Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Irreversible proliferation arrest (also called senescence) has emerged recently as a drug-responsive program able to influence the outcome of cancer chemotherapy. Since the drug amounts required for induction of proliferation arrest are much lower than those necessitated for induction of cell death, forcing cancer cells to undergo senescence may represent a less aggressive approach to control tumor progression. However, to achieve a long-standing control of proliferation, the ability of cancer cells to escape senescence and become drug resistant must be inhibited. Therefore, a clear understanding of the mechanisms that govern drug-induced senescence is critical and can lead to discovery of novel approaches to suppress drug resistance. The present review discusses the relevance of senescence in response to chemotherapy and the onset of drug resistance development. Particular emphasis is directed toward the utilization of findings from the field of research on aging, that can be applied to induction of senescence in cancer cells and reversal of their drug resistance phenotype. Proof of principle for this relationship is represented by the identification of inhibitors of aging associated proteases such as the proteasome and cathepsin L as novel and potent cancer drug resistance reversing agents.
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PMID:Targeting senescence pathways to reverse drug resistance in cancer. 1569 59

The association between expression of the 67 kDa laminin receptor (67LR) and tumor aggressiveness has been convincingly demonstrated although the exact function of this molecule in the metastatic process has remained unclear. In this study, we tested whether the laminin-1, upon interaction with 67LR, promotes tumor cell aggressiveness; the investigation was based on: (i) the previous demonstration that soluble 67LR, as well as a 20-amino-acid peptide corresponding to the 67LR laminin binding site, changes the conformation of laminin upon interaction with this adhesion molecule and (ii) the known relevance of microenvironment remodeling by the tumor, leading to structural modification of extracellular matrix components in tumor progression. MDAMB231 breast carcinoma cells plated on peptide G-treated laminin-1 exhibited a polygonal array of actin filament bundles compared with cells seeded on native laminin-1 which presented the actin bundles organized as multiple cables parallel to margins. Furthermore, in cells seeded on peptide G-treated laminin-1, 67LR was distinct from the alpha6 integrin subunit in filopodia protrusions in addition to colocalizing with this integrin in focal adhesion plaques as it occurs when cells are plated on native laminin-1. In addition to differences in tumor cell adhesion and migration found in cells exposed to peptide G-treated vs native laminin-1, breast carcinoma cells seeded on modified laminin-1 showed a 6-fold increase in invasion capability compared with cells seeded on unmodified laminin-1. Alterations in actin organization as well as adhesion, migration and especially invasion observed in MDAMB231 cells in the presence of peptide G-treated laminin-1 were even found in MDAMB231 cells that, after selection for 67LR high expression, were seeded on native laminin-1. As the 67LR shedding is proportional to its expression level, these findings indicate a role for 67LR in changing laminin structure. Expression analysis of 97 genes encoding proteins that mediate cell matrix interactions, revealed significant differences between cells exposed to modified vs unmodified laminin-1 in 19 genes, 17 of which--including those encoding alpha3 integrin, extracellular matrix protein 1, proteolytic enzymes (such as MT1-MMP, stromelysin-3 and cathepsin L) and their inhibitors--were up-modulated in cells treated with modified laminin-1. Zymogram analysis clearly indicated a significant increase in the activity of the gelatinolytic enzyme MMP-2 in the culture supernatant from cells exposed to modified laminin-1, without an increase in mRNA abundance as observed in microarray analysis. Invasiveness of tumor cells conditioned by modified laminin-1, evaluated as the capability to cross Matrigel basement, was significantly more inhibited by MMPinhibitor TIMP-2 than invasiveness induced by native laminin-1. Taken together, our findings indicate that the role of 67LR in tumor aggressiveness rests in its ability to modify laminin-1 thereby activating proteolytic enzymes that promote tumor cell invasion through extracellular matrix degradation.
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PMID:The 67 kDa laminin receptor increases tumor aggressiveness by remodeling laminin-1. 1594 11

