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Cancers
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Proteolysis in Cancer Progression
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Proteolysis in Cancer Progression

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 16577

Special Issue Editor

Prof. Thomas Reinheckel

E-Mail Website
Guest Editor
Institute of Molecular Medicine and Cell Research, Universitat Freiburg im Breisgau, Freiburg im Breisgau, Germany
Interests: cysteine and aspartic cathepsins; metalloproteinases; cancer cell motility; cancer stem cells; cancer cell /stroma interactions; tumor microenvironment; tumor immunity; and metastasis

Special Issue Information

Dear Colleagues,

The 589 proteolytic enzymes and 244 protease inhibitors encoded in the human genome build regulated proteolytic cascades and complex proteolytic systems that determine the fate and function of virtually every protein. Therefore, the involvement of proteases and their inhibitors in cancer and metastasis is no surprise. Traditionally, proteases have been regarded as promotors of cancer progression, while protease inhibitors have been shown to check malignancy. In consequence, protease inhibition as a measure of cancer therapy has emerged as a major motivation for elucidating protease functions in cancers. Initially unsuspected, there is now increasing evidence for tumor-attenuating functions of proteases and tumor promotion by protease inhibitors. At the same time, the expression of proteases and their inhibitors has been scrutinized regarding their prognostic value in human cancers, while their usually high expression in cancer cells and in cells of the tumor stroma has led to their use as prodrug activators and targets for protease-based tumor imaging.

This Special Issue will highlight current developments in elucidating the in vivo functions of proteases and their inhibitors in cancer cells, tumor-associated immune cells, and other cell types of the tumor stroma. Contributions with proteolysis-related implications for the prevention, early diagnosis, and therapy of cancers are very welcome.

Prof. Thomas Reinheckel
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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Published Papers (5 papers)

