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Remodelling of the tumour microenvironment by the kallikrein-related peptidases

Nature Reviews Cancer volume 22, pages 223–238 (2022)Cite this article

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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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Fig. 1: KLKs regulate interactions of cancer cells with TME.
Fig. 2: Role of KLKs in molecular crosstalk between cancer cells and stromal cells.
Fig. 3: KLKs play a regulatory role in the immune contexture of cancer.
Fig. 4: Contribution of KLKs in the multistep process of metastasis.

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References

  1. Kalinska, M., Meyer-Hoffert, U., Kantyka, T. & Potempa, J. Kallikreins — the melting pot of activity and function. Biochimie 122, 270–282 (2016).

    Article  CAS  PubMed  Google Scholar 

  2. Skala, W. et al. Structure–function analyses of human kallikrein-related peptidase 2 establish the 99-loop as master regulator of activity. J. Biol. Chem. 289, 34267–34283 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Guo, S. et al. A single glycan at the 99-loop of human kallikrein-related peptidase 2 regulates activation and enzymatic activity. J. Biol. Chem. 291, 593–604 (2016). This reference highlights the structural loops and the significance of glycosylation for KLK enzymatic function.

    Article  CAS  PubMed  Google Scholar 

  4. Koumandou, V. L. & Scorilas, A. Evolution of the plasma and tissue kallikreins, and their alternative splicing isoforms. PLoS ONE 8, e68074 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Filippou, P. S. et al. Expression profile of human tissue kallikrein 15 provides preliminary insights into its roles in the prostate and testis. Clin. Biochem. 59, 78–85 (2018).

    Article  CAS  PubMed  Google Scholar 

  6. Kishibe, M. Physiological and pathological roles of kallikrein-related peptidases in the epidermis. J. Dermatol. Sci. 95, 50–55 (2019).

    Article  CAS  PubMed  Google Scholar 

  7. Muytjens, C. M., Vasiliou, S. K., Oikonomopoulou, K., Prassas, I. & Diamandis, E. P. Putative functions of tissue kallikrein-related peptidases in vaginal fluid. Nat. Rev. Urol. 13, 596–607 (2016).

    Article  CAS  PubMed  Google Scholar 

  8. Stefanini, A. C., da Cunha, B. R., Henrique, T. & Tajara, E. H. Involvement of kallikrein-related peptidases in normal and pathologic processes. Dis. Markers 2015, 946572 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Di Paolo, C. T., Diamandis, E. P. & Prassas, I. The role of kallikreins in inflammatory skin disorders and their potential as therapeutic targets. Crit. Rev. Clin. Lab. Sci. 58, 1–16 (2020).

    Article  PubMed  Google Scholar 

  10. Filippou, P. S., Karagiannis, G. S., Musrap, N. & Diamandis, E. P. Kallikrein-related peptidases (KLKs) and the hallmarks of cancer. Crit. Rev. Clin. Lab. Sci. 53, 277–291 (2016).

    Article  CAS  PubMed  Google Scholar 

  11. Kryza, T., Silva, M. L., Loessner, D., Heuze-Vourc’h, N. & Clements, J. A. The kallikrein-related peptidase family: dysregulation and functions during cancer progression. Biochimie 122, 283–299 (2016).

    Article  CAS  PubMed  Google Scholar 

  12. Lawrence, M. G., Lai, J. & Clements, J. A. Kallikreins on steroids: structure, function, and hormonal regulation of prostate-specific antigen and the extended kallikrein locus. Endocr. Rev. 31, 407–446 (2010).

    Article  CAS  PubMed  Google Scholar 

  13. Avgeris, M., Mavridis, K. & Scorilas, A. Kallikrein-related peptidases in prostate, breast, and ovarian cancers: from pathobiology to clinical relevance. Biol. Chem. 393, 301–317 (2012).

    Article  CAS  PubMed  Google Scholar 

  14. Pasic, M. D., Olkhov, E., Bapat, B. & Yousef, G. M. Epigenetic regulation of kallikrein-related peptidases: there is a whole new world out there. Biol. Chem. 393, 319–330 (2012).

    Article  CAS  PubMed  Google Scholar 

  15. Adamopoulos, P. G., Kontos, C. K. & 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 111, 642–652 (2019).

    Article  CAS  PubMed  Google Scholar 

  16. Di Meo, A., Wang, C., Cheng, Y., Diamandis, E. P. & Yousef, G. M. The miRNA–kallikrein interaction: a mosaic of epigenetic regulation in cancer. Biol. Chem. 399, 973–982 (2018).

    Article  PubMed  Google Scholar 

  17. Masurier, N., Arama, D. P., El Amri, C. & Lisowski, V. Inhibitors of kallikrein-related peptidases: an overview. Med. Res. Rev. 38, 655–683 (2018).

    Article  CAS  PubMed  Google Scholar 

  18. Goettig, P. Effects of glycosylation on the enzymatic activity and mechanisms of proteases. Int. J. Mol. Sci. 17, 1969 (2016).

    Article  PubMed Central  Google Scholar 

  19. Guo, S., Briza, P., Magdolen, V., Brandstetter, H. & Goettig, P. Activation and activity of glycosylated KLKs 3, 4 and 11. Biol. Chem. 399, 1009–1022 (2018).

    Article  CAS  PubMed  Google Scholar 

  20. Srinivasan, S. et al. Prostate cancer risk-associated single-nucleotide polymorphism affects prostate-specific antigen glycosylation and its function. Clin. Chem. 65, e1–e9 (2019).

    Article  PubMed  Google Scholar 

  21. Gratacos-Mulleras, A. et al. Characterisation of the main PSA glycoforms in aggressive prostate cancer. Sci. Rep. 10, 18974 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Fortelny, N. et al. Network analyses reveal pervasive functional regulation between proteases in the human protease web. PLoS Biol. 12, e1001869 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Gong, W. et al. Characterization of kallikrein-related peptidase 4 (KLK4) mRNA expression in tumor tissue of advanced high-grade serous ovarian cancer patients. PLoS ONE 14, e0212968 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tailor, P. D. et al. Diagnostic and prognostic biomarker potential of kallikrein family genes in different cancer types. Oncotarget 9, 17876–17888 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Peng, Q. et al. Biomarker implication of kallikrein-related peptidases as prognostic tissue substrates of poor survival in colorectal cancer. Cancer Cell Int. 20, 260 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chang, J. S. et al. Kallikrein 5 overexpression is associated with poor prognosis in uterine cervical cancer. J. Gynecol. Oncol. 31, e78 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gong, W. et al. Prognostic value of kallikrein-related peptidase 7 (KLK7) mRNA expression in advanced high-grade serous ovarian cancer. J. Ovarian Res. 13, 125 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hua, Q. et al. Upregulation of KLK8 predicts poor prognosis in pancreatic cancer. Front Oncol 11, 624837 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Dorn, J. et al. Function and clinical relevance of kallikrein-related peptidases and other serine proteases in gynecological cancers. Crit. Rev. Clin. Lab. Sci. 51, 63–84 (2014).

    Article  CAS  PubMed  Google Scholar 

  30. Kolin, D. L. et al. Prognostic significance of human tissue kallikrein-related peptidases 11 and 15 in gastric cancer. Tumour Biol. 37, 437–446 (2016). Together with Gong et al. (2019), Tailor et al. (2018), Peng et al. (2020), Chang et al. (2020), Gong et al. (2020), Hua et al. (2021) and Dorn et al. (2014), this work highlights the significance of KLKs in tumour progression and metastasis and their clinical relevance.