The activity of a set of peptidases (proteases) involved in cancer progression is collectively known as the cancer 'degradome'. Invasion and metastasis were initially considered as late events in cancer development and the processes in which proteases were involved. However, recent studies indicate that invasion and metastasis are not late events, but can occur during early stages as well. Moreover, other processes occurring in various stages of cancer progression are also protease-dependent, such as (upregulation of) cell proliferation, (downregulation of) apoptosis, involvement of white blood cells, angiogenesis and induction of multi-drug resistance. Proteolytic activity in tumours is regulated in a complex manner, as both genetically unstable cancer cells and stable stromal cells, such as fibroblasts, endothelial cells and inflammatory cells, are involved. In vitro studies and studies using animal models have clearly shown protease dependency of many processes in carcinogenesis. However, clinical trials using protease inhibitors have thus far been unsuccessful except for a few applications of matrix metalloprotease (MMP) inhibitors when used in combination with cytostatic anticancer agents and/or in the early stages of cancer. Antithrombotics, such as low-molecular-weight heparin and warfarin, were also successful in clinical trials, probably by interfering with proteases of the coagulation cascade. The two-way association between cancer and thrombosis has long been recognised in the clinic. The poor outcome of other clinical trials of protease inhibitors is probably due to the late stages of cancer of the patient populations included, and the limited understanding of the complex regulation and effects of the activity of the various proteases in tumours depending on, among others, tumour type and stage, interactions between the cancer cells, other cells and the extracellular matrix in tumours. Therefore, a better fundamental understanding of the proteolytic complexity in tumours is essential before clinical trials can be rationally designed. At present, antithrombotics, the urokinase-type plasminogen activator system, the membrane-bound membrane-type 1-MMP, cathepsin L and the proteasome seem the most promising candidates as targets for anticancer strategies in early stages of cancer in combination with cytotoxic drugs. Moreover, metronomic therapy is an attractive approach using low doses of inhibitors for prolonged periods of time without interruption to specifically target endothelial cells that are involved in angiogenesis.
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PMID:Antiprotease therapy in cancer: hot or not? 1650 35

Cigarette smoke, which contains several carcinogens known to initiate and promote tumorigenesis and metastasis, is the major cause of oral cancer. Lysosomal cathepsin proteases play important roles in tumor progression, invasion and metastasis. In the present work we investigated the effects of cigarette smoke condensate (CSC) on cathepsin (B, D and L) expression and protease-mediated invasiveness in human oral squamous cell carcinoma (OSCC) cells. Our results show that treatment of OSCC cells (686Tu and 101A) with CSC activated cathepsins B, D and L in a dose-dependent manner. Both expression and activity of these cathepsins were up-regulated in CSC-exposed versus non-exposed cells. Although cathepsin L had the lowest basal level, it had the highest induction in exposed cells compared to cathepsins B and D. Suppression of CSC-induced cathepsin B and L activities by specific chemical inhibitors decreased the invasion process, suggesting that these proteases are involved in the invasion process. Overall, our results indicate that CSC activates cathepsin B and L proteolytic activity and enhances invasiveness in OSCC cells, a response that may play a role in CSC-mediated tumor progression and metastasis dissemination.
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PMID:Cigarette smoke condensate increases cathepsin-mediated invasiveness of oral carcinoma cells. 1739 18

The environmental toxin 2,3,7,8-tetrachlorodibenzodioxin (TCDD) is a known human carcinogen; however, its precise mechanism of action remains unclear. Here we show that TCDD induces mitochondrial dysfunction, stress signaling, and tumor invasion by a mechanism similar to that described for mtDNA-depleted cells. Treatment of C2C12 cells with TCDD disrupted mitochondrial transmembrane potential in a time-dependent fashion and inhibited mitochondrial transcription and translation. TCDD also increased cytosolic [Ca(2+)](c) and RyR1-specific Ca(2+) release. These changes were associated with increased calcineurin (CnA) levels and activation of CnA-sensitive NF-kappaB/Rel (IkappaBbeta-dependent) factors. Cells treated with TCDD displayed resistance to apoptosis, increased expression of the tumor marker cathepsin L, and a high degree of invasiveness as tested by the Matrigel membrane invasion assay. These effects were reversed by the CnA inhibitor FK506, and CnA mRNA silencing suggesting that TCDD triggers a signaling pathway similar to mtDNA depletion. Taken together, these results reveal that TCDD may promote tumor progression in vivo by directly targeting mitochondrial transcription and induction of mitochondrial stress signaling.
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PMID:Dioxin-mediated tumor progression through activation of mitochondria-to-nucleus stress signaling. 1817 13

Cathepsin L, a cysteine protease, is considered to be a potential therapeutic target in cancer treatment. Proteases are involved in the development and progression of cancer. Inhibition of activity of specific proteases may slow down cancer progression. In this review, we evaluate recent studies on the inhibition of cathepsin L in cancer. The effects of cathepsin L inhibition as a monotherapy on apoptosis and angiogenesis in cancer are ambiguous. Cathepsin L inhibition seems to reduce invasion and metastasis, but there is concern that selective cathepsin L inhibition induces compensatory activity by other cathepsins. The combination of cathepsin L inhibition with conventional chemotherapy seems to be more promising and has yielded more consistent results. Future research should be focused on the mechanisms and effects of this combination therapy.
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PMID:Cathepsin L, target in cancer treatment? 1995 82

