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Open Access 01-12-2024 | Bevacizumab | Research

High serum proteinase-3 levels predict poor progression-free survival and lower efficacy of bevacizumab in metastatic colorectal cancer

Authors: Kei Furuya, Masao Nakajima, Ryouichi Tsunedomi, Yuki Nakagami, Ming Xu, Hiroto Matsui, Yukio Tokumitsu, Yoshitaro Shindo, Yusaku Watanabe, Shinobu Tomochika, Noriko Maeda, Michihisa Iida, Nobuaki Suzuki, Shigeru Takeda, Shoichi Hazama, Tatsuya Ioka, Yoshinobu Hoshii, Tomio Ueno, Hiroaki Nagano

Published in: BMC Cancer | Issue 1/2024

Abstract

Background

To improve the prognosis of patients with metastatic colorectal cancer (mCRC), investigating predictive biomarkers of their prognosis and chemotherapeutic responsiveness is necessary. This study aimed to analyze the clinical significance of serum proteinase-3 (PRTN3) as a predictor for prognosis and chemosensitivity, especially to bevacizumab therapy, in mCRC.

Methods

This single-center retrospective observational study enrolled 79 patients with mCRC in our hospital and 353 patients with colorectal cancer in the TCGA database. Preoperative serum PRTN3 levels were measured using an enzyme-linked immunosorbent assay. The clinicopathological characteristics and prognosis according to serum PRTN3 levels were then evaluated. PRTN3 expression in tumor and stromal cells was evaluated immunohistochemically. The impact of PRTN3 levels on angiogenesis and bevacizumab sensitivity was evaluated using the tube formation assay.

Results

Serum PRTN3 levels were an independent poor prognostic factor for progression-free survival (PFS) (hazard ratio, 2.082; 95% confidence interval, 1.118-3.647; P=0.010) in patients with mCRC. Similarly, prognostic analysis with TCGA data sets showed poorer overall survival in patients with PRTN3 expression than that in patients without PRTN3 expression, especially in patients with stage IV. Immunohistochemical analysis of resected specimens revealed that stromal neutrophils expressed PRTN3, and their expression level was significantly correlated with serum PRTN3 levels. Interestingly, the effectiveness of first-line chemotherapy was significantly poorer in the high serum PRTN3 level group. High serum PRTN3 was significantly associated with poor PFS (hazard ratio, 3.027; 95% confidence interval, 1.175–7.793; P=0.0161) in patients treated with bevacizumab, an anti-angiogenic inhibitor. The tube formation assay revealed that PRTN3 administration notably augmented angiogenesis while simultaneously attenuating the anti-angiogenic influence exerted by bevacizumab therapy.

Conclusions

Serum PRTN3 levels could be a novel predictive biomarker of PFS of first-line chemotherapy, especially for bevacizumab therapy, in patients with mCRC

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World Health Organization. Colorectal cancer. https://www.who.int/news-room/fact-sheets/detail/colorectal-cancer. Accessed 13 Dec 2023.

Yoshino T, Arnold D, Taniguchi H, Pentheroudakis G, Yamazaki K, Xu RH, et al. Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer: a JSMO-ESMO initiative endorsed by CSCO, KACO, MOS SSO and TOS. Ann Oncol. 2018;29:44–70. https://doi.org/10.1093/annonc/mdx738.CrossRefPubMed

Margonis GA, Vauthey JN. Precision surgery for colorectal liver metastases: Current knowledge and future perspectives. Ann Gastroenterol Surg. 2022;6:606–15. https://doi.org/10.1002/ags3.12591.CrossRefPubMedPubMedCentral

Ogawa H, Yajima T, Sohda M, Shirabe K, Saeki H. Role of surgical resection and its alternative local therapy for pulmonary metastasis of colorectal cancer. Ann Gastroenterol Surg. 2021;5:747–53. https://doi.org/10.1002/ags3.12472.CrossRefPubMedPubMedCentral

Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: Beyond discovery and development. Cell. 2019;176:1248–64. https://doi.org/10.1016/j.cell.2019.01.021.CrossRefPubMedPubMedCentral