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Research

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17 pages, 43608 KiB  
Article
Kallikrein-Related Peptidase 6 Is Associated with the Tumour Microenvironment of Pancreatic Ductal Adenocarcinoma
by Juliana B. Candido, Oscar Maiques, Melanie Boxberg, Verena Kast, Eleonora Peerani, Elena Tomás-Bort, Wilko Weichert, Amiram Sananes, Niv Papo, Viktor Magdolen, Victoria Sanz-Moreno and Daniela Loessner
Cancers 2021, 13(16), 3969; https://doi.org/10.3390/cancers13163969 - 5 Aug 2021
Cited by 11 | Viewed by 3226
Abstract
As cancer-associated factors, kallikrein-related peptidases (KLKs) are components of the tumour microenvironment, which represents a rich substrate repertoire, and considered attractive targets for the development of novel treatments. Standard-of-care therapy of pancreatic cancer shows unsatisfactory results, indicating the need for alternative therapeutic approaches. [...] Read more.
As cancer-associated factors, kallikrein-related peptidases (KLKs) are components of the tumour microenvironment, which represents a rich substrate repertoire, and considered attractive targets for the development of novel treatments. Standard-of-care therapy of pancreatic cancer shows unsatisfactory results, indicating the need for alternative therapeutic approaches. We aimed to investigate the expression of KLKs in pancreatic cancer and to inhibit the function of KLK6 in pancreatic cancer cells. KLK6, KLK7, KLK8, KLK10 and KLK11 were coexpressed and upregulated in tissues from pancreatic cancer patients compared to normal pancreas. Their high expression levels correlated with each other and were linked to shorter survival compared to low KLK levels. We then validated KLK6 mRNA and protein expression in patient-derived tissues and pancreatic cancer cells. Coexpression of KLK6 with KRT19, αSMA or CD68 was independent of tumour stage, while KLK6 was coexpressed with KRT19 and CD68 in the invasive tumour area. High KLK6 levels in tumour and CD68+ cells were linked to shorter survival. KLK6 inhibition reduced KLK6 mRNA expression, cell metabolic activity and KLK6 secretion and increased the secretion of other serine and aspartic lysosomal proteases. The association of high KLK levels and poor prognosis suggests that inhibiting KLKs may be a therapeutic strategy for precision medicine. Full article
(This article belongs to the Special Issue Proteolysis in Cancer Progression)
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15 pages, 3743 KiB  
Article
KLK4 Induces Anti-Tumor Effects in Human Xenograft Mouse Models of Orthotopic and Metastatic Prostate Cancer
by Brian W.-C. Tse, Thomas Kryza, Mei-Chun Yeh, Ying Dong, Kamil A. Sokolowski, Carina Walpole, Tobias Dreyer, Johanna Felber, Jonathan Harris, Viktor Magdolen, Pamela J. Russell and Judith A. Clements
Cancers 2020, 12(12), 3501; https://doi.org/10.3390/cancers12123501 - 24 Nov 2020
Cited by 6 | Viewed by 2580
Abstract
Recent reports have suggested the role of kallikrein-related peptidase 4 (KLK4) to be that of remodeling the tumor microenvironment in many cancers, including prostate cancer. Notably, these studies have suggested a pro-tumorigenic role for KLK4, especially in prostate cancer. However, these have been [...] Read more.
Recent reports have suggested the role of kallikrein-related peptidase 4 (KLK4) to be that of remodeling the tumor microenvironment in many cancers, including prostate cancer. Notably, these studies have suggested a pro-tumorigenic role for KLK4, especially in prostate cancer. However, these have been primarily in vitro studies, with limited in vivo studies performed to date. Herein, we employed an orthotopic inoculation xenograft model to mimic the growth of primary tumors, and an intracardiac injection to induce metastatic dissemination to determine the in vivo tumorigenic effects of KLK4 overexpressed in PC3 prostate cancer cells. Notably, we found that these KLK4-expressing cells gave rise to smaller localized tumors and decreased metastases than the parent PC-3 cells. To our knowledge, this is the first report of an anti-tumorigenic effect of KLK4, particularly in prostate cancer. These findings also provide a cautionary tale of the need for in vivo analyses to substantiate in vitro experimental data. Full article
(This article belongs to the Special Issue Proteolysis in Cancer Progression)
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25 pages, 5098 KiB  
Article
Conditional Gene Targeting Reveals Cell Type-Specific Roles of the Lysosomal Protease Cathepsin L in Mammary Tumor Progression
by María Alejandra Parigiani, Anett Ketscher, Sylvia Timme, Peter Bronsert, Manuel Schlimpert, Bernd Kammerer, Arnaud Jacquel, Paul Chaintreuil and Thomas Reinheckel
Cancers 2020, 12(8), 2004; https://doi.org/10.3390/cancers12082004 - 22 Jul 2020
Cited by 6 | Viewed by 2807
Abstract
Background: Cathepsin L (Ctsl) is a cysteine protease mainly located within the endosomal/lysosomal cell compartment. High expression of Ctsl indicates poor prognosis in human breast cancer. However, the cell type-specific Ctsl functions responsible for this association remain elusive. Methods: Because constitutive Ctsl−/− [...] Read more.
Background: Cathepsin L (Ctsl) is a cysteine protease mainly located within the endosomal/lysosomal cell compartment. High expression of Ctsl indicates poor prognosis in human breast cancer. However, the cell type-specific Ctsl functions responsible for this association remain elusive. Methods: Because constitutive Ctsl−/− mice develop a complex phenotype, we developed a conditional model allowing for cell type-specific inactivation of Ctsl in mammary epithelium or myeloid cells in the transgenic mouse mammary tumor virus (MMTV)-polyoma middle T (PyMT) breast cancer model. Results: Ctsl ablation in mammary epithelial cells resulted in delayed initiation and end-stage of cancers. The latter displayed large dead cell areas. Inducible in vitro deletion of Ctsl in MMTV-PyMT-derived breast cancer cells revealed expansion of the acidic cell compartment, alteration of intracellular amino acid levels, and impaired mTOR signaling. In consequence, Ctsl-deficient cells exhibited slow growth rates and high apoptosis susceptibility. In contrast to Ctsl-deficient mammary epithelium, selective knockout of Ctsl in myeloid cells had no effects on primary tumors, but promoted lung metastasis formation. Conclusions: Our cell type-specific in vivo analysis provides strong evidence for a cancer cell-intrinsic, tumor-promoting role of Ctsl in primary breast cancer, whereas metastasis is negatively regulated by Ctsl expressed by bone marrow-derived cells. Full article
(This article belongs to the Special Issue Proteolysis in Cancer Progression)
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Review