    Article  CAS  PubMed  Google Scholar 

  31. Assel, M. J. et al. Kallikrein markers performance in pretreatment blood to predict early prostate cancer recurrence and metastasis after radical prostatectomy among very high-risk men. Prostate 80, 51–56 (2020).

    Article  CAS  PubMed  Google Scholar 

  32. Lunger, L. et al. KLK3 and TMPRSS2 for molecular lymph-node staging in prostate cancer patients undergoing radical prostatectomy. Prostate Cancer Prostatic Dis. 24, 362–369 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Schmitt, M. et al. Emerging clinical importance of the cancer biomarkers kallikrein-related peptidases (KLK) in female and male reproductive organ malignancies. Radiol. Oncol. 47, 319–329 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Halaoui, R. et al. Progressive polarity loss and luminal collapse disrupt tissue organization in carcinoma. Genes Dev. 31, 1573–1587 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Filippou, P. S. et al. Kallikrein-related peptidases protein expression in lymphoid tissues suggests potential implications in immune response. Clin. Biochem. 77, 41–47 (2020).

    Article  CAS  PubMed  Google Scholar 

  36. Prassas, I., Eissa, A., Poda, G. & Diamandis, E. P. Unleashing the therapeutic potential of human kallikrein-related serine proteases. Nat. Rev. Drug Discov. 14, 183–202 (2015).

    Article  CAS  PubMed  Google Scholar 

  37. Silva, L. M. et al. Integration of two in-depth quantitative proteomics approaches determines the kallikrein-related peptidase 7 (KLK7) degradome in ovarian cancer cell secretome. Mol. Cell Proteom. 18, 818–836 (2019).

    Article  CAS  Google Scholar 

  38. Kapadia, C., Ghosh, M. C., Grass, L. & Diamandis, E. P. Human kallikrein 13 involvement in extracellular matrix degradation. Biochem. Biophys. Res. Commun. 323, 1084–1090 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Ghosh, M. C., Grass, L., Soosaipillai, A., Sotiropoulou, G. & Diamandis, E. P. Human kallikrein 6 degrades extracellular matrix proteins and may enhance the metastatic potential of tumour cells. Tumour Biol. 25, 193–199 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Michael, I. P. et al. Biochemical and enzymatic characterization of human kallikrein 5 (hK5), a novel serine protease potentially involved in cancer progression. J. Biol. Chem. 280, 14628–14635 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Dong, Y. et al. Metastasis of ovarian cancer is mediated by kallikrein related peptidases. Clin. Exp. Metastasis 31, 135–147 (2014).

    Article  CAS  PubMed  Google Scholar 

  42. Dong, Y. et al. Activation of membrane-bound proteins and receptor systems: a link between tissue kallikrein and the KLK-related peptidases. Biol. Chem. 395, 977–990 (2014).

    Article  CAS  PubMed  Google Scholar 

  43. Blaber, M., Yoon, H., Juliano, M. A., Scarisbrick, I. A. & Blaber, S. I. Functional intersection of the kallikrein-related peptidases (KLKs) and thrombostasis axis. Biol. Chem. 391, 311–320 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Beaufort, N. et al. Interplay of human tissue kallikrein 4 (hK4) with the plasminogen activation system: hK4 regulates the structure and functions of the urokinase-type plasminogen activator receptor (uPAR). Biol. Chem. 387, 217–222 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Sotiropoulou, G., Pampalakis, G. & Diamandis, E. P. Functional roles of human kallikrein-related peptidases. J. Biol. Chem. 284, 32989–32994 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ohler, A., Debela, M., Wagner, S., Magdolen, V. & Becker-Pauly, C. Analyzing the protease web in skin: meprin metalloproteases are activated specifically by KLK4, 5 and 8 vice versa leading to processing of proKLK7 thereby triggering its activation. Biol. Chem. 391, 455–460 (2010).

    Article  CAS  PubMed  Google Scholar 

  47. Yoon, H. et al. Activation profiles and regulatory cascades of the human kallikrein-related peptidases. J. Biol. Chem. 282, 31852–31864 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Neuhaus, J. et al. Protease expression levels in prostate cancer tissue can explain prostate cancer-associated seminal biomarkers — an explorative concept study. Int. J. Mol. Sci. 18, 976 (2017).

    Article  PubMed Central  Google Scholar 

  49. Yoon, H., Blaber, S. I., Li, W., Scarisbrick, I. A. & Blaber, M. Activation profiles of human kallikrein-related peptidases by matrix metalloproteinases. Biol. Chem. 394, 137–147 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Loessner, D. et al. Combined expression of KLK4, KLK5, KLK6, and KLK7 by ovarian cancer cells leads to decreased adhesion and paclitaxel-induced chemoresistance. Gynecol. Oncol. 127, 569–578 (2012).

    Article  CAS  PubMed  Google Scholar 

  51. Dong, Y. et al. Kallikrein-related peptidase 7 promotes multicellular aggregation via the α5β1 integrin pathway and paclitaxel chemoresistance in serous epithelial ovarian carcinoma. Cancer Res. 70, 2624–2633 (2010).

    Article  CAS  PubMed  Google Scholar 

  52. Johnson, S. K., Ramani, V. C., Hennings, L. & Haun, R. S. Kallikrein 7 enhances pancreatic cancer cell invasion by shedding E-cadherin. Cancer 109, 1811–1820 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Ramani, V. C., Hennings, L. & Haun, R. S. Desmoglein 2 is a substrate of kallikrein 7 in pancreatic cancer. BMC Cancer 8, 373 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Jiang, R., Shi, Z., Johnson, J. J., Liu, Y. & Stack, M. S. Kallikrein-5 promotes cleavage of desmoglein-1 and loss of cell–cell cohesion in oral squamous cell carcinoma. J. Biol. Chem. 286, 9127–9135 (2011).

    Article  CAS  PubMed  Google Scholar 

  55. Schrader, C. H. et al. Kallikrein-related peptidase 6 regulates epithelial-to-mesenchymal transition and serves as prognostic biomarker for head and neck squamous cell carcinoma patients. Mol. Cancer 14, 107 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Delaunay, T. et al. Aberrant expression of kallikrein-related peptidase 7 is correlated with human melanoma aggressiveness by stimulating cell migration and invasion. Mol. Oncol. 11, 1330–1347 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Klucky, B. et al. Kallikrein 6 induces E-cadherin shedding and promotes cell proliferation, migration, and invasion. Cancer Res. 67, 8198–8206 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Veveris-Lowe, T. L. et al. Kallikrein 4 (hK4) and prostate-specific antigen (PSA) are associated with the loss of E-cadherin and an epithelial–mesenchymal transition (EMT)-like effect in prostate cancer cells. Endocr. Relat. Cancer 12, 631–643 (2005).

    Article  CAS  PubMed  Google Scholar 

  59. Kourtidis, A., Lu, R., Pence, L. J. & Anastasiadis, P. Z. A central role for cadherin signaling in cancer. Exp. Cell Res. 358, 78–85 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Reid, J. C. et al. Pericellular regulation of prostate cancer expressed kallikrein-related peptidases and matrix metalloproteinases by cell surface serine proteases. Am. J. Cancer Res. 7, 2257–2274 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Sahai, E. et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat. Rev. Cancer 20, 174–186 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kryza, T. et al. Kallikrein-related peptidase 4 induces cancer-associated fibroblast features in prostate-derived stromal cells. Mol. Oncol. 11, 1307–1329 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Oikonomopoulou, K. et al. Kallikrein-mediated cell signalling: targeting proteinase-activated receptors (PARs). Biol. Chem. 387, 817–824 (2006).