Greiner J, Schmitt M, Li L, Giannopoulos K, Bosch K, Schmitt A, et al. Expression of tumor-associated antigens in acute myeloid leukemia: Implications for specific immunotherapeutic approaches. Blood. 2006;108:4109–17. https://doi.org/10.1182/blood-2006-01-023127.CrossRefPubMed

Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307:58–62. https://doi.org/10.1126/science.1104819.ADSCrossRefPubMed

Saltz L, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2023;41:3663–9. https://doi.org/10.1200/JCO.22.02760.CrossRefPubMed

Lin PS, Semrad TJ. Molecular testing for the treatment of advanced colorectal cancer: an overview. Methods Mol Biol. 2018;1765:281–97. https://doi.org/10.1007/978-1-4939-7765-9_18.CrossRefPubMed

10.

Huang M, Lin Y, Wang C, Deng L, Chen M, Assaraf YG, et al. New insights into antiangiogenic therapy resistance in cancer: Mechanisms and therapeutic aspects. Drug Resist Updat. 2022;64:100849. https://doi.org/10.1016/j.drup.2022.100849.CrossRefPubMed

11.

Kitahara M, Hazama S, Tsunedomi R, Takenouchi H, Kanekiyo S, Inoue Y, et al. Prediction of the efficacy of immunotherapy by measuring the integrity of cell-free DNA in plasma in colorectal cancer. Cancer Sci. 2016;107:1825–9. https://doi.org/10.1111/cas.13085.CrossRefPubMedPubMedCentral

12.

Hazama S, Tamada K, Yamaguchi Y, Kawakami Y, Nagano H. Current status of immunotherapy against gastrointestinal cancers and its biomarkers: Perspective for precision immunotherapy. Ann Gastroenterol Surg. 2018;2:289–303. https://doi.org/10.1002/ags3.12180.CrossRefPubMedPubMedCentral

13.

Kono K. Advances in cancer immunotherapy for gastroenterological malignancy. Ann Gastroenterol Surg. 2018;2:244–5. https://doi.org/10.1002/ags3.12184.CrossRefPubMedPubMedCentral

14.

Kijima T, Hazama S, Tsunedomi R, Tanaka H, Takenouchi H, Kanekiyo S, et al. MicroRNA-6826 and −6875 in plasma are valuable non-invasive biomarkers that predict the efficacy of vaccine treatment against metastatic colorectal cancer. Oncol Rep. 2017;37:23–30. https://doi.org/10.3892/or.2016.5267.CrossRefPubMed

15.

Nakashima-Nakasuga C, Hazama S, Suzuki N, Nakagami Y, Xu M, Yoshida S, et al. Serum LOX-1 is a novel prognostic biomarker of colorectal cancer. Int J Clin Oncol. 2020;25:1308–17. https://doi.org/10.1007/s10147-020-01673-2.CrossRefPubMed

16.

Yamada K, Hazama S, Suzuki N, Xu M, Nakagami Y, Fujiwara N, et al. Siglec-7 is a predictive biomarker for the efficacy of cancer vaccination against metastatic colorectal cancer. Oncol Lett. 2021;21:10. https://doi.org/10.3892/ol.2020.12271.CrossRefPubMed

17.

Chidimatsu H, Tsunedomi R, Nakagami Y, Xu M, Nakajima M, Nakashima-Nakasuga C, et al. Serum CCL7 is a novel prognostic biomarker of metastatic colorectal cancer. Anticancer Res. 2023;43:105–14. https://doi.org/10.21873/anticanres.16139.CrossRefPubMed

18.

Campanelli D, Detmers PA, Nathan CF, Gabay JE. Azurocidin and a homologous serine protease from neutrophils. Differential antimicrobial and proteolytic properties. J Clin Invest. 1990;85:904–15. https://doi.org/10.1172/JCI114518.CrossRefPubMedPubMedCentral

19.

van der Geld YM, Limburg PC, Kallenberg CG. Proteinase 3, Wegener’s autoantigen: from gene to antigen. J Leukoc Biol. 2001;69:177–90.CrossRefPubMed

20.

