Concentrations of lysosomal cysteine proteases are decreased in renal cell carcinoma compared with normal kidney

Kirschke, Heidrun; Clausen, Tobias; Göhring, Barbara; Günther, Dagmar; Heucke, Edwin; Laube, Friedemann; Löwe, Eckhard; Neef, H; Papesch, Henriette; Peinze, Skadi; Plehn, Gunnar; Rebmann, U.; Rinne, Ari; Rüdrich, Roland; Weber, Ekkehard

doi:10.1007/bf01240124

Cited by 16 publications

(9 citation statements)

References 11 publications

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“…64 Interestingly, there are some indications that success of therapeutic trials targeting MMP activity is linked to the lack of cathepsin B in the tumors. For example, inhibition of MMP activity in renal cell carcinoma, a type of cancer with exceptionally low levels of cathepsin B, 65 was one of the rare MMPI trials where the overall survival of the patients was significantly prolonged. 66 Our results are consistent with the initial observations that MMPs act mostly as regulators of tumor angiogenesis, 13,14 while cysteine cathepsins contribute to invasion potential of the tumors.…”

Section: Discussionmentioning

confidence: 99%

Increased invasiveness of MMP-9-deficient tumors in two mouse models of neuroendocrine tumorigenesis

Shchors

Nozawa

et al. 2012

Oncogene

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Despite their apparent success in pre-clinical trials, metalloproteinase (MMP) inhibitors proved to be inefficacious in clinical settings. In an effort to understand the underlying causes of this unanticipated outcome, we modeled the consequences of long-term MMP inhibition by removing one of the major players in tumorigenesis, MMP9, in two complimentary mouse models of pancreatic neuroendocrine carcinogenesis: Myc;BclXl and RIP1-Tag2. By employing gel zymography and a fluoregenic solution assay, we first established that MMP9 is expressed and activated in Myc;BclXl tumors in an interleukin-1b-dependent manner. The genetic deletion of MMP9 in Myc;BclXl mice impairs tumor angiogenesis and growth analogous to its absence in the RIP1-Tag2 model. Notably, tumors that developed in the context of MMP9-deficient backgrounds in both models were markedly more invasive than their typical wild-type counterparts, and expressed elevated levels of pro-invasive cysteine cathepsin B. The increased invasion of MMP9-deficient tumors was associated with a switch in the spectrum of inflammatory cells at the tumor margins, involving homing of previously undetected, cathepsin-B expressing CD11b;Gr1-positive cells to the invasive fronts. Thus, plasticity in the tumor inflammatory compartment is partially responsible for changes in the expression pattern of tumorassociated proteases, and may contribute to the compensatory effects observed on MMP inhibition, hence accounting for the heightened tumor progression described in late stage clinical trials.Oncogene advance online publication, 5 March 2012; doi:10.1038/onc.2012.60Keywords: tumor; metalloproteinase; invasion; cathepsin; Myc; interleukin-1b INTRODUCTIONMatrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases that contribute to development and tissue homeostasis, and modulate cancer progression by digesting a variety of substrates. Owing to the role of MMP in extracellular matrix (ECM) re-arrangement (also referred to as remodeling or degradation), and in the promotion of neoangiogenesis, it was anticipated that MMP inhibition in vivo would have an anti-tumorigenic effect. However, phase III clinical trials with an MMP inhibitor (MMPI), combined with standard-of-care chemotherapy, failed to demonstrate clinical benefit for late stage cancer patients and, remarkably, was in some cases worse than the chemotherapyonly control arm. For instance, the use of Bay 12-9566 in treating patients with pancreatic cancer reduced both median progressionfree survival and quality-of-life when compared with standard care gemcitabine.1 In another case, treatment of glioblastoma patients rendered no statistically significant survival benefits.2 Additionally, the clinical trials in small-cell lung carcinomas had to be terminated prematurely.3 This failure led to the early cessation of ongoing trials, and to reconsideration of the merit of a variety of MMPIs in clinical development by a number of pharmaceutical companies. 4 --6 The molecular mechanism behind this disappointing outc...