    CAS  PubMed  Google Scholar 

  64. Wojtukiewicz, M. Z., Hempel, D., Sierko, E., Tucker, S. C. & Honn, K. V. Protease-activated receptors (PARs) — biology and role in cancer invasion and metastasis. Cancer Metastasis Rev. 34, 775–796 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Hollenberg, M. D. KLKs and their hormone-like signaling actions: a new life for the PSA–KLK family. Biol. Chem. 395, 915–929 (2014).

    Article  CAS  PubMed  Google Scholar 

  66. Heuberger, D. M. & Schuepbach, R. A. Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases. Thromb. J. 17, 4 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Sebert, M., Sola-Tapias, N., Mas, E., Barreau, F. & Ferrand, A. Protease-activated receptors in the intestine: focus on inflammation and cancer. Front. Endocrinol. 10, 717 (2019).

    Article  Google Scholar 

  68. Michel, N. et al. Growth and survival of lung cancer cells: regulation by kallikrein-related peptidase 6 via activation of proteinase-activated receptor 2 and the epidermal growth factor receptor. Biol. Chem. 395, 1015–1025 (2014).

    Article  CAS  PubMed  Google Scholar 

  69. Wang, W., Mize, G. J., Zhang, X. & Takayama, T. K. Kallikrein-related peptidase-4 initiates tumor–stroma interactions in prostate cancer through protease-activated receptor-1. Int. J. Cancer 126, 599–610 (2010).

    Article  CAS  PubMed  Google Scholar 

  70. Zhang, X. & Hwang, Y. S. Cancer-associated fibroblast stimulates cancer cell invasion in an interleukin-1 receptor (IL-1R)-dependent manner. Oncol. Lett. 18, 4645–4650 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Fuhrman-Luck, R. A., Loessner, D. & Clements, J. A. Kallikrein-related peptidases in prostate cancer: from molecular function to clinical application. EJIFCC 25, 269–281 (2014).

    PubMed  PubMed Central  Google Scholar 

  72. Dallas, S. L. et al. Preferential production of latent transforming growth factor β2 by primary prostatic epithelial cells and its activation by prostate-specific antigen. J. Cell Physiol. 202, 361–370 (2005).

    Article  CAS  PubMed  Google Scholar 

  73. Shahinian, H. et al. Secretome and degradome profiling shows that Kallikrein-related peptidases 4, 5, 6, and 7 induce TGFβ-1 signaling in ovarian cancer cells. Mol. Oncol. 8, 68–82 (2014). This work is the first cell-contextual proteomic and degradomic analysis for KLK4–KLK7 highlighting the significance of such studies in annotating the role of proteases in tumour biology.

    Article  CAS  PubMed  Google Scholar 

  74. Bellomo, C., Caja, L. & Moustakas, A. Transforming growth factor β as regulator of cancer stemness and metastasis. Br. J. Cancer 115, 761–769 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Costanza, B., Umelo, I. A., Bellier, J., Castronovo, V. & Turtoi, A. Stromal modulators of TGF-β in cancer. J. Clin. Med. 6, 7 (2017).

    Article  PubMed Central  Google Scholar 

  76. Ping, Q. R. et al. Cancer-associated fibroblasts: overview, progress, challenges, and directions. Cancer Gene Ther. 28, 984–999 (2021).

    Article  CAS  PubMed  Google Scholar 

  77. Cohen, P. et al. Prostate-specific antigen (PSA) is an insulin-like growth factor binding protein-3 protease found in seminal plasma. J. Clin. Endocrinol. Metab. 75, 1046–1053 (1992).

    CAS  PubMed  Google Scholar 

  78. Matsumura, M. et al. Substrates of the prostate-specific serine protease prostase/KLK4 defined by positional-scanning peptide libraries. Prostate 62, 1–13 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. Sutkowski, D. M. et al. Growth regulation of prostatic stromal cells by prostate-specific antigen. J. Natl Cancer Inst. 91, 1663–1669 (1999).

    Article  CAS  PubMed  Google Scholar 

  80. Mukai, S. et al. Activation of hepatocyte growth factor activator zymogen (pro-HGFA) by human kallikrein 1-related peptidases. FEBS J. 275, 1003–1017 (2008).

    Article  CAS  PubMed  Google Scholar 

  81. Reid, J. C. et al. In vitro evidence that KLK14 regulates the components of the HGF/Met axis, pro-HGF and HGF-activator inhibitor 1A and 1B. Biol. Chem. 397, 1299–1305 (2016).

    Article  CAS  PubMed  Google Scholar 

  82. Koh, S. A. & Lee, K. H. Function of hepatocyte growth factor in gastric cancer proliferation and invasion. Yeungnam Univ. J. Med. 37, 73–78 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Wilkinson, R. et al. Human kallikrein 4 signal peptide induces cytotoxic T cell responses in healthy donors and prostate cancer patients. Cancer Immunol. Immunother. 61, 169–179 (2012).

    Article  CAS  PubMed  Google Scholar 

  84. Japp, A. S. et al. Dysfunction of PSA-specific CD8+ T cells in prostate cancer patients correlates with CD38 and Tim-3 expression. Cancer Immunol. Immunother. 64, 1487–1494 (2015).

    Article  CAS  PubMed  Google Scholar 

  85. Karan, D. Formulation of the bivalent prostate cancer vaccine with surgifoam elicits antigen-specific effector T cells in PSA-transgenic mice. Vaccine 35, 5794–5798 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Schuster, H. et al. The immunopeptidomic landscape of ovarian carcinomas. Proc. Natl Acad. Sci. USA 114, E9942–E9951 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Ehrenfeld, P., Figueroa, C. D. & Bhoola, K. D. Kinins: kallikreins and kinins in cancer. Kinins 382, 77–89 (2012).

    Google Scholar 

  88. Weidmann, H. et al. The plasma contact system, a protease cascade at the nexus of inflammation, coagulation and immunity. Biochim. Biophys. Acta Mol. Cell. Res. 1864, 2118–2127 (2017).

    Article  CAS  PubMed  Google Scholar 

  89. Molina, L. et al. Stimulation of the bradykinin B1 receptor induces the proliferation of estrogen-sensitive breast cancer cells and activates the ERK1/2 signaling pathway. Breast Cancer Res. Treat. 118, 499–510 (2009).

    Article  CAS  PubMed  Google Scholar 

  90. Ehrenfeld, P. et al. Bioregulation of kallikrein-related peptidases 6, 10 and 11 by the kinin B1 receptor in breast cancer cells. Anticancer. Res. 34, 6925–6938 (2014).

    CAS  PubMed  Google Scholar 

  91. Kodaira, H. et al. ANXA10 induction by interaction with tumor-associated macrophages promotes the growth of esophageal squamous cell carcinoma. Pathol. Int. 69, 135–147 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Grunberg, M. et al. Kallikrein-related peptidases are activators of the CC chemokine CCL14. Eur. J. Immunol. 48, 1592–1594 (2018).

    Article  PubMed  Google Scholar 

  93. Yamamoto, Y. et al. Tumour and immune cell dynamics explain the PSA bounce after prostate cancer brachytherapy. Br. J. Cancer 115, 195–202 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Manning, M. L., Williams, S. A., Jelinek, C. A., Kostova, M. B. & Denmeade, S. R. Proteolysis of complement factors iC3b and C5 by the serine protease prostate-specific antigen in prostatic fluid and seminal plasma. J. Immunol. 190, 2567–2574 (2013).

