Remodelling of the Tumour Microenvironment by the Kallikrein-related Peptidases

Overview

Journal Nat Rev Cancer

Specialty Oncology

Date 2022 Feb 1

PMID 35102281

Authors

Srilakshmi Srinivasan

Thomas Kryza

Jyotsna Batra

Judith Clements

Affiliations

Soon will be listed here.

Abstract

Kallikrein-related peptidases (KLKs) are critical regulators of the tumour microenvironment. KLKs are proteolytic enzymes regulating multiple functions of bioactive molecules including hormones and growth factors, membrane receptors and the extracellular matrix architecture involved in cancer progression and metastasis. Perturbations of the proteolytic cascade generated by these peptidases, and their downstream signalling actions, underlie tumour emergence or blockade of tumour growth. Recent studies have also revealed their role in tumour immune suppression and resistance to cancer therapy. Here, we present an overview of the complex biology of the KLK family and its context-dependent nature in cancer, and discuss the different therapeutic strategies available to potentially target these proteases.

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References

Kalinska M, Meyer-Hoffert U, Kantyka T, Potempa J . Kallikreins - The melting pot of activity and function. Biochimie. 2015; 122:270-82. PMC: 4747678. DOI: 10.1016/j.biochi.2015.09.023. View

Skala W, Utzschneider D, Magdolen V, Debela M, Guo S, Craik C . Structure-function analyses of human kallikrein-related peptidase 2 establish the 99-loop as master regulator of activity. J Biol Chem. 2014; 289(49):34267-83. PMC: 4256358. DOI: 10.1074/jbc.M114.598201. View

Guo S, Skala W, Magdolen V, Briza P, Biniossek M, Schilling O . A Single Glycan at the 99-Loop of Human Kallikrein-related Peptidase 2 Regulates Activation and Enzymatic Activity. J Biol Chem. 2015; 291(2):593-604. PMC: 4705380. DOI: 10.1074/jbc.M115.691097. View

Koumandou V, Scorilas A . Evolution of the plasma and tissue kallikreins, and their alternative splicing isoforms. PLoS One. 2013; 8(7):e68074. PMC: 3707919. DOI: 10.1371/journal.pone.0068074. View

Filippou P, Ren A, Soosaipillai A, Papaioannou M, Korbakis D, Safar R . Expression profile of human tissue kallikrein 15 provides preliminary insights into its roles in the prostate and testis. Clin Biochem. 2018; 59:78-85. DOI: 10.1016/j.clinbiochem.2018.06.017. View

Kishibe M . Physiological and pathological roles of kallikrein-related peptidases in the epidermis. J Dermatol Sci. 2019; 95(2):50-55. DOI: 10.1016/j.jdermsci.2019.06.007. View

Muytjens C, Vasiliou S, Oikonomopoulou K, Prassas I, Diamandis E . Putative functions of tissue kallikrein-related peptidases in vaginal fluid. Nat Rev Urol. 2016; 13(10):596-607. DOI: 10.1038/nrurol.2016.161. View

Stefanini A, da Cunha B, Henrique T, Tajara E . Involvement of Kallikrein-Related Peptidases in Normal and Pathologic Processes. Dis Markers. 2016; 2015:946572. PMC: 4689925. DOI: 10.1155/2015/946572. View

Di Paolo C, Diamandis E, Prassas I . The role of kallikreins in inflammatory skin disorders and their potential as therapeutic targets. Crit Rev Clin Lab Sci. 2020; 58(1):1-16. DOI: 10.1080/10408363.2020.1775171. View

10.

Filippou P, Karagiannis G, Musrap N, Diamandis E . Kallikrein-related peptidases (KLKs) and the hallmarks of cancer. Crit Rev Clin Lab Sci. 2016; 53(4):277-91. DOI: 10.3109/10408363.2016.1154643. View

11.

Kryza T, Silva M, Loessner D, Heuze-Vourch N, Clements J . The kallikrein-related peptidase family: Dysregulation and functions during cancer progression. Biochimie. 2015; 122:283-99. DOI: 10.1016/j.biochi.2015.09.002. View

12.

Lawrence M, Lai J, Clements J . Kallikreins on steroids: structure, function, and hormonal regulation of prostate-specific antigen and the extended kallikrein locus. Endocr Rev. 2010; 31(4):407-46. DOI: 10.1210/er.2009-0034. View

13.

Avgeris M, Mavridis K, Scorilas A . Kallikrein-related peptidases in prostate, breast, and ovarian cancers: from pathobiology to clinical relevance. Biol Chem. 2012; 393(5):301-17. DOI: 10.1515/hsz-2011-0260. View

14.

Pasic M, Olkhov E, Bapat B, Yousef G . Epigenetic regulation of kallikrein-related peptidases: there is a whole new world out there. Biol Chem. 2012; 393(5):319-30. DOI: 10.1515/hsz-2011-0273. View

15.

Adamopoulos P, Kontos C, Scorilas A . Discovery of novel transcripts of the human tissue kallikrein (KLK1) and kallikrein-related peptidase 2 (KLK2) in human cancer cells, exploiting Next-Generation Sequencing technology. Genomics. 2018; 111(4):642-652. DOI: 10.1016/j.ygeno.2018.03.022. View

16.

Di Meo A, Wang C, Cheng Y, Diamandis E, Yousef G . The miRNA-kallikrein interaction: a mosaic of epigenetic regulation in cancer. Biol Chem. 2018; 399(9):973-982. DOI: 10.1515/hsz-2018-0112. View

17.

Masurier N, Arama D, El Amri C, Lisowski V . Inhibitors of kallikrein-related peptidases: An overview. Med Res Rev. 2017; 38(2):655-683. DOI: 10.1002/med.21451. View

18.

Guo S, Briza P, Magdolen V, Brandstetter H, Goettig P . Activation and activity of glycosylated KLKs 3, 4 and 11. Biol Chem. 2018; 399(9):1009-1022. DOI: 10.1515/hsz-2018-0148. View

19.

Srinivasan S, Stephens C, Wilson E, Panchadsaram J, DeVoss K, Koistinen H . Prostate Cancer Risk-Associated Single-Nucleotide Polymorphism Affects Prostate-Specific Antigen Glycosylation and Its Function. Clin Chem. 2018; 65(1):e1-e9. PMC: 6643286. DOI: 10.1373/clinchem.2018.295790. View

20.

Gratacos-Mulleras A, Duran A, Asadi Shehni A, Ferrer-Batalle M, Ramirez M, Comet J . Characterisation of the main PSA glycoforms in aggressive prostate cancer. Sci Rep. 2020; 10(1):18974. PMC: 7643140. DOI: 10.1038/s41598-020-75526-3. View