Localization patterns of cathepsins K and X and their predictive value in glioblastoma

Breznik, Barbara; Limback, Clara; Porčnik, Andrej; Blejec, Andrej; Krajnc, Miha Koprivnikar; Bošnjak, Roman; Kos, Janko; Noorden, C. J. F. Van; Lah, Tamara T.

doi:10.2478/raon-2018-0040

Cited by 18 publications

(13 citation statements)

References 57 publications

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“…88,89 CatK can degrade and inactivate SDF-1α by proteolytic cleavages of its N-terminus 90 and co-localization of inactive Catk with SDF-1α in peri-arteriolar GSC niches was detected in our previous studies. 5,7,90,91 These studies indicate that mobilization of GSCs out of niches in glioblastoma are mediated by similar mechanisms including activation of CatK and possibly other cathepsins as in HSC niches in bone marrow.…”

Section: Discussionmentioning

confidence: 84%

“…GSCs are localized in niches where they are maintained as slowly dividing cells, which results in resistance to therapy. 1–5 It has been hypothesized that forcing GSCs out of their protective niches has therapeutic potential, because it sensitizes GSCs to irradiation and chemotherapy. Understanding of the functioning of GSC niches, that is, molecular mechanisms that retain GSCs in these protective niches, is required for the development of novel therapeutic strategies targeted against GSCs.…”

Section: Introductionmentioning

confidence: 99%

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Similarities Between Stem Cell Niches in Glioblastoma and Bone Marrow: Rays of Hope for Novel Treatment Strategies

Hira

Breznik

Vittori

et al. 2019

J Histochem Cytochem.

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Glioblastoma is the most aggressive primary brain tumor. Slowly dividing and therapy-resistant glioblastoma stem cells (GSCs) reside in protective peri-arteriolar niches and are held responsible for glioblastoma recurrence. Recently, we showed similarities between GSC niches and hematopoietic stem cell (HSC) niches in bone marrow. Acute myeloid leukemia (AML) cells hijack HSC niches and are transformed into therapy-resistant leukemic stem cells (LSCs). Current clinical trials are focussed on removal of LSCs out of HSC niches to differentiate and to become sensitized to chemotherapy. In the present study, we elaborated further on these similarities by immunohistochemical analyses of 17 biomarkers in paraffin sections of human glioblastoma and human bone marrow. We found all 17 biomarkers to be expressed both in hypoxic peri-arteriolar HSC niches in bone marrow and hypoxic peri-arteriolar GSC niches in glioblastoma. Our findings implicate that GSC niches are being formed in glioblastoma as a copy of HSC niches in bone marrow. These similarities between HSC niches and GSC niches provide a theoretic basis for the development of novel strategies to force GSCs out of their niches, in a similar manner as in AML, to induce GSC differentiation and proliferation to render them more sensitive to anti-glioblastoma therapies.

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Section: Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Similarities Between Stem Cell Niches in Glioblastoma and Bone Marrow: Rays of Hope for Novel Treatment Strategies

Hira

Breznik

Vittori

et al. 2019

J Histochem Cytochem.

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“…Research into the role of cathepsin B and cathepsin D in tumorigenesis, so far, has mainly focused on their independent influence on tumor invasiveness. Malignant transformation results in the overproduction of cathepsin B (42) and elevated cathepsin B levels correlate with increased invasiveness and recurrence of MG (32, 39, 43, 44), astrocytoma and gliomas (39, 45). As an intracellular lysosomal protease, cathepsin B has been found in the extracellular matrix (ECM) of colorectal cancer, localized to the invasive front of the tumor (46).…”

Section: Discussionmentioning

confidence: 99%

“…The expression of cathepsin B by the stem cell niche on the microvessels in GB has been reported recently (31), with this staining pattern being a negative prognostic factor (32). This study was aimed at investigating the expression of cathepsins B, D, and G in WHO grade I MG, in relation to the putative TSC population we have previously identified (17).…”