    Article  CAS  PubMed  Google Scholar 

  95. Roumenina, L. T., Daugan, M. V., Petitprez, F., Sautes-Fridman, C. & Fridman, W. H. Context-dependent roles of complement in cancer. Nat. Rev. Cancer 19, 698–715 (2019).

    Article  CAS  PubMed  Google Scholar 

  96. Oikonomopoulou, K. et al. Induction of complement C3a receptor responses by kallikrein-related peptidase 14. J. Immunol. 191, 3858–3866 (2013).

    Article  CAS  PubMed  Google Scholar 

  97. Cheteh, E. H. et al. Interleukin-6 derived from cancer-associated fibroblasts attenuates the p53 response to doxorubicin in prostate cancer cells. Cell Death Discov. 6, 42 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Johnson, J. J. et al. Protease-activated receptor-2 (PAR-2)-mediated NF-κB activation suppresses inflammation-associated tumor suppressor microRNAs in oral squamous cell carcinoma. J. Biol. Chem. 291, 6936–6945 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Scarisbrick, I. A. et al. Functional role of kallikrein 6 in regulating immune cell survival. PLoS ONE 6, e18376 (2011). This study points out the novel molecular mechanism involving kallikreins in lymphocyte survival and maintenance of cellular homeostasis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Sotiropoulou, G. & Pampalakis, G. Kallikrein-related peptidases: bridges between immune functions and extracellular matrix degradation. Biol. Chem. 391, 321–331 (2010).

    Article  CAS  PubMed  Google Scholar 

  101. Chen, J.-Q., Liang, B.-H., Li, H.-P., Mo, Z.-Y. & Zhu, H.-L. Roles of kallikrein-related peptidase in epidermal barrier function and related skin diseases. J. Dermatol. Sci. 2, 150–155 (2019).

    Google Scholar 

  102. Chen, J. et al. Functional implications of cathelicidin antimicrobial protein in breast cancer and tumor-associated macrophage microenvironment. Biomolecules 10, 688 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  103. Piktel, E. et al. The role of cathelicidin LL-37 in cancer development. Arch. Immunol. Ther. Exp. 64, 33–46 (2016).

    Article  CAS  Google Scholar 

  104. Deraison, C. et al. LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction. Mol. Biol. Cell 18, 3607–3619 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Briot, A. et al. Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome. J. Exp. Med. 206, 1135–1147 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Pampalakis, G. et al. The KLK5 protease suppresses breast cancer by repressing the mevalonate pathway. Oncotarget 5, 2390–2403 (2014).

    Article  PubMed  Google Scholar 

  107. Lim, S. C., Kee, K. H., Lee, M. J., Hong, R. & Han, S. I. Extracellular acidity-induced expression of Kallikrein-related peptidases 7 and 8 is involved in increased invasiveness of gastric cancer cells. Oncol. Rep. 43, 1705–1713 (2020). This study demonstrates that tumour invasion is, in part, regulated through the COX/KLK7 and KLK8 axis in gastric cancer.

    CAS  PubMed  Google Scholar 

  108. Tian, J. et al. Identification of MFGE8 and KLK5/7 as mediators of breast tumorigenesis and resistance to COX-2 inhibition. Breast Cancer Res. 23, 23 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Ehrenfeld, P., Bhoola, K. D., Matus, C. E. & Figueroa, C. D. Functional interrelationships between the kallikrein-related peptidases family and the classical kinin system in the human neutrophil. Biol. Chem. 399, 925–935 (2018). This study highlights the importance of the bioregulation of KLKs by kinins.

    Article  CAS  PubMed  Google Scholar 

  110. Lizama, A. J. et al. Expression and bioregulation of the kallikrein-related peptidases family in the human neutrophil. Innate Immun. 21, 575–586 (2015).

    Article  CAS  PubMed  Google Scholar 

  111. Petrova, E. & Hovnanian, A. Advances in understanding of Netherton syndrome and therapeutic implications. Expert Opin. Orphan Drugs 8, 455–487 (2020).

    Article  Google Scholar 

  112. Kiss, M. et al. IL1β promotes immune suppression in the tumor microenvironment independent of the inflammasome and gasdermin D. Cancer Immunol. Res. 9, 309–323 (2021).

    Article  CAS  PubMed  Google Scholar 

  113. Bhoola, K. et al. Kallikrein and kinin receptor expression in inflammation and cancer. Biol. Chem. 382, 77–89 (2001).

    Article  CAS  PubMed  Google Scholar 

  114. Chen, S. et al. Single-cell analysis reveals transcriptomic remodellings in distinct cell types that contribute to human prostate cancer progression. Nat. Cell Biol. 23, 87–98 (2021). This transcriptome profiling study in prostate primary tumours shows the involvement of KLK3 in micrometastasis.

    Article  CAS  PubMed  Google Scholar 

  115. Nauroy, P. & Nystrom, A. Kallikreins: essential epidermal messengers for regulation of the skin microenvironment during homeostasis, repair and disease. Matrix Biol. Plus 6–7, 100019 (2020).

    Article  PubMed  Google Scholar 

  116. Yoon, H. & Scarisbrick, I. A. Kallikrein-related peptidase 6 exacerbates disease in an autoimmune model of multiple sclerosis. Biol. Chem. 397, 1277–1286 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Kryza, T. et al. Human kallikrein-related peptidase 12 stimulates endothelial cell migration by remodeling the fibronectin matrix. Sci. Rep. 8, 6331 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Chadha, K. C. et al. Anti-angiogenic activity of PSA-derived peptides. Prostate 75, 1285–1299 (2015).

    Article  CAS  PubMed  Google Scholar 

  119. Lee, P., Chandel, N. S. & Simon, M. C. Cellular adaptation to hypoxia through hypoxia inducible factors and beyond. Nat. Rev. Mol. Cell Biol. 21, 268–283 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Horii, K. et al. Androgen-dependent gene expression of prostate-specific antigen is enhanced synergistically by hypoxia in human prostate cancer cells. Mol. Cancer Res. 5, 383–391 (2007).

    Article  CAS  PubMed  Google Scholar 

  121. Kryza, T. et al. Angiogenesis stimulated by human kallikrein-related peptidase 12 acting via a platelet-derived growth factor B-dependent paracrine pathway. FASEB J. 28, 740–751 (2014).

    Article  CAS  PubMed  Google Scholar 

  122. Yao, Y. et al. Tissue kallikrein-modified human endothelial progenitor cell implantation improves cardiac function via enhanced activation of akt and increased angiogenesis. Lab. Invest. 93, 577–591 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Giusti, B. et al. The antiangiogenic tissue kallikrein pattern of endothelial cells in systemic sclerosis. Arthritis Rheum. 52, 3618–3628 (2005).

    Article  CAS  PubMed  Google Scholar 

  124. Kryza, T. et al. Pro-angiogenic effect of human kallikrein-related peptidase 12 (KLK12) in lung endothelial cells does not depend on kinin-mediated activation of B2 receptor. Biol. Chem. 394, 385–391 (2012).