Ge S, Zhu X, Xu Q, Wang J, An C, Hu Y, et al. Neutrophils in ANCA-associated vasculitis: Mechanisms and implications for management. Front Pharmacol. 2022;13:957660. https://doi.org/10.3389/fphar.2022.957660.CrossRefPubMedPubMedCentral

21.

Shamamian P, Pocock BJ, Schwartz JD, Monea S, Chuang N, Whiting D, et al. Neutrophil-derived serine proteinases enhance membrane type-1 matrix metalloproteinase-dependent tumor cell invasion. Surgery. 2000;127:142–7. https://doi.org/10.1067/msy.2000.101155.CrossRefPubMed

22.

Shamamian P, Schwartz JD, Pocock BJ, Monea S, Whiting D, Marcus SG, et al. Activation of progelatinase A (MMP-2) by neutrophil elastase, cathepsin G, and proteinase-3: a role for inflammatory cells in tumor invasion and angiogenesis. J Cell Physiol. 2001;189:197–206. https://doi.org/10.1002/jcp.10014.CrossRefPubMed

23.

Hu D, Ansari D, Zhou Q, Sasor A, Said Hilmersson K, Andersson R. Low P4HA2 and high PRTN3 expression predicts poor survival in patients with pancreatic cancer. Scand J Gastroenterol. 2019;54:246–51. https://doi.org/10.1080/00365521.2019.1574360.CrossRefPubMed

24.

Wei Z, Wu B, Wang L, Zhang J. A large-scale transcriptome analysis identified ELANE and PRTN3 as novel methylation prognostic signatures for clear cell renal cell carcinoma. J Cell Physiol. 2020;235:2582–9. https://doi.org/10.1002/jcp.29162.CrossRefPubMed

25.

Fatalska A, Rusetska N, Bakuła-Zalewska E, Kowalik A, Zięba S, Wroblewska A et al. Inflammatory proteins HMGA2 and PRTN3 as drivers of vulvar squamous cell carcinoma progression. Cancers (Basel) 2020;13. https://doi.org/10.3390/cancers13010027

26.

The Cancer Genome Atlas database. PanCancer Atlas. https://portal.gdc.cancer.gov/ Accessed 13 Dec 2023.

27.

Wang J, Wang X, Guo Y, Ye L, Li D, Hu A, et al. Therapeutic targeting of SPIB/SPI1-facilitated interplay of cancer cells and neutrophils inhibits aerobic glycolysis and cancer progression. Clin Transl Med. 2021;11:e588. https://doi.org/10.1002/ctm2.588.CrossRefPubMedPubMedCentral

28.

Stryker Z, Rajabi M, Davis P, Mousa SA. Evaluation of angiogenesis assays. Biomedicines. 2019;7:37. https://doi.org/10.3390/biomedicines7020037.CrossRefPubMedPubMedCentral

29.

Weng M, Yue Y, Wu D, Zhou C, Guo M, Sun C, et al. Increased MPO in colorectal cancer is associated with high peripheral neutrophil counts and a poor prognosis: A TCGA with propensity score-matched analysis. Front Oncol. 2022;12:940706. https://doi.org/10.3389/fonc.2022.940706.CrossRefPubMedPubMedCentral

30.

Kemik O, Sumer A, Kemik AS, Hasirci I, Purisa S, Dulger AC, et al. The relationship among acute-phase response proteins, cytokines and hormones in cachectic patients with colon cancer. World J Surg Oncol. 2010;8:85. https://doi.org/10.1186/1477-7819-8-85.CrossRefPubMedPubMedCentral

31.

Zhou JM, Jiang H, Yuan T, Zhou GX, Li XB, Wen KM. High hnRNP AB expression is associated with poor prognosis in patients with colorectal cancer. Oncol Lett. 2019;18:6459–68. https://doi.org/10.3892/ol.2019.11034.CrossRefPubMedPubMedCentral

32.

Ishigami SI, Arii S, Furutani M, Niwano M, Harada T, Mizumoto M, et al. Predictive value of vascular endothelial growth factor (VEGF) in metastasis and prognosis of human colorectal cancer. Br J Cancer. 1998;78:1379–84. https://doi.org/10.1038/bjc.1998.688.CrossRefPubMedPubMedCentral

33.