To define a functional role for the endosomal/lysosomal cysteine protease cathepsin L (Ctsl) during squamous carcinogenesis, we generated mice harboring a constitutive Ctsl deficiency in addition to epithelial expression of the human papillomavirus type 16 oncogenes (human cytokeratin 14 (K14)-HPV16). We found enhanced tumor progression and metastasis in the absence of Ctsl. As tumor progression in K14-HPV16 mice is dependent on inflammation and angiogenesis, we examined immune cell infiltration and vascularization without finding any effect of the Ctsl genotype. In contrast, keratinocyte-specific transgenic expression of cathepsin V, the human orthologue of mouse Ctsl, in otherwise Ctsl-deficient K14-HPV16 mice restored the phenotype observed in the control HPV16 skin. To better understand this phenotype at the molecular level, we measured several oncogenic signal transduction pathways in primary keratinocytes on stimulation with keratinocyte-conditioned cell culture medium. We found increased activation of protein kinase B/Akt and mitogen-activated protein kinase pathways in protease-deficient cells, especially if treated with media conditioned by Ctsl-deficient keratinocytes. Similarly, the level of active GTP-Ras was increased in Ctsl-deficient epidermis. We conclude that Ctsl is critical for the termination of growth factor signaling in the endosomal/lysosomal compartment of keratinocytes and, therefore, functions as an anti-tumor protease.
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PMID:Deficiency for the cysteine protease cathepsin L promotes tumor progression in mouse epidermis. 2002 99

Lysosomal cysteine protease cathepsin L (CTSL) is believed to play a role in tumor progression and is considered a marker for clinically invasive tumors. Studies from our laboratory using the classical mouse skin carcinogenesis model, with 7,12-dimethyl-benz[a]anthracene (DMBA) for initiation and 12-O-tetradecanoylphorbol-13-acetate (TPA) for promotion, showed that expression of CTSL is increased in papillomas and squamous cell carcinomas (SCC). We also carried out carcinogenesis studies using Ctsl-deficient nackt (nkt) mutant mice on three different inbred backgrounds. Unexpectedly, the multiplicity of papillomas was significantly higher in Ctsl-deficient than in wild-type mice on two unrelated backgrounds. Topical applications of TPA or DMBA alone to the skin of nkt/nkt mice did not induce papillomas, and there was no increase in spontaneous tumors in nkt/nkt mice on any of the three inbred backgrounds. Reduced epidermal cell proliferation in Ctsl-deficient nkt/nkt mice after TPA treatment suggested that they are not more sensitive than wild-type mice to TPA promotion. We also showed that deficiency of CTSL delays terminal differentiation of keratinocytes, and we propose that decreased elimination of initiated cells is at least partially responsible for the increased papilloma formation in the nackt model.
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PMID:Protective role of cathepsin L in mouse skin carcinogenesis. 2153 79

Prostate cancer is the most common malignancy in men in the United States, and one in seven men with prostate cancer dies of the disease. A major issue of prostate diagnosis is that there is no good method to reliably distinguish aggressive prostate cancer from nonaggressive prostate cancer. This leads to significant unnecessary suffering among prostate cancer patients and massive unnecessary health care expenditures. In this study, we aim to identify glycoproteins associated with aggressive prostate cancer using optimal cutting temperature (OCT)-embedded frozen tissues obtained from patients with known clinical outcome. To eliminate the interference of mass spectrometric analysis by the compounds in OCT and identify extracellular proteins that are likely to serve as biomarkers in body fluids, we employed glycoproteomic analysis using solid-phase extraction of glycopeptides, which allowed the immobilization of glycopeptides to solid support and removal of OCT from sample proteins before releasing the glycopeptides from the solid support for mass spectrometry analysis. Tumor tissues were cryostat microdissected from four cases of aggressive and four cases of nonaggressive prostate tumors, and glycopeptides were isolated and labeled with iTRAQ reagents before the samples were analyzed with LTQ Orbitrap Velos. From the aggressive prostate cancer tissues, we identified the overexpression of three glycoproteins involved in an extracellular matrix remodeling and further examined two glycoproteins, cathepsin L and periostin, using Western blot and immunohistochemistry analyses. This is the first proteomic study to identify proteins potentially associated with aggressive prostate cancer using OCT-embedded frozen tissues. Further study of these proteins will be needed to understand the roles of extracellular matrix proteins in cancer progression and their potential clinical utility in improving diagnosis of aggressive prostate cancer.
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PMID:Quantitative glycoproteomic analysis of optimal cutting temperature-embedded frozen tissues identifying glycoproteins associated with aggressive prostate cancer. 2178 Jul 47

A number of cyclohexenyl chalcone Diels-Alder natural products possess promising biological properties including strong cytotoxicity in various human cancer cells. Herein, we show that natural products in this class including panduratin A and nicolaioidesin C inhibit cysteine cathepsins as indicated by protease profiling assays and cell-free cathepsin L enzyme assays. Owing to the critical roles of cathepsins in the biology of human tumor progression, invasion, and metastasis, these findings should pave the way for development of novel antitumor agents for use in clinical settings.
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PMID:Synthetic cyclohexenyl chalcone natural products possess cytotoxic activities against prostate cancer cells and inhibit cysteine cathepsins in vitro. 2298 51


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