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Proteases: Role and Function in Cancer

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 32024

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Prof. Dr. Janko Kos

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Guest Editor

Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia
Interests: peptidases; inhibitors; cathepsins; cystatins; cancer; immune response; cytotoxic cells; delivery systems; diagnostics
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Jörg W. Bartsch

E-Mail Website
Co-Guest Editor

Department of Neurosurgery/Lab, Philipps University Marburg, Marburg, Germany
Interests: molecular oncology; proteases; extracellular matrix; tumor microenvironment; extracellular vesicles

Special Issue Information

Dear Colleagues,

Peptidases are involved in various stages of development and progression of cancer. Although much emphasis was initially given to tumor cell-associated peptidases, a growing number of studies have shown that peptidases associated with tumor stroma, such as fibroblasts and immune and endothelial cells, can also contribute significantly to cancer progression. In addition, the crosstalk between tumor cells and their microenvironment creates conditions favorable for tumor invasion, angiogenesis, and metastasis. Peptidases are important in modulating antitumor immune response as well as growth and development of cancer stem cells and transition between epithelial and mesenchymal cell types.

The Special Issue “Proteases: Role and Function in Cancer” aims to focus on basic science and translational research to highlight the role of this group of enzymes in tumor development and to assess their potential in cancer diagnosis and therapy. It encourages researchers to contribute new achievements on the role of complex proteolytic system in mechanisms of cancer progression and new approaches on how to impair cancer-associated harmful function of proteolytic enzymes in order to improve patient treatment.

Prof. Janko Kos
Guest Editor
Prof. Dr. Jörg W. Bartsch
Co-Guest Editor

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Keywords

Peptidases
Cancer
Inhibitors
Invasion
Migration
Signaling
Angiogenesis
Apoptosis
Tumor microenvironment
Cancer stem cells
Epithelial/mesenchymal transition
Antitumor immune response
Diagnosis
Prognosis
Therapy

Published Papers (10 papers)

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Editorial

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4 pages, 198 KiB

Open AccessEditorial

Proteases: Role and Function in Cancer

by Janko Kos

Int. J. Mol. Sci. 2022, 23(9), 4632; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094632 - 22 Apr 2022

Cited by 4 | Viewed by 1415

Abstract

The Special Issue “Proteases: Role and Function in Cancer” aimed to focus on basic and translational research to highlight the role of peptidases in tumor development and to assess their potential in cancer diagnosis and therapy [...] Full article

(This article belongs to the Special Issue Proteases: Role and Function in Cancer)

Research

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18 pages, 3589 KiB

Open AccessArticle

ADAM8-Dependent Extracellular Signaling in the Tumor Microenvironment Involves Regulated Release of Lipocalin 2 and MMP-9

by Lena Cook, Marie Sengelmann, Birte Winkler, Constanze Nagl, Sarah Koch, Uwe Schlomann, Emily P. Slater, Miles A. Miller, Elke Pogge von Strandmann, Bastian Dörsam, Christian Preußer and Jörg W. Bartsch

Int. J. Mol. Sci. 2022, 23(4), 1976; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23041976 - 10 Feb 2022

Cited by 9 | Viewed by 3423

Abstract

The metalloprotease-disintegrin ADAM8 is critically involved in the progression of pancreatic cancer. Under malignant conditions, ADAM8 is highly expressed and could play an important role in cell–cell communication as expression has been observed in tumor and immune cells of the tumor microenvironment (TME) such as macrophages. To analyze the potential role of ADAM8 in the TME, ADAM8 knockout PDAC tumor cells were generated, and their release of extracellular vesicles (EVs) was analyzed. In EVs, ADAM8 is present as an active protease and associated with lipocalin 2 (LCN2) and matrix metalloprotease 9 (MMP-9) in an ADAM8-dependent manner, as ADAM8 KO cells show a lower abundance of LCN2 and MMP-9. Sorting of ADAM8 occurs independent of TSG101, even though ADAM8 contains the recognition motif PTAP for the ESCRTI protein TSG101 within the cytoplasmic domain (CD). When tumor cells were co-cultured with macrophages (THP-1 cells), expression of LCN2 and MMP-9 in ADAM8 KO cells was induced, suggesting that macrophage signaling can overcome ADAM8-dependent intracellular signaling in PDAC cells. In co-culture with macrophages, regulation of MMP-9 is independent of the M1/M2 polarization state, whereas LCN2 expression is preferentially affected by M1-like macrophages. From these data, we conclude that ADAM8 has a systemic effect in the tumor microenvironment, and its expression in distinct cell types has to be considered for ADAM8 targeting in tumors. Full article