Nakayama M, Niki Y, Kawasaki T, Takeda Y, Ikegami H, Toyama Y, et al. IL-32-PAR2 axis is an innate immunity sensor providing alternative signaling for LPS-TRIF axis. Sci Rep. 2013;3:2960. https://doi.org/10.1038/srep02960.ADSCrossRefPubMedPubMedCentral

34.

Novick D, Rubinstein M, Azam T, Rabinkov A, Dinarello CA, Kim SH. Proteinase 3 is an IL-32 binding protein. Proc Natl Acad Sci U S A. 2006;103:3316–21. https://doi.org/10.1073/pnas.0511206103.ADSCrossRefPubMedPubMedCentral

35.

Kawaguchi M, Yamamoto K, Kataoka H, Izumi A, Yamashita F, Kiwaki T, Nishida T, Camerer E, Fukushima T. Protease-activated receptor-2 accelerates intestinal tumor formation through activation of nuclear factor-κB signaling and tumor angiogenesis in ApcMin/+ mice. Cancer Sci. 2020;111:1193–202. https://doi.org/10.1111/cas.14335.CrossRefPubMedPubMedCentral

36.

Pawar NR, Buzza MS, Antalis TM. Membrane-anchored serine proteases and protease-activated Receptor-2-Mediated signaling: Co-conspirators in cancer progression. Cancer Res. 2019;79:301–10. https://doi.org/10.1158/0008-5472.CAN-18-1745.CrossRefPubMedPubMedCentral

37.

Ferrara N, Adamis AP. Ten years of anti-vascular endothelial growth factor therapy. Nat Rev Drug Discov. 2016;15:385–403. https://doi.org/10.1038/nrd.2015.17.CrossRefPubMed

38.

Schiffmann LM, Fritsch M, Gebauer F, Günther SD, Stair NR, Seeger JM, Thangarajah F, Dieplinger G, Bludau M, Alakus H, Göbel H. Tumour-infiltrating neutrophils counteract anti-VEGF therapy in metastatic colorectal cancer. Br J Cancer. 2019;120:69–78. https://doi.org/10.1038/s41416-018-0198-3.CrossRefPubMed

39.

Jaillon S, Ponzetta A, Di Mitri D, Santoni A, Bonecchi R, Mantovani A. Neutrophil diversity and plasticity in tumour progression and therapy. Nat Rev Cancer. 2020;20:485–503. https://doi.org/10.1038/s41568-020-0281-y.CrossRefPubMed

40.

Hwang TL, Wang WH, Wang TY, Yu HP, Hsieh PW. Synthesis and pharmacological characterization of 2-aminobenzaldehyde oxime analogs as dual inhibitors of neutrophil elastase and proteinase 3. Bioorg Med Chem. 2015;23:1123–34. https://doi.org/10.1016/j.bmc.2014.12.056.CrossRefPubMed

41.

Huang X, Ni B, Xi Y, Chu X, Zhang R, You H. Protease-activated receptor 2 (PAR-2) antagonist AZ3451 as a novel therapeutic agent for osteoarthritis. Aging (Albany NY). 2019;11:12532–45. https://doi.org/10.18632/aging.102586.CrossRefPubMed

Title: High serum proteinase-3 levels predict poor progression-free survival and lower efficacy of bevacizumab in metastatic colorectal cancer
Authors: Kei Furuya
Masao Nakajima
Ryouichi Tsunedomi
Yuki Nakagami
Ming Xu
Hiroto Matsui
Yukio Tokumitsu
Yoshitaro Shindo
Yusaku Watanabe
Shinobu Tomochika
Noriko Maeda
Michihisa Iida
Nobuaki Suzuki
Shigeru Takeda
Shoichi Hazama
Tatsuya Ioka
Yoshinobu Hoshii
Tomio Ueno
Hiroaki Nagano
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: Bevacizumab
Colorectal Cancer
Colorectal Cancer
Cytostatic Therapy
Biomarkers
Published in: BMC Cancer / Issue 1/2024
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-024-11924-4

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Abstract

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