting of integrin alphavbeta6 in breast cancer. J Natl Cancer Inst 106
Boogerd LS, Boonstra MC, Beck AJ et al (2016) Concordance of folate receptor-alpha expression between biopsy, primary tumor and metastasis in breast cancer and lung cancer patients. Oncotarget 7:17442–17454
doi: 10.18632/oncotarget.7856
pubmed: 26943581
pmcid: 4951224
Liu Y, Tamimi RM, Collins LC et al (2011) The association between vascular endothelial growth factor expression in invasive breast cancer and survival varies with intrinsic subtypes and use of adjuvant systemic therapy: results from the Nurses’ Health Study. Breast Cancer Res Treat 129:175–184
doi: 10.1007/s10549-011-1432-3
pubmed: 21390493
pmcid: 3640508
Yadati T, Houben T, Bitorina A, Shiri-Sverdlov R (2020) The Ins and Outs of Cathepsins: Physiological Function and Role in Disease Management. Cells9
Olson OC, Joyce JA (2015) Cysteine cathepsin proteases: regulators of cancer progression and therapeutic response. Nat Rev Cancer 15:712–729
doi: 10.1038/nrc4027
pubmed: 26597527
Mieog JSD, Achterberg FB, Zlitni A et al (2022) Fundamentals and developments in fluorescence-guided cancer surgery. Nat Rev Clin Oncol 19:9–22
doi: 10.1038/s41571-021-00548-3
pubmed: 34493858