(This article belongs to the Special Issue Proteases: Role and Function in Cancer)

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20 pages, 3582 KiB

Open AccessArticle

Upregulation of Cathepsin X in Glioblastoma: Interplay with γ-Enolase and the Effects of Selective Cathepsin X Inhibitors

by Bernarda Majc, Anamarija Habič, Metka Novak, Ana Rotter, Andrej Porčnik, Jernej Mlakar, Vera Župunski, Urša Pečar Fonović, Damijan Knez, Nace Zidar, Stanislav Gobec, Janko Kos, Tamara Lah Turnšek, Anja Pišlar and Barbara Breznik

Int. J. Mol. Sci. 2022, 23(3), 1784; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031784 - 04 Feb 2022

Cited by 11 | Viewed by 2656

Abstract

Glioblastoma (GBM) is the most common and deadly primary brain tumor in adults. Understanding GBM pathobiology and discovering novel therapeutic targets are critical to finding efficient treatments. Upregulation of the lysosomal cysteine carboxypeptidase cathepsin X has been linked to immune dysfunction and neurodegenerative diseases, but its role in cancer and particularly in GBM progression in patients is unknown. In this study, cathepsin X expression and activity were found to be upregulated in human GBM tissues compared to low-grade gliomas and nontumor brain tissues. Cathepsin X was localized in GBM cells as well as in tumor-associated macrophages and microglia. Subsequently, potent irreversible (AMS36) and reversible (Z7) selective cathepsin X inhibitors were tested in vitro. Selective cathepsin X inhibitors decreased the viability of patient-derived GBM cells as well as macrophages and microglia that were cultured in conditioned media of GBM cells. We next examined the expression pattern of neuron-specific enzyme γ-enolase, which is the target of cathepsin X. We found that there was a correlation between high proteolytic activity of cathepsin X and C-terminal cleavage of γ-enolase and that cathepsin X and γ-enolase were colocalized in GBM tissues, preferentially in GBM-associated macrophages and microglia. Taken together, our results on patient-derived material suggest that cathepsin X is involved in GBM progression and is a potential target for therapeutic approaches against GBM. Full article

(This article belongs to the Special Issue Proteases: Role and Function in Cancer)

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17 pages, 3514 KiB

Open AccessArticle

Cathepsin X Activity Does Not Affect NK-Target Cell Synapse but Is Rather Distributed to Cytotoxic Granules

by Tanja Jakoš, Mateja Prunk, Anja Pišlar and Janko Kos

Int. J. Mol. Sci. 2021, 22(24), 13495; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413495 - 16 Dec 2021