    Article  Google Scholar 

  125. Groppa, E. et al. EphrinB2/EphB4 signaling regulates non-sprouting angiogenesis by VEGF. EMBO Rep. 19, e45054 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Lisle, J. E. et al. Murine, but not human, ephrin-B2 can be efficiently cleaved by the serine protease kallikrein-4: implications for xenograft models of human prostate cancer. Exp. Cell Res. 333, 136–146 (2015). Together with Silva et al. (2019), Kapadia et al. (2004), Ghosh et al. (2004), Michael et al. (2005), Beaufort et al. (2006) and Reid et al. (2017), this work reports the association of KLKs with cell surface proteins in promoting cancer.

    Article  CAS  PubMed  Google Scholar 

  127. Heidtmann, H. H. et al. Generation of angiostatin-like fragments from plasminogen by prostate-specific antigen. Br. J. Cancer 81, 1269–1273 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Koistinen, H. et al. Novel small molecule inhibitors for prostate-specific antigen. Prostate 68, 1143–1151 (2008).

    Article  CAS  PubMed  Google Scholar 

  129. Mattsson, J. M. et al. Proteolytic activity of prostate-specific antigen (PSA) towards protein substrates and effect of peptides stimulating PSA activity. PLoS ONE 9, e107819 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Fortier, A. H., Nelson, B. J., Grella, D. K. & Holaday, J. W. Antiangiogenic activity of prostate-specific antigen. J. Natl Cancer Inst. 91, 1635–1640 (1999).

    Article  CAS  PubMed  Google Scholar 

  131. Fortier, A. H. et al. Recombinant prostate specific antigen inhibits angiogenesis in vitro and in vivo. Prostate 56, 212–219 (2003). Together with Kryza et al. (2014) and Heidtmann et al. (1999), this work shows the effect of KLKs on angiogenesis.

    Article  CAS  PubMed  Google Scholar 

  132. Naidoo, S. & Raidoo, D. M. Angiogenesis in cervical cancer is mediated by HeLa metabolites through endothelial cell tissue kallikrein. Oncol. Rep. 22, 285–293 (2009).

    CAS  PubMed  Google Scholar 

  133. Fuhrman-Luck, R. A., Stansfield, S. H., Stephens, C. R., Loessner, D. & Clements, J. A. Prostate cancer-associated kallikrein-related peptidase 4 activates matrix metalloproteinase-1 and thrombospondin-1. J. Proteome Res. 15, 2466–2478 (2016).

    Article  CAS  PubMed  Google Scholar 

  134. Jha, S. K. et al. KLK3/PSA and cathepsin D activate VEGF-C and VEGF-D. eLife 8, e44478 (2019). This study is the first to show the cleaving ability of KLKs on VEGF-C and VEGF-D, linking this molecular event to lymphangiogenesis.

    Article  PubMed  PubMed Central  Google Scholar 

  135. Guillon-Munos, A. et al. Kallikrein-related peptidase 12 hydrolyzes matricellular proteins of the CCN family and modifies interactions of CCN1 and CCN5 with growth factors. J. Biol. Chem. 286, 25505–25518 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Jia, Q., Xu, B., Zhang, Y., Ali, A. & Liao, X. CCN family proteins in cancer: insight into their structures and coordination role in tumor microenvironment. Front. Genet. 12, 649387 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Caliendo, G. et al. Kallikrein protease activated receptor (PAR) axis: an attractive target for drug development. J. Med. Chem. 55, 6669–6686 (2012).

    Article  CAS  PubMed  Google Scholar 

  138. Filippou, P. S. et al. Biochemical characterization of human tissue kallikrein 15 and examination of its potential role in cancer. Clin. Biochem. 58, 108–115 (2018).

    Article  CAS  PubMed  Google Scholar 

  139. LaValley, D. J. et al. Matrix stiffness enhances VEGFR-2 internalization, signaling, and proliferation in endothelial cells. Converg. Sci. Phys. Oncol. 3, 044001 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Brassard-Jollive, N., Monnot, C., Muller, L. & Germain, S. In vitro 3D systems to model tumor angiogenesis and interactions with stromal cells. Front. Cell Dev. Biol. 8, 594903 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Winkler, J., Abisoye-Ogunniyan, A., Metcalf, K. J. & Werb, Z. Concepts of extracellular matrix remodelling in tumour progression and metastasis. Nat. Commun. 11, 5120 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Chou, R. H., Lin, S. C., Wen, H. C., Wu, C. W. & Chang, W. S. Epigenetic activation of human kallikrein 13 enhances malignancy of lung adenocarcinoma by promoting N-cadherin expression and laminin degradation. Biochem. Biophys. Res. Commun. 409, 442–447 (2011).

    Article  CAS  PubMed  Google Scholar 

  143. Ishige, S. et al. Decreased expression of kallikrein-related peptidase 13: possible contribution to metastasis of human oral cancer. Mol. Carcinog. 53, 557–565 (2014).

    Article  CAS  PubMed  Google Scholar 

  144. Zhu, S., Shi, J., Zhang, S. & Li, Z. KLK6 promotes growth, migration, and invasion of gastric cancer cells. J. Gastric Cancer 18, 356–367 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Chen, H. et al. Kallikrein 6 protease advances colon tumorigenesis via induction of the high mobility group A2 protein. Oncotarget 10, 6062–6078 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Pampalakis, G. et al. Biochemical pathways mediated by KLK6 protease in breast cancer. Mol. Oncol. 13, 2329–2343 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Pampalakis, G. et al. A tumor-protective role for human kallikrein-related peptidase 6 in breast cancer mediated by inhibition of epithelial-to-mesenchymal transition. Cancer Res. 69, 3779–3787 (2009).

    Article  CAS  PubMed  Google Scholar 

  148. Lei, S., Zhang, Q., Yin, F., He, X. & Wang, J. Expression and clinical significance of KLK5–8 in endometrial cancer. Am. J. Transl. Res. 11, 4180–4191 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Chen, E. et al. Analysis of expression and prognosis of KLK7 in ovarian cancer. Open Med. 15, 932–939 (2020).

    Article  CAS  Google Scholar 

  150. Hua, Q. et al. KLK8 promotes the proliferation and metastasis of colorectal cancer via the activation of EMT associated with PAR1. Cell Death Dis. 12, 860 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Kaneko, N. et al. Differential roles of kallikrein-related peptidase 6 in malignant transformation and ΔNp63β-mediated epithelial–mesenchymal transition of oral squamous cell carcinoma. Oral. Oncol. 75, 148–157 (2017).

    Article  CAS  PubMed  Google Scholar 

  152. Gao, L. et al. Tissue kallikrein promotes prostate cancer cell migration and invasion via a protease-activated receptor-1-dependent signaling pathway. Biol. Chem. 391, 803–812 (2010).

    Article  CAS  PubMed  Google Scholar 

  153. Ramsay, A. J. et al. Prostatic trypsin-like kallikrein-related peptidases (KLKs) and other prostate-expressed tryptic proteinases as regulators of signalling via proteinase-activated receptors (PARs). Biol. Chem. 389, 653–668 (2008).

    Article  CAS  PubMed  Google Scholar 

  154. Ramsay, A. J. et al. Kallikrein-related peptidase 4 (KLK4) initiates intracellular signaling via protease-activated receptors (PARs). KLK4 and PAR-2 are co-expressed during prostate cancer progression. J. Biol. Chem. 283, 12293–12304 (2008).

    Article  CAS  PubMed  Google Scholar 

  155. Avgeris, M. & Scorilas, A. Kallikrein-related peptidases (KLKs) as emerging therapeutic targets: focus on prostate cancer and skin pathologies. Expert Opin. Ther. Targets 20, 801–818 (2016).