Section: Introductionmentioning

confidence: 87%

Expression of Cathepsins B, D, and G in WHO Grade I Meningioma

et al. 2019

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Aim: We have recently demonstrated the presence of putative tumor stem cells (TSCs) in World Health Organization (WHO) grade I meningioma (MG) localized to the microvessels, which expresses components of the renin-angiotensin system (RAS). The RAS is known to be dysregulated and promotes tumorigenesis in many cancer types, including glioblastoma. Cathepsins B, D, and G are isoenzymes that catalyze the production of angiotensin peptides, hence providing bypass loops for the RAS. This study investigated the expression of cathepsins B, D, and G in WHO grade I MG in relation to the putative TSC population we have previously demonstrated. Methods: 3,3-Diaminobenzidine (DAB) immunohistochemical (IHC) staining with antibodies for cathepsins B, D, and G was performed on WHO grade I MG tissue samples from 10 patients. Three of the MG samples subjected to DAB IHC staining underwent immunofluorescence (IF) IHC staining to investigate co-expression of each of these cathepsins using combinations of smooth muscle actin (SMA) and embryonic stem cell marker OCT4. NanoString mRNA expression ( n = 6) and Western blotting (WB; n = 5) analyses, and enzyme activity assays (EAAs; n = 3), were performed on snap-frozen WHO grade I MG tissue samples to confirm transcriptional activation, protein expression, and functional activity of these proteins, respectively. Results: DAB IHC staining demonstrated expression of cathepsins B, D, and G in all 10 MG samples. NanoString mRNA expression and WB analyses showed transcriptional activation and protein expression of all three cathepsins, although cathepsin G was expressed at low levels. EAAs demonstrated that cathepsin B and cathepsin D were functionally active. IF IHC staining illustrated localization of cathepsin B and cathepsin D to the endothelium and SMA + pericyte layer of the microvessels, while cathepsin G was localized to cells scattered within the interstitium, away from the microvessels. Conclusion: Cathepsin B and cathepsin D, and to a lesser extent cathepsin G, are expressed in WHO grade I MG. Cathepsin B and cathepsin D are enzymatically active and are localized to the putative TSC population on the microvessels, whereas cathepsin G was localized to cells scattered within the interstitium, These results suggest the presence of bypass loops for the RAS, within WHO grade I MG.

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“…Release of cathepsins B and L was recently reported in different melanoma cell lines, where Abl/Arg nonreceptor tyrosine kinases were shown to play an important role in cathepsin B and L expression and their release from the cells [122]. Tumor progression and increased cell invasiveness following cathepsin B release are also characteristic for pancreatic ductal adenocarcinoma [123], esophageal adenocarcinoma [124], and glioma, where cathepsins K and X were also found to be involved [125,126,127]. Recently, a mechanism of cathepsin B release followed by enhanced lung cancer cell migration was proposed [128], indicating a possible role in the progression of lung cancer.…”

Section: Ecm Proteolysis and The Cathepsinsmentioning

confidence: 99%

Cysteine Cathepsins and Their Extracellular Roles: Shaping the Microenvironment

Vidak

Javoršek

Vizovišek

et al. 2019

Cells

306

228

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: For a long time, cysteine cathepsins were considered primarily as proteases crucial for nonspecific bulk proteolysis in the endolysosomal system. However, this view has dramatically changed, and cathepsins are now considered key players in many important physiological processes, including in diseases like cancer, rheumatoid arthritis, and various inflammatory diseases. Cathepsins are emerging as important players in the extracellular space, and the paradigm is shifting from the degrading enzymes to the enzymes that can also specifically modify extracellular proteins. In pathological conditions, the activity of cathepsins is often dysregulated, resulting in their overexpression and secretion into the extracellular space. This is typically observed in cancer and inflammation, and cathepsins are therefore considered valuable diagnostic and therapeutic targets. In particular, the investigation of limited proteolysis by cathepsins in the extracellular space is opening numerous possibilities for future break-through discoveries. In this review, we highlight the most important findings that establish cysteine cathepsins as important players in the extracellular space and discuss their roles that reach beyond processing and degradation of extracellular matrix (ECM) components. In addition, we discuss the recent developments in cathepsin research and the new possibilities that are opening in translational medicine.

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Localization patterns of cathepsins K and X and their predictive value in glioblastoma

Cited by 18 publications

References 57 publications

Similarities Between Stem Cell Niches in Glioblastoma and Bone Marrow: Rays of Hope for Novel Treatment Strategies

Similarities Between Stem Cell Niches in Glioblastoma and Bone Marrow: Rays of Hope for Novel Treatment Strategies

Expression of Cathepsins B, D, and G in WHO Grade I Meningioma

Cysteine Cathepsins and Their Extracellular Roles: Shaping the Microenvironment

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