Cited by 3 | Viewed by 1770

Abstract

Cathepsin X is a lysosomal peptidase that is involved in tumour progression and represents a potential target for therapeutic interventions. In addition, it regulates important functions of immune cells and is implicated in the modulation of tumour cell–immune cell crosstalk. Selective cathepsin X inhibitors have been proposed as prospective antitumour agents to prevent cancer progression; however, their impact on the antitumour immune response has been overlooked. Previous studies indicate that the migration and adhesion of T cells and dendritic cells are affected by diminished cathepsin X activity. Meanwhile, the influence of cathepsin X inhibition on natural killer (NK) cell function has not yet been explored. Here, we examined the localization patterns of cathepsin X and the role of its inhibitors on the cytotoxicity of cell line NK-92, which is used for adoptive cellular immunotherapy in cancer patients. NK-92 cells depend on lymphocyte function-associated antigen 1 (LFA-1) to form stable immunoconjugates with target cells, providing, in this way, optimal cytotoxicity. Since LFA-1 is a substrate for cathepsin X activity in other types of cells, we hypothesized that cathepsin X could disturb the formation of NK-92 immunoconjugates. Thus, we employed cathepsin X reversible and irreversible inhibitors and evaluated their effects on the NK-92 cell interactions with target cells and on the NK-92 cell cytotoxicity. We show that cathepsin X inhibition does not impair stable conjugate formation or the lytic activity of NK-92 cells. Similarly, the conjugate formation between Jurkat T cells and target cells was not affected by cathepsin X activity. Unlike in previous migration and adhesion studies on T cells, in NK-92 cells cathepsin X was not co-localized with LFA-1 at the plasma membrane but was, rather, redistributed to the cytotoxic granules and secreted during degranulation. Full article

(This article belongs to the Special Issue Proteases: Role and Function in Cancer)

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20 pages, 3233 KiB

Open AccessArticle

Integrated Multi-Omics Investigations of Metalloproteinases in Colon Cancer: Focus on MMP2 and MMP9

by Miriam Buttacavoli, Gianluca Di Cara, Elena Roz, Ida Pucci-Minafra, Salvatore Feo and Patrizia Cancemi

Int. J. Mol. Sci. 2021, 22(22), 12389; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212389 - 17 Nov 2021

Cited by 41 | Viewed by 2679

Abstract

Colorectal cancer (CRC) develops by genetic and epigenetic alterations. However, the molecular mechanisms underlying metastatic dissemination remain unclear and could benefit from multi-omics investigations of specific protein families. Matrix metalloproteinases (MMPs) are proteolytic enzymes involved in ECM remodeling and the processing of bioactive molecules. Increased MMP expression promotes the hallmarks of tumor progression, including angiogenesis, invasion, and metastasis, and is correlated with a shortened survival. Nevertheless, the collective role and the possible coordination of MMP members in CRC are poorly investigated. Here, we performed a multi-omics analysis of MMP expression in CRC using data mining and experimental investigations. Several databases were used to deeply mine different expressions between tumor and normal tissues, the genetic and epigenetic alterations, the prognostic value as well as the interrelationships with tumor immune-infiltrating cells (TIICs). A special focus was placed on to MMP2 and MMP9: their expression was correlated with immune markers and the interaction network of co-expressed genes disclosed their implication in epithelial to mesenchymal transition (EMT) and immune response. Finally, the activity levels of MMP2 and MMP9 in a cohort of colon cancer samples, including tissues and the corresponding sera, was also investigated by zymography. Our findings suggested that MMPs could have a high potency, as they are targeted in colon cancer, and might serve as novel biomarkers, especially for their involvement in the immune response. However, further studies are needed to explore the detailed biological functions and molecular mechanisms of MMPs in CRC, also in consideration of their expression and different regulation in several tissues. Full article

(This article belongs to the Special Issue Proteases: Role and Function in Cancer)

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17 pages, 932 KiB

Open AccessArticle

Metalloproteinases 1 and 3 as Potential Biomarkers in Breast Cancer Development

by Angela Ximena Argote Camacho, Amanda Rocío González Ramírez, Alejandro José Pérez Alonso, Juan David Rejón García, María Auxiliadora Olivares Urbano, Pablo Torné Poyatos, Sandra Ríos Arrabal and María Isabel Núñez

Int. J. Mol. Sci. 2021, 22(16), 9012; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22169012 - 20 Aug 2021