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Section: Discussionmentioning

confidence: 99%

Increased invasiveness of MMP-9-deficient tumors in two mouse models of neuroendocrine tumorigenesis

Shchors

Nozawa

et al. 2012

Oncogene

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“…Sir, In a recent paper published in this journal, Kirschke et al (1997) reported that renal cell carcinomas contained lower concentrations of cathepsins B, C, H, L and S than normal kidney parenchyma. The author demonstrated decreased levels both by activity measurements and protein determinations, such as enzyme-linked immunoassays and immunoblotting.…”

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confidence: 99%

“…It has been suggested that the balance between proteases and their endogenous inhibitors, in the case of cathepsins the so-called cysteine protease inhibitors (CPI), determines the invasive and metastatic characteristics of tumour cells (Twining 1994). We therefore read the publication of Kirschke et al (1997) with great interest because our research is engaged in the same ®eld. Since we have carried out experiments measuring both cathepsins and CPI, we will soon report on them to complement the data and conclusions of Kirschke et al (1997).…”

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confidence: 99%

“…We therefore read the publication of Kirschke et al (1997) with great interest because our research is engaged in the same ®eld. Since we have carried out experiments measuring both cathepsins and CPI, we will soon report on them to complement the data and conclusions of Kirschke et al (1997).…”

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confidence: 99%

“…The cathepsins were extracted by a two-step homogenisation procedure with 0.25% Triton X-100 solution in 10 mM phosphate buer, pH 7.46, and 10 mM CaCl 2 , using a Wheaton homogeniser. Fluorimetric assays similar to those described by Kirschke et al (1997) were applied, but with ®nal substrate concentrations of 5 lM for all the three enzymes and a ®nal inhibitor concentration of 0.5 lM Z-PhePhe-CH 2 for the determination of cathepsin L. Heatstable CPI were determined in supernatants of samples heated at 100°C for 10 min (Lah et al 1992) by testing their inhibitory capacities against puri®ed cathepsin B from human placenta. The tumour stage was assigned to each patient according to the TNM system and the histological grade of the cancer was classi®ed as 1, 2 or 3 (UICC 1992).…”

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Cathepsins B, H, L and cysteine proteinase inhibitors in renal cell carcinoma: no evidence for dysregulated proteolytic balance

Jung¹,

Friedrich²,

Türk³

et al. 1998

Journal of Cancer Research and Clinical Oncology

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Activity, expression, and transcription rate of the cathepsins B, D, H, and L in cutaneous malignant melanoma

Frőhlich¹,

Schlagenhauff²,

Möhrle

et al. 2001

Cancer

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BACKGROUND Increased activity of the protease cathepsin B has been demonstrated in many tumor cells. A correlation of cathepsin B activity and metastatic potential of melanoma has been well established. METHODS The cathepsins B, D, H, and L were evaluated in normal skin, nevi, and melanoma samples to obtain information about their role and their regulation in melanoma. The authors localized specific proteolytic activity with histochemistry, cathepsin protein immunohistochemistry, and mRNA with in situ hybridization. RESULTS Activities and immunoreactivities of the cathepsins B and L were found to be increased in all melanocytic lesions. However, the staining for the corresponding mRNA levels was elevated only in melanomas. Cathepsin D protein and mRNA were expressed to a higher degree only in the dysplastic nevus and in melanomas. The increase was due to tumor cells and cells of the surrounding tissue. Cathepsin H activity, immunoreactivity, and mRNA appeared to be correlated inversely with the invasive potential of the lesion. CONCLUSIONS It may be relevant for the malignant potential of the lesion whether the increase in activity is accompanied by an increase in the mRNA level. Two different mechanisms—the existence of different mRNAs and the higher transcription rate of the cathepsin gene—have been proposed for the regulation of cathepsin B activity in tumor cells. The current data suggest that, depending on the thickness of the melanoma, cathepsin activity is regulated by different mechanisms. The up‐regulation of cathepsin gene transcription appears to be characteristic for more invasive tumor cells. Cancer 2001;91:972–82. © 2001 American Cancer Society.

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Concentrations of lysosomal cysteine proteases are decreased in renal cell carcinoma compared with normal kidney

Cited by 16 publications

References 11 publications

Increased invasiveness of MMP-9-deficient tumors in two mouse models of neuroendocrine tumorigenesis

Increased invasiveness of MMP-9-deficient tumors in two mouse models of neuroendocrine tumorigenesis

Cathepsins B, H, L and cysteine proteinase inhibitors in renal cell carcinoma: no evidence for dysregulated proteolytic balance

Activity, expression, and transcription rate of the cathepsins B, D, H, and L in cutaneous malignant melanoma

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