    Article  CAS  PubMed  Google Scholar 

  156. Takayama, T. K., McMullen, B. A., Nelson, P. S., Matsumura, M. & Fujikawa, K. Characterization of hK4 (prostase), a prostate-specific serine protease: activation of the precursor of prostate specific antigen (pro-PSA) and single-chain urokinase-type plasminogen activator and degradation of prostatic acid phosphatase. Biochemistry 40, 15341–15348 (2001).

    Article  CAS  PubMed  Google Scholar 

  157. Dong, Y. et al. Paclitaxel resistance and multicellular spheroid formation are induced by kallikrein-related peptidase 4 in serous ovarian cancer cells in an ascites mimicking microenvironment. PLoS ONE 8, e57056 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Loessner, D. et al. A bioengineered 3D ovarian cancer model for the assessment of peptidase-mediated enhancement of spheroid growth and intraperitoneal spread. Biomaterials 34, 7389–7400 (2013).

    Article  CAS  PubMed  Google Scholar 

  159. Tse, B. W. et al. KLK4 induces anti-tumor effects in human xenograft mouse models of orthotopic and metastatic prostate cancer. Cancers (Basel) 12, 3501 (2020).

    Article  CAS  Google Scholar 

  160. Emami, N. & Diamandis, E. P. Potential role of multiple members of the kallikrein-related peptidase family of serine proteases in activating latent TGFβ1 in semen. Biol. Chem. 391, 85–95 (2010).

    Article  CAS  PubMed  Google Scholar 

  161. Roblek, M. et al. CCL2 is a vascular permeability factor inducing CCR2-dependent endothelial retraction during lung metastasis. Mol. Cancer Res. 17, 783–793 (2019).

    Article  CAS  PubMed  Google Scholar 

  162. Magnen, M. et al. Tissue kallikrein regulates alveolar macrophage apoptosis early in influenza virus infection. Am. J. Physiol. Lung Cell Mol. Physiol. 316, L1127–L1140 (2019).

    Article  PubMed  Google Scholar 

  163. Gao, J. et al. Kallikrein 4 is a potential mediator of cellular interactions between cancer cells and osteoblasts in metastatic prostate cancer. Prostate 67, 348–360 (2007).

    Article  CAS  PubMed  Google Scholar 

  164. Yang, F. et al. Stromal TGF-β signaling induces AR activation in prostate cancer. Oncotarget 5, 10854–10869 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Ghahremanifard, P., Chanda, A., Bonni, S. & Bose, P. TGF-β mediated immune evasion in cancer-spotlight on cancer-associated fibroblasts. Cancers (Basel) 12, 3650 (2020).

    Article  CAS  Google Scholar 

  166. Ao, M. et al. Cross-talk between paracrine-acting cytokine and chemokine pathways promotes malignancy in benign human prostatic epithelium. Cancer Res. 67, 4244–4253 (2007).

    Article  CAS  PubMed  Google Scholar 

  167. Xie, F., Ling, L., van Dam, H., Zhou, F. & Zhang, L. TGF-β signaling in cancer metastasis. Acta Biochim. Biophys. Sin. 50, 121–132 (2018).

    Article  CAS  PubMed  Google Scholar 

  168. Nadiminty, N. et al. Prostate-specific antigen modulates genes involved in bone remodeling and induces osteoblast differentiation of human osteosarcoma cell line SaOS-2. Clin. Cancer Res. 12, 1420–1430 (2006).

    Article  CAS  PubMed  Google Scholar 

  169. Zhang, X. Y. Interactions between cancer cells and bone microenvironment promote bone metastasis in prostate cancer. Cancer Commun. 39, 76 (2019).

    Article  Google Scholar 

  170. Cohen, P., Peehl, D. M., Graves, H. C. & Rosenfeld, R. G. Biological effects of prostate specific antigen as an insulin-like growth factor binding protein-3 protease. J. Endocrinol. 142, 407–415 (1994).

    Article  CAS  PubMed  Google Scholar 

  171. Cramer, S. D., Chen, Z. & Peehl, D. M. Prostate specific antigen cleaves parathyroid hormone-related protein in the PTH-like domain: inactivation of PTHrP-stimulated cAMP accumulation in mouse osteoblasts. J. Urol. 156, 526–531 (1996).

    Article  CAS  PubMed  Google Scholar 

  172. Iwamura, M., Hellman, J., Cockett, A. T., Lilja, H. & Gershagen, S. Alteration of the hormonal bioactivity of parathyroid hormone-related protein (PTHrP) as a result of limited proteolysis by prostate-specific antigen. Urology 48, 317–325 (1996).

    Article  CAS  PubMed  Google Scholar 

  173. Martin, T. J. Parathyroid hormone-related protein, its regulation of cartilage and bone development, and role in treating bone diseases. Physiol. Rev. 96, 831–871 (2016).

    Article  CAS  PubMed  Google Scholar 

  174. Frieling, J. S. & Lynch, C. C. Proteolytic regulation of parathyroid hormone-related protein: functional implications for skeletal malignancy. Int. J. Mol. Sci. 20, 2814 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  175. Josson, S., Matsuoka, Y., Chung, L. W., Zhau, H. E. & Wang, R. Tumor–stroma co-evolution in prostate cancer progression and metastasis. Semin. Cell Dev. Biol. 21, 26–32 (2010).

    Article  CAS  PubMed  Google Scholar 

  176. Drucker, K. L. et al. Clinical significance and novel mechanism of action of kallikrein 6 in glioblastoma. Neuro Oncol. 15, 305–318 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Kim, T. W. et al. Kallikrein-related peptidase 6 induces chemotherapeutic resistance by attenuating auranofin-induced cell death through activation of autophagy in gastric cancer. Oncotarget 7, 85332–85348 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  178. Jin, Y. et al. Molecular circuit involving KLK4 integrates androgen and mTOR signaling in prostate cancer. Proc. Natl Acad. Sci. USA 110, E2572 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Sotiropoulou, G. & Pampalakis, G. Targeting the kallikrein-related peptidases for drug development. Trends Pharmacol. Sci. 33, 623–634 (2012).

    Article  CAS  PubMed  Google Scholar 

  180. Goettig, P., Magdolen, V. & Brandstetter, H. Natural and synthetic inhibitors of kallikrein-related peptidases (KLKs). Biochimie 92, 1546–1567 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Mavridis, K., Avgeris, M. & Scorilas, A. Targeting kallikrein-related peptidases in prostate cancer. Expert Opin. Ther. Targets 18, 365–383 (2014).

    Article  CAS  PubMed  Google Scholar 

  182. Cereda, V., Formica, V., Menghi, A., Pellicori, S. & Roselli, M. Kallikrein-related peptidases targeted therapies in prostate cancer: perspectives and challenges. Expert Opin. Investig. Drugs 24, 929–947 (2015).

    Article  CAS  PubMed  Google Scholar 

  183. Oikonomopoulou, K. et al. Functional proteomics of kallikrein-related peptidases in ovarian cancer ascites fluid. Biol. Chem. 391, 381–390 (2010).

    Article  CAS  PubMed  Google Scholar 

  184. Sauer, A. K. et al. Zinc deficiency in men over 50 and its implications in prostate disorders. Front. Oncol. 10, 1293 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  185. Hekim, C. et al. Novel peptide inhibitors of human kallikrein 2. J. Biol. Chem. 281, 12555–12560 (2006).