Cited by 17 | Viewed by 2646

Abstract

Breast cancer continues to be one of the main causes of morbidity and mortality globally and was the leading cause of cancer death in women in Spain in 2020. Early diagnosis is one of the most effective methods to lower the incidence and mortality rates of breast cancer. The human metalloproteinases (MMP) mainly function as proteolytic enzymes degrading the extracellular matrix and plays important roles in most steps of breast tumorigenesis. This retrospective cohort study shows the immunohistochemical expression levels of MMP-1, MMP-2, MMP-3, and MMP-9 in 154 women with breast cancer and 42 women without tumor disease. The samples of breast tissue are assessed using several tissue matrices (TMA). The percentages of staining (≤50%–>50%) and intensity levels of staining (weak, moderate, or intense) are considered. The immunohistochemical expression of the MMP-1-intensity (p = 0.043) and MMP-3 percentage (p = 0.018) and intensity, (p = 0.025) present statistically significant associations with the variable group (control–case); therefore, expression in the tumor tissue samples of these MMPs may be related to the development of breast cancer. The relationships between these MMPs and some clinicopathological factors in breast cancer are also evaluated but no correlation is found. These results suggest the use of MMP-1 and MMP-3 as potential biomarkers of breast cancer diagnosis. Full article

(This article belongs to the Special Issue Proteases: Role and Function in Cancer)

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15 pages, 1302 KiB

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Human CD4+ T-Cell Clone Expansion Leads to the Expression of the Cysteine Peptidase Inhibitor Cystatin F

by Milica Perišić Nanut, Graham Pawelec and Janko Kos

Int. J. Mol. Sci. 2021, 22(16), 8408; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168408 - 05 Aug 2021

Cited by 3 | Viewed by 2318

Abstract

The existence of CD4+ cytotoxic T cells (CTLs) at relatively high levels under different pathological conditions in vivo suggests their role in protective and/or pathogenic immune functions. CD4+ CTLs utilize the fundamental cytotoxic effector mechanisms also utilized by CD8+ CTLs and natural killer cells. During long-term cultivation, CD4+ T cells were also shown to acquire cytotoxic functions. In this study, CD4+ human T-cell clones derived from activated peripheral blood lymphocytes of healthy young adults were examined for the expression of cytotoxic machinery components. Cystatin F is a protein inhibitor of cysteine cathepsins, synthesized by CD8+ CTLs and natural killer cells. Cystatin F affects the cytotoxic efficacy of these cells by inhibiting the major progranzyme convertases cathepsins C and H as well as cathepsin L, which is involved in perforin activation. Here, we show that human CD4+ T-cell clones express the cysteine cathepsins that are involved in the activation of granzymes and perforin. CD4+ T-cell clones contained both the inactive, dimeric form as well as the active, monomeric form of cystatin F. As in CD8+ CTLs, cysteine cathepsins C and H were the major targets of cystatin F in CD4+ T-cell clones. Furthermore, CD4+ T-cell clones expressed the active forms of perforin and granzymes A and B. The levels of the cystatin F decreased with time in culture concomitantly with an increase in the activities of granzymes A and B. Therefore, our results suggest that cystatin F plays a role in regulating CD4+ T cell cytotoxicity. Since cystatin F can be secreted and taken up by bystander cells, our results suggest that CD4+ CTLs may also be involved in regulating immune responses through cystatin F secretion. Full article

(This article belongs to the Special Issue Proteases: Role and Function in Cancer)

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Review

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53 pages, 5000 KiB

Open AccessReview

Matrix Metalloproteinases Shape the Tumor Microenvironment in Cancer Progression

by Stephan Niland, Andrea Ximena Riscanevo and Johannes Andreas Eble

Int. J. Mol. Sci. 2022, 23(1), 146; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010146 - 23 Dec 2021

