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Remodelling of the tumour microenvironment by the kallikrein-related peptidases

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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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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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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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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