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Cysteine cathepsin proteases: regulators of cancer progression and therapeutic response

Nature Reviews Cancer volume 15, pages 712–729 (2015)Cite this article

Subjects

Key Points

  • In many cancer types cathepsin proteases are upregulated and display altered trafficking and localization. Increased cathepsin expression generally correlates with increased malignancy and poor patient prognosis.

  • Secretion of cathepsin proteases by cancer cells and infiltrating immune cells into the extracellular space disrupts intercellular adhesion complexes, induces angiogenesis and drives local invasion by tumour cells.

  • Genetic experiments have identified crucial non-redundant roles for individual cathepsin proteases in the tumorigenesis of multiple genetically engineered mouse models.

  • The pro- or antitumorigenic properties of individual cathepsins are context dependent and specific to the tissue and cell of origin or site of metastasis.

  • Cathepsin activity exists within a larger integrated network of protease activity known as the protease web. Through interactions with other proteases and their inhibitors, cathepsins can alter general proteolytic activity within the tumour microenvironment.

  • Cathepsin proteases have demonstrated roles in intrinsic and acquired resistance to radiation and chemotherapy. Concurrent inhibition of cathepsins with different therapeutic modalities improves outcome in preclinical models.

Abstract

Cysteine cathepsin protease activity is frequently dysregulated in the context of neoplastic transformation. Increased activity and aberrant localization of proteases within the tumour microenvironment have a potent role in driving cancer progression, proliferation, invasion and metastasis. Recent studies have also uncovered functions for cathepsins in the suppression of the response to therapeutic intervention in various malignancies. However, cathepsins can be either tumour promoting or tumour suppressive depending on the context, which emphasizes the importance of rigorous in vivo analyses to ascertain function. Here, we review the basic research and clinical findings that underlie the roles of cathepsins in cancer, and provide a roadmap for the rational integration of cathepsin-targeting agents into clinical treatment.

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Figure 1: Integration of cysteine cathepsin proteases within a proteolytic network.
Figure 2: The yin and yang of cancer-associated lysosomal biogenesis.
Figure 3: Cathepsin proteases in tumour progression and the metastatic cascade.
Figure 4: Cathepsin proteases and therapeutic resistance.

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Acknowledgements

J.A.J. is supported by grants from the National Cancer Institute, the American Cancer Society, the Breast Cancer Research Foundation and the Center for Metastasis Research at Memorial Sloan Kettering Cancer Center. O.C.O. is supported by F31 CA171384-04 from the National Cancer Institute. The authors are grateful to L. Akkari and L. Sevenich for insightful comments on the manuscript. The authors apologize to all the investigators whose research could not be appropriately cited because of the journal's space limitations.

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Authors and Affiliations

  1. Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center,

    Oakley C. Olson & Johanna A. Joyce

  2. Gerstner Sloan Kettering Graduate School of Biomedical Science, Memorial Sloan Kettering Cancer Center, New York, 10065, New York, USA

    Oakley C. Olson

  3. Department of Oncology, University of Lausanne,

    Johanna A. Joyce

  4. Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, CH-1066, Switzerland

    Johanna A. Joyce

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PowerPoint slides

Glossary

Extracellular matrix

(ECM). The ECM represents the multitude of proteins and macromolecules secreted by cells into the extracellular space, including collagens, laminins and fibronectin, which provide structural support as well as organizational architecture within the tissue. Tumorigenesis is characterized by remodelling of the ECM in association with disease progression.

Protease web

The interconnected system of biological interactions between all proteases and protease inhibitors.

N-terminomic and C-terminomic approaches

Covalent labelling of either the N terminus or C terminus within a protein sample allows identification of the original terminus in proteomic mass spectrometry analysis.

Cystatins

A protein family of cysteine protease inhibitors.

Tumour-associated macrophages

(TAMs). These macrophages are 'educated' in the tumour microenvironment where they provide various tumour-promoting functions. TAMs have been shown to promote tumour angiogenesis, invasion and metastasis, immunosuppression and therapeutic resistance.

RIP1-Tag2 PanNET mouse model

Expression of the SV40 large T antigen (Tag) under the control of the rat insulin promoter (RIP) causes β-cell hyperplasia, which progresses through a series of rate-limiting stages to invasive pancreatic neuroendocrine tumour (PanNET).

MMTV-PyMT mammary carcinoma mouse model

Expression of the polyomavirus middle T (PyMT) oncoprotein under control of the mouse mammary tumour virus (MMTV) long terminal repeat promoter induces mammary neoplasia reminiscent of that observed in human breast cancer. MMTV-PyMT tumours progress through stereotypical stages of cancer progression and metastasize to the lung.

K14-HPV16 mouse model of squamous cell carcinoma

Use of the keratin 14 promoter (K14) to drive expression of human papilloma virus type 16 (HPV16) E6 and E7 genes in basal cells of the squamous epithelium results in stepwise progression to squamous cell carcinoma.

KPC mouse model

Addition of the LSL-Trp53R172H allele to the KC model, results in widely metastatic invasive pancreatic ductal carcinoma.

Angiogenic switching

The stage at which incipient tumours acquire the capacity to induce angiogenesis.

Apoptosome

A pro-apoptotic structure comprising cytochrome c, apoptotic protease-activating factor 1 (APAF1) and caspase 9 formed upon mitochondrial outer membrane permeabilization and release of cytochrome c into the cytosol.

Blood–brain barrier

A highly selective vascular barrier between the circulation and the extracellular fluid of the brain.

Myeloid-derived suppressor cells

Tumour-associated myeloid cells that are phenotypically characterized by their ability to suppress T cell function.

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Olson, O., Joyce, J. Cysteine cathepsin proteases: regulators of cancer progression and therapeutic response. Nat Rev Cancer 15, 712–729 (2015). https://doi.org/10.1038/nrc4027

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