Cited by 134 | Viewed by 7828

Abstract

Cancer progression with uncontrolled tumor growth, local invasion, and metastasis depends largely on the proteolytic activity of numerous matrix metalloproteinases (MMPs), which affect tissue integrity, immune cell recruitment, and tissue turnover by degrading extracellular matrix (ECM) components and by releasing matrikines, cell surface-bound cytokines, growth factors, or their receptors. Among the MMPs, MMP-14 is the driving force behind extracellular matrix and tissue destruction during cancer invasion and metastasis. MMP-14 also influences both intercellular as well as cell–matrix communication by regulating the activity of many plasma membrane-anchored and extracellular proteins. Cancer cells and other cells of the tumor stroma, embedded in a common extracellular matrix, interact with their matrix by means of various adhesive structures, of which particularly invadopodia are capable to remodel the matrix through spatially and temporally finely tuned proteolysis. As a deeper understanding of the underlying functional mechanisms is beneficial for the development of new prognostic and predictive markers and for targeted therapies, this review examined the current knowledge of the interplay of the various MMPs in the cancer context on the protein, subcellular, and cellular level with a focus on MMP14. Full article

(This article belongs to the Special Issue Proteases: Role and Function in Cancer)

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21 pages, 1844 KiB

Open AccessReview

The Duality of Caspases in Cancer, as Told through the Fly

by Caitlin Hounsell and Yun Fan

Int. J. Mol. Sci. 2021, 22(16), 8927; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168927 - 19 Aug 2021

Cited by 17 | Viewed by 3390

Abstract

Caspases, a family of cysteine-aspartic proteases, have an established role as critical components in the activation and initiation of apoptosis. Alongside this a variety of non-apoptotic caspase functions in proliferation, differentiation, cellular plasticity and cell migration have been reported. The activity level and context are important factors in determining caspase function. As a consequence of their critical role in apoptosis and beyond, caspases are uniquely situated to have pathological roles, including in cancer. Altered caspase function is a common trait in a variety of cancers, with apoptotic evasion defined as a “hallmark of cancer”. However, the role that caspases play in cancer is much more complex, acting both to prevent and to promote tumourigenesis. This review focuses on the major findings in Drosophila on the dual role of caspases in tumourigenesis. This has major implications for cancer treatments, including chemotherapy and radiotherapy, with the activation of apoptosis being the end goal. However, such treatments may inadvertently have adverse effects on promoting tumour progression and acerbating the cancer. A comprehensive understanding of the dual role of caspases will aid in the development of successful cancer therapeutic approaches. Full article

(This article belongs to the Special Issue Proteases: Role and Function in Cancer)

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15 pages, 12086 KiB

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Intrinsically Connected: Therapeutically Targeting the Cathepsin Proteases and the Bcl-2 Family of Protein Substrates as Co-regulators of Apoptosis

by Surinder M. Soond, Maria V. Kozhevnikova, Lyudmila V. Savvateeva, Paul A. Townsend and Andrey A. Zamyatnin, Jr.

Int. J. Mol. Sci. 2021, 22(9), 4669; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094669 - 28 Apr 2021

Cited by 12 | Viewed by 2889

Abstract

Taken with the growing importance of cathepsin-mediated substrate proteolysis in tumor biology and progression, the focus and emphasis placed on therapeutic design and development is coming into fruition. Underpinning this approach is the invariable progression from the direction of fully characterizing cathepsin protease members and their substrate targets, towards targeting such an interaction with tangible therapeutics. The two groups of such substrates that have gained much attention over the years are the pro- and anti- apoptotic protein intermediates from the extrinsic and intrinsic signaling arms of the apoptosis pathway. As proteins that are central to determining cellular fate, some of them present themselves as very favorable candidates for therapeutic targeting. However, considering that both anti- and pro- apoptotic signaling intermediates have been reported to be downstream substrates for certain activated cathepsin proteases, therapeutic targeting approaches based on greater selectivity do need to be given greater consideration. Herein, we review the relationships shared by the cathepsin proteases and the Bcl-2 homology domain proteins, in the context of how the topical approach of adopting ‘BH3-mimetics’ can be explored further in modulating the relationship between the anti- and pro- apoptotic signaling intermediates from the intrinsic apoptosis pathway and their upstream cathepsin protease regulators. Based on this, we highlight important future considerations for improved therapeutic design. Full article

(This article belongs to the Special Issue Proteases: Role and Function in Cancer)

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