    Article  CAS  PubMed  Google Scholar 

  186. Cloutier, S. M. et al. Development of recombinant inhibitors specific to human kallikrein 2 using phage-display selected substrates. Eur. J. Biochem. 271, 607–613 (2004).

    Article  CAS  PubMed  Google Scholar 

  187. Pakkala, M. et al. Activity and stability of human kallikrein-2-specific linear and cyclic peptide inhibitors. J. Pept. Sci. 13, 348–353 (2007).

    Article  CAS  PubMed  Google Scholar 

  188. LeBeau, A. M., Banerjee, S. R., Pomper, M. G., Mease, R. C. & Denmeade, S. R. Optimization of peptide-based inhibitors of prostate-specific antigen (PSA) as targeted imaging agents for prostate cancer. Bioorgan Med. Chem. 17, 4888–4893 (2009).

    Article  CAS  Google Scholar 

  189. Deperthes, D. & Kundig, C. Kallikrein-related peptidases as pharmaceutical targets. Trends Pharmacol. Sci. 33, 623–634 (2012).

    Article  Google Scholar 

  190. Riley, B. T. et al. KLK4 inhibition by cyclic and acyclic peptides: structural and dynamical insights into standard-mechanism protease inhibitors. Biochemistry 58, 2524–2533 (2019).

    Article  CAS  PubMed  Google Scholar 

  191. Riley, B. T. et al. Direct and indirect mechanisms of KLK4 inhibition revealed by structure and dynamics. Sci. Rep. 6, 35385 (2016). Together with Koistinen et al. (2008), Hekim et al. (2006), Cloutier et al. (2004) and Pakkala et al. (2007), this work highlights the utility of peptides in inhibiting specific kallikreins.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. de Veer, S. J. et al. Mechanism-based selection of a potent kallikrein-related peptidase 7 inhibitor from a versatile library based on the sunflower trypsin inhibitor SFTI-1. Biopolymers 100, 510–518 (2013).

    Article  PubMed  Google Scholar 

  193. de Veer, S. J. et al. Selective substrates and inhibitors for kallikrein-related peptidase 7 (KLK7) shed light on KLK proteolytic activity in the stratum corneum. J. Invest. Dermatol. 137, 430–439 (2017).

    Article  PubMed  Google Scholar 

  194. Sananes, A. et al. A potent, proteolysis-resistant inhibitor of kallikrein-related peptidase 6 (KLK6) for cancer therapy, developed by combinatorial engineering. J. Biol. Chem. 293, 12663–12680 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Candido, J. B. et al. Kallikrein-related peptidase 6 is associated with the tumour microenvironment of pancreatic ductal adenocarcinoma. Cancers (Basel) 13, 3969 (2021).

    Article  CAS  Google Scholar 

  196. Kostova, M. B., Rosen, D. M., Chen, Y., Mease, R. C. & Denmeade, S. R. Structural optimization, biological evaluation, and application of peptidomimetic prostate specific antigen inhibitors. J. Med.Chem. 56, 4224–4235 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. LeBeau, A. M., Singh, P., Isaacs, J. T. & Denmeade, S. R. Potent and selective peptidyl boronic acid inhibitors of the serine protease prostate-specific antigen. Chem. Biol. 15, 665–674 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Lovell, S. et al. A suite of activity-based probes to dissect the KLK activome in drug-resistant prostate cancer. J. Am. Chem. Soc. 143, 8911–8924 (2021).

    Article  CAS  PubMed  Google Scholar 

  199. Pereira, S. G. T. et al. Intracellular activation of a prostate specific antigen-cleavable doxorubicin prodrug: a key feature toward prodrug-nanomedicine design. Mol. Pharm. 16, 1573–1585 (2019).

    Article  CAS  PubMed  Google Scholar 

  200. DiPaola, R. S. et al. Characterization of a novel prostate-specific antigen-activated peptide-doxorubicin conjugate in patients with prostate cancer. J. Clin. Oncol. 20, 1874–1879 (2002).

    Article  CAS  PubMed  Google Scholar 

  201. Barve, A., Jain, A., Liu, H., Jin, W. & Cheng, K. An enzyme-responsive conjugate improves the delivery of a PI3K inhibitor to prostate cancer. Nanomedicine 12, 2373–2381 (2016).

    Article  CAS  PubMed  Google Scholar 

  202. Li, B. et al. Synergistic tumor growth-inhibitory effect of the prostate-specific antigen-activated fusion peptide BSD352 for prostate cancer therapy. Anticancer. Drugs 22, 213–222 (2011).

    Article  CAS  PubMed  Google Scholar 

  203. Denmeade, S. R. et al. Prostate-specific antigen-activated thapsigargin prodrug as targeted therapy for prostate cancer. J. Natl Cancer Inst. 95, 990–1000 (2003).

    Article  CAS  PubMed  Google Scholar 

  204. Janssen, S. et al. Pharmacokinetics, biodistribution, and antitumor efficacy of a human glandular kallikrein 2 (hK2)-activated thapsigargin prodrug. Prostate 66, 358–368 (2006).

    Article  CAS  PubMed  Google Scholar 

  205. Aloysius, H. & Hu, L. Improving the specificity of the prostate-specific antigen substrate Glutaryl-Hyp-Ala-Ser-Chg-Gln as a promoiety. Chem. Biol. Drug Des. 86, 837–848 (2015).

    Article  CAS  PubMed  Google Scholar 

  206. Aloysius, H. & Hu, L. Q. Synthesis and evaluation of new peptide-linked doxorubicin conjugates as prodrugs activated by prostate-specific antigen. Med. Chem. Res. 29, 1280–1299 (2020).

    Article  CAS  Google Scholar 

  207. Williams, S. A. et al. A prostate-specific antigen-activated channel-forming toxin as therapy for prostatic disease. J. Natl Cancer Inst. 99, 376–385 (2007).

    Article  CAS  PubMed  Google Scholar 

  208. Rogers, O. C. et al. Microparticle encapsulation of a prostate-targeted biologic for the treatment of liver metastases in a preclinical model of castration-resistant prostate cancer. Mol. Cancer Ther. 19, 2353–2362 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Timmermand, O. V. et al. Preclinical imaging of kallikrein-related peptidase 2 (hK2) in prostate cancer with a 111In-radiolabelled monoclonal antibody, 11B6. EJNMMI Res. 4, 51 (2014). This study presents a novel theranostic approach targeting KLK2 for prostate cancer.

    Article  PubMed  PubMed Central  Google Scholar 

  210. Evans-Axelsson, S. et al. Targeting free prostate-specific antigen for in vivo imaging of prostate cancer using a monoclonal antibody specific for unique epitopes accessible on free prostate-specific antigen alone. Cancer Biother Radiopharm. 27, 243–251 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Du, D., Fu, H. J., Ren, W. W., Li, X. L. & Guo, L. H. PSA targeted dual-modality manganese oxide–mesoporous silica nanoparticles for prostate cancer imaging. Biomed. Pharmacother. 121, 109614 (2020).

    Article  CAS  PubMed  Google Scholar 

  212. McDevitt, M. R. et al. Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer. Nat. Commun. 9, 1629 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  213. Veach, D. R. et al. PSA-targeted α-, β-, and positron-emitting immunotheranostics in murine prostate cancer models and nonhuman primates. Clin. Cancer Res. 27, 2050–2060 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Timmermand, O. V., Larsson, E., Ulmert, D., Tran, T. A. & Strand, S. E. Radioimmunotherapy of prostate cancer targeting human kallikrein-related peptidase 2. EJNMMI Res. 6, 27 (2016).