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15 pages, 682 KiB  
Review
SENP Proteases as Potential Targets for Cancer Therapy
by Paulina Tokarz and Katarzyna Woźniak
Cancers 2021, 13(9), 2059; https://doi.org/10.3390/cancers13092059 - 24 Apr 2021
Cited by 47 | Viewed by 3997
Abstract
SUMOylation is a reversible post-translational modification (PTM) involving a covalent attachment of small ubiquitin-related modifier (SUMO) proteins to substrate proteins. SUMO-specific proteases (SENPs) are cysteine proteases with isopeptidase activity facilitating the de-conjugation of SUMO proteins and thus participating in maintaining the balance between [...] Read more.
SUMOylation is a reversible post-translational modification (PTM) involving a covalent attachment of small ubiquitin-related modifier (SUMO) proteins to substrate proteins. SUMO-specific proteases (SENPs) are cysteine proteases with isopeptidase activity facilitating the de-conjugation of SUMO proteins and thus participating in maintaining the balance between the pools of SUMOylated and unSUMOylated proteins and in SUMO recycling. Several studies have reported that SENPs’ aberrant expression is associated with the development and progression of cancer. In this review, we will discuss the role of SENPs in the pathogenesis of cancer, focusing on DNA repair and the cell cycle—cellular pathways malfunctioning in most cancer cells. The plausible role of SENPs in carcinogenesis resulted in the design and development of their inhibitors, including synthetic protein-based, peptide-based, and small molecular weight inhibitors, as well as naturally occurring compounds. Computational methods including virtual screening have been implemented to identify a number of lead structures in recent years. Some inhibitors suppressed the proliferation of prostate cancer cells in vitro and in vivo, confirming that SENPs are suitable targets for anti-cancer treatment. Further advances in the development of SENP-oriented inhibitors are anticipated toward SENP isoform-specific molecules with therapeutic potential. Full article
(This article belongs to the Special Issue Proteolysis in Cancer Progression)
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18 pages, 747 KiB  
Review
Cystatin M/E (Cystatin 6): A Janus-Faced Cysteine Protease Inhibitor with Both Tumor-Suppressing and Tumor-Promoting Functions
by Gilles Lalmanach, Mariana Kasabova-Arjomand, Fabien Lecaille and Ahlame Saidi
Cancers 2021, 13(8), 1877; https://doi.org/10.3390/cancers13081877 - 14 Apr 2021
Cited by 14 | Viewed by 3178
Abstract
Alongside its contribution in maintaining skin homeostasis and its probable involvement in fetal and placental development, cystatin M/E (also known as cystatin 6) was first described as a tumor suppressor of breast cancer. This review aims to provide an update on cystatin M/E [...] Read more.
Alongside its contribution in maintaining skin homeostasis and its probable involvement in fetal and placental development, cystatin M/E (also known as cystatin 6) was first described as a tumor suppressor of breast cancer. This review aims to provide an update on cystatin M/E with particular attention paid to its role during tumorigenesis. Cystatin M/E, which is related to type 2 cystatins, displays the unique property of being a dual tight-binding inhibitor of both legumain (also known as asparagine endopeptidase) and cysteine cathepsins L, V and B, while its expression level is epigenetically regulated via the methylation of the CST6 promoter region. The tumor-suppressing role of cystatin M/E was further reported in melanoma, cervical, brain, prostate, gastric and renal cancers, and cystatin M/E was proposed as a biomarker of prognostic significance. Contrariwise, cystatin M/E could have an antagonistic function, acting as a tumor promoter (e.g., oral, pancreatic cancer, thyroid and hepatocellular carcinoma). Taking into account these apparently divergent functions, there is an urgent need to decipher the molecular and cellular regulatory mechanisms of the expression and activity of cystatin M/E associated with the safeguarding homeostasis of the proteolytic balance as well as its imbalance in cancer. Full article
(This article belongs to the Special Issue Proteolysis in Cancer Progression)
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