Proteases Regulate Cancer Stem Cell Properties and Remodel Their Microenvironment

Habič, Anamarija; Novak, Metka; Majc, Bernarda; Turnšek, Tamara Lah; Breznik, Barbara

doi:10.1369/00221554211035192

Cited by 10 publications

(5 citation statements)

References 218 publications

(236 reference statements)

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“…As discussed in this Review, the inhibitors developed so far effectively inhibit the activity and/or function of ectoproteases originating from mature tumour cells, endothelial cells, as well as CAFs and immune cells. Recent studies have indicated that CSCs express DPP4, APN, ADAM17, and MMP2/9 [12,73,[234][235][236][237][238][239][240].…”

Section: New Avenues For Ectoproteases In the Context Of Cancer Therapymentioning

confidence: 99%

Validating Cell Surface Proteases as Drug Targets for Cancer Therapy: What Do We Know, and Where Do We Go?

Verhulst

Garnier

Meester

et al. 2022

Cancers

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Cell surface proteases (also known as ectoproteases) are transmembrane and membrane-bound enzymes involved in various physiological and pathological processes. Several members, most notably dipeptidyl peptidase 4 (DPP4/CD26) and its related family member fibroblast activation protein (FAP), aminopeptidase N (APN/CD13), a disintegrin and metalloprotease 17 (ADAM17/TACE), and matrix metalloproteinases (MMPs) MMP2 and MMP9, are often overexpressed in cancers and have been associated with tumour dysfunction. With multifaceted actions, these ectoproteases have been validated as therapeutic targets for cancer. Numerous inhibitors have been developed to target these enzymes, attempting to control their enzymatic activity. Even though clinical trials with these compounds did not show the expected results in most cases, the field of ectoprotease inhibitors is growing. This review summarizes the current knowledge on this subject and highlights the recent development of more effective and selective drugs targeting ectoproteases among which small molecular weight inhibitors, peptide conjugates, prodrugs, or monoclonal antibodies (mAbs) and derivatives. These promising avenues have the potential to deliver novel therapeutic strategies in the treatment of cancers.

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Section: New Avenues For Ectoproteases In the Context Of Cancer Therapymentioning

confidence: 99%

Validating Cell Surface Proteases as Drug Targets for Cancer Therapy: What Do We Know, and Where Do We Go?

Verhulst

Garnier

Meester

et al. 2022

Cancers

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“…Cathepsins have been shown to be strong predictive biomarkers for GBM patient survival [27,28,33]. In this study, high levels of cathepsin X do not correlate with survival of GBM patients, although we showed by its selective inhibition that cathepsin X promotes viability of GBM cells and GBM-associated macrophages and microglia as well as proliferation and invasion of GBM cells.…”

Section: Discussionmentioning

confidence: 54%

“…In tumors, the expression of lysosomal cysteine cathepsins is often elevated and is generally associated with poor patient prognosis [26]. Cathepsins have been shown to exert tumor-promoting functions [27], such as promoting tumor growth, invasion [28], and resistance to therapy [26,29], although some of them also contribute to tumor suppression [30][31][32][33].…”

Section: Introductionmentioning

confidence: 99%

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

Majc

Habič

Novak

et al. 2022

IJMS

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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.

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“…183 Recently, involvement of cell types and proteins in CSCs and in particular in GSCs has been reviewed, such as a novel cell type, the telocyte, 184 scaffold proteins, 185,186 the renin-angiotensin system, 187 and specific proteases and their endogenous inhibitors. 188 MSCs are another cell type that infiltrates glioblastoma tumors and are present in GSC niches, as they are in HSC niches in bone marrow (Fig. 5).…”

Section: Energy Metabolism Of Gscsmentioning

confidence: 99%

Cell Biology Meets Cell Metabolism: Energy Production Is Similar in Stem Cells and in Cancer Stem Cells in Brain and Bone Marrow

Noorden

Breznik

Novak

et al. 2021

J Histochem Cytochem.

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Energy production by means of ATP synthesis in cancer cells has been investigated frequently as a potential therapeutic target in this century. Both (an)aerobic glycolysis and oxidative phosphorylation (OXPHOS) have been studied. Here, we review recent literature on energy production in glioblastoma stem cells (GSCs) and leukemic stem cells (LSCs) versus their normal counterparts, neural stem cells (NSCs) and hematopoietic stem cells (HSCs), respectively. These two cancer stem cell types were compared because their niches in glioblastoma tumors and in bone marrow are similar. In this study, it became apparent that (1) ATP is produced in NSCs and HSCs by anaerobic glycolysis, whereas fatty acid oxidation (FAO) is essential for their stem cell fate and (2) ATP is produced in GSCs and LSCs by OXPHOS despite the hypoxic conditions in their niches with FAO and amino acids providing its substrate. These metabolic processes appeared to be under tight control of cellular regulation mechanisms which are discussed in depth. However, our conclusion is that systemic therapeutic targeting of ATP production via glycolysis or OXPHOS is not an attractive option because of its unwanted side effects in cancer patients.

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Proteases Regulate Cancer Stem Cell Properties and Remodel Their Microenvironment

Cited by 10 publications

References 218 publications

Validating Cell Surface Proteases as Drug Targets for Cancer Therapy: What Do We Know, and Where Do We Go?

Validating Cell Surface Proteases as Drug Targets for Cancer Therapy: What Do We Know, and Where Do We Go?

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

Cell Biology Meets Cell Metabolism: Energy Production Is Similar in Stem Cells and in Cancer Stem Cells in Brain and Bone Marrow

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