    Article  Google Scholar 

  215. Abdul Sater, H. et al. Neoadjuvant PROSTVAC prior to radical prostatectomy enhances T-cell infiltration into the tumor immune microenvironment in men with prostate cancer. J Immunother Cancer 8, e000655 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  216. Tang, L. et al. Long non-coding RNA LINC01314 represses cell migration, invasion, and angiogenesis in gastric cancer via the Wnt/β-catenin signaling pathway by down-regulating KLK4. Cancer Cell Int. 19, 94 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  217. Zhu, S. P., Wang, J. Y., Wang, X. G. & Zhao, J. P. Long intergenic non-protein coding RNA 00858 functions as a competing endogenous RNA for miR-422a to facilitate the cell growth in non-small cell lung cancer. Aging 9, 475–486 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Matin, F. et al. microRNA-3162-5p-mediated crosstalk between kallikrein family members including prostate-specific antigen in prostate cancer. Clin. Chem. 65, 771–780 (2019).

    Article  CAS  PubMed  Google Scholar 

  219. Fields, G. B. The rebirth of matrix metalloproteinase inhibitors: moving beyond the dogma. Cells 8, 984 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  220. Michael, I. P. et al. Human tissue kallikrein 5 is a member of a proteolytic cascade pathway involved in seminal clot liquefaction and potentially in prostate cancer progression. J. Biol. Chem. 281, 12743–12750 (2006).

    Article  CAS  PubMed  Google Scholar 

  221. Du, J. P. et al. Kallikrein-related peptidase 7 is a potential target for the treatment of pancreatic cancer. Oncotarget 9, 12894–12906 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  222. Prezas, P. et al. Overexpression of the human tissue kallikrein genes KLK4, 5, 6, and 7 increases the malignant phenotype of ovarian cancer cells. Biol. Chem. 387, 807–811 (2006).

    Article  CAS  PubMed  Google Scholar 

  223. Loessner, D., Little, J. P., Pettet, G. J. & Hutmacher, D. W. A multiscale road map of cancer spheroids — incorporating experimental and mathematical modelling to understand cancer progression. J. Cell Sci. 126, 2761–2771 (2013).

    CAS  PubMed  Google Scholar 

  224. Wang, P. et al. Kallikrein-related peptidases 4, 5, 6 and 7 regulate tumour-associated factors in serous ovarian cancer. Br. J. Cancer 119, 1–9 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Oikonomopoulou, K., Diamandis, E. P. & Hollenberg, M. D. Kallikrein-related peptidases: proteolysis and signaling in cancer, the new frontier. Biol. Chem. 391, 299–310 (2010).

    Article  CAS  PubMed  Google Scholar 

  226. Mize, G. J., Wang, W. & Takayama, T. K. Prostate-specific kallikreins-2 and -4 enhance the proliferation of DU-145 prostate cancer cells through protease-activated receptors-1 and -2. Mol. Cancer Res. 6, 1043–1051 (2008).

    Article  CAS  PubMed  Google Scholar 

  227. Shah, M. R. et al. Direct intra-tumoral injection of zinc-acetate halts tumor growth in a xenograft model of prostate cancer. J. Exp. Clin. Cancer Res. 28, 84 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  228. Elhilali, M. M. et al. Prospective, randomized, double-blind, vehicle controlled, multicenter phase IIb clinical trial of the pore forming protein PRX302 for targeted treatment of symptomatic benign prostatic hyperplasia. J. Urol. 189, 1421–1426 (2013).

    Article  CAS  PubMed  Google Scholar 

  229. Karan, D. et al. Dual antigen target-based immunotherapy for prostate cancer eliminates the growth of established tumors in mice. Immunotherapy 3, 735–746 (2011).

    Article  CAS  PubMed  Google Scholar 

  230. Gamat-Huber, M. et al. Treatment combinations with DNA vaccines for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Cancers (Basel) 12, 2831 (2020).

    Article  CAS  Google Scholar 

  231. Sinha, A. A., Quast, B. J., Reddy, P. K., Elson, M. K. & Wilson, M. J. Intravenous injection of an immunoconjugate (anti-PSA-IgG conjugated to 5-fluoro-2′-deoxyuridine) selectively inhibits cell proliferation and induces cell death in human prostate cancer cell tumors grown in nude mice. Anticancer. Res. 19, 893–902 (1999).

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by a Translational Research Institute spore grant to J.B., J.C. and S.S., a Department of Defense Idea Development Award to J.B. and a National Health and Medical Research Council (NHMRC) Principal Research Fellowship to J.C. T.K. is a National Breast Cancer Foundation Fellow. The authors thank S. Seth for contributing to formation of the tables. S.S. is supported by an Advance Queensland Industry Early Career Research Fellowship. J.B. is supported by an Advance Queensland Industry Mid Career Research Fellowship. J.C. is an Emeritus Distinguished Professor at Queensland University of Technology.

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Authors and Affiliations

  1. School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia

    Srilakshmi Srinivasan, Jyotsna Batra & Judith Clements

  2. Australian Prostate Cancer Research Centre-Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia

    Srilakshmi Srinivasan, Thomas Kryza, Jyotsna Batra & Judith Clements

  3. Mater Research Institute, The University of Queensland, Woolloongabba, Brisbane, Queensland, Australia

    Thomas Kryza

  4. Centre for Genomics and Personalised Medicine, Queensland University of Technology, Brisbane, Queensland, Australia

    Jyotsna Batra

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  1. Srilakshmi Srinivasan
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Contributions

S.S. researched the data and drafted the article. T.K. contributed the figures. All authors made substantial contribution to the discussion of content, and reviewed and edited the manuscript before submission.

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Correspondence to Judith Clements.

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Nature Reviews Cancer thanks Johann de Bono, Hannu Koistinen, who co-reviewed the manuscript with Ruusu-Maaria Kovanen, and Andreas Scorilas for their contribution to the peer review of this work.

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Supplementary information

Glossary

Zymogen forms

Proteolytically inactive precursor forms of a protease.

Tumour microenvironment

(TME). The area surrounding a tumour, in which other cell types, molecules and components such as blood vessels, immune cells, (myo)fibroblasts, cancer-associated fibroblasts (CAFs), tumour-associated macrophages (TAMs), bone marrow-derived stromal cells, signalling molecules and extracellular matrix (ECM) also are also found and considered to be altered owing to this changed cancer-associated environment.

Extracellular matrix

(ECM). The structural matrix that consists of a multitude of proteins that provide structural support and organizational architecture to tissue.

Cancer-associated fibroblasts

(CAFs). Activated fibroblasts associated with malignant tumours that have diverse functions such as creating extracellular matrix (ECM) and metabolic and immune reprogramming of the tumour microenvironment.

Desmoplastic stroma

Tumour stroma consisting of dense fibrous or connective tissue.

Meprins

Meprin proteinases are members of the metzincin superfamily and are proteases involved in tissue homeostasis, extracellular matrix (ECM) remodelling and immunological processes.

Angiogenesis

Formation of new blood vessels.

Lymphangiogenesis

Formation of new lymphatic vessels from pre-existing lymphatic vessels.

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Srinivasan, S., Kryza, T., Batra, J. et al. Remodelling of the tumour microenvironment by the kallikrein-related peptidases. Nat Rev Cancer 22, 223–238 (2022). https://doi.org/10.1038/s41568-021-00436-z

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