scholarly journals The role of lysosomal cysteine proteases in tumor progression

2009 ◽  
Vol 8 (2) ◽  
pp. 85-90
Author(s):  
M. S. Korovin ◽  
V. V. Novitsky ◽  
O. S. Vasiliyeva
Keyword(s):  
Tumor Progression ◽  
Cancer Progression ◽  
Serine Proteases ◽  
Molecular Mechanisms ◽  
Cysteine Proteases ◽  
Tumour Microenvironment ◽  
Cysteine Cathepsins ◽  
Proteolytic Cascade ◽  
Long Time ◽  
Lysosomal Cysteine Proteases

Cysteine cathepsins have been known for a long time to play an important role in cancer progression. Here we summarize their impact to the hallmark processes of malignant growth such as cell proliferation, apoptosis, angiogenesis, invasion and metastasis. We discuss the molecular mechanisms where cysteine cathepsins are participating through the degradation of the extracellular matrix, initiation of the proteolytic cascade by activating serine proteases and urokinase plasminogen precursors. Moreover, in addition to the tumorigenic and pro-metastatic functions of lysosomal cysteine proteases in the cancer cells, cathepsins originating from cells of the tumour microenvironment has been shown to participate in the processes leading to the tumor progression and metastasis. Taken together, that data support the concept of cysteine cathepsins as promising molecular targets for cancer therapy.

scholarly journals Type II transmembrane serine proteases as potential targets for cancer therapy

2016 ◽  
Vol 397 (9) ◽  
pp. 815-826 ◽  
Author(s):  
Andrew S. Murray ◽  
Fausto A. Varela ◽  
Karin List
Keyword(s):  
Cancer Progression ◽  
Serine Proteases ◽  
Molecular Mechanisms ◽  
Inflammatory Cells ◽  
Activity Levels ◽  
Type Ii ◽  
Neoplastic Progression ◽  
Treatment Regimens ◽  
Proinflammatory Mediators ◽  
Transmembrane Serine Protease

Abstract Carcinogenesis is accompanied by increased protein and activity levels of extracellular cell-surface proteases that are capable of modifying the tumor microenvironment by directly cleaving the extracellular matrix, as well as activating growth factors and proinflammatory mediators involved in proliferation and invasion of cancer cells, and recruitment of inflammatory cells. These complex processes ultimately potentiate neoplastic progression leading to local tumor cell invasion, entry into the vasculature, and metastasis to distal sites. Several members of the type II transmembrane serine protease (TTSP) family have been shown to play critical roles in cancer progression. In this review the knowledge collected over the past two decades about the molecular mechanisms underlying the pro-cancerous properties of selected TTSPs will be summarized. Furthermore, we will discuss how these insights may facilitate the translation into clinical settings in the future by specifically targeting TTSPs as part of novel cancer treatment regimens.

scholarly journals A bi-directional dialog between vascular cells and monocytes/macrophages regulates tumor progression

2021 ◽  
Author(s):  
Victor Delprat ◽  
Carine Michiels
Keyword(s):  
Tumor Progression ◽  
Cancer Progression ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
The Body ◽  
Vascular Cells ◽  
Tumor Associated Macrophage ◽  
Immune Cell Activation ◽  
The Impact

AbstractCancer progression largely depends on tumor blood vessels as well on immune cell infiltration. In various tumors, vascular cells, namely endothelial cells (ECs) and pericytes, strongly regulate leukocyte infiltration into tumors and immune cell activation, hence the immune response to cancers. Recently, a lot of compelling studies unraveled the molecular mechanisms by which tumor vascular cells regulate monocyte and tumor-associated macrophage (TAM) recruitment and phenotype, and consequently tumor progression. Reciprocally, TAMs and monocytes strongly modulate tumor blood vessel and tumor lymphatic vessel formation by exerting pro-angiogenic and lymphangiogenic effects, respectively. Finally, the interaction between monocytes/TAMs and vascular cells is also impacting several steps of the spread of cancer cells throughout the body, a process called metastasis. In this review, the impact of the bi-directional dialog between blood vascular cells and monocytes/TAMs in the regulation of tumor progression is discussed. All together, these data led to the design of combinations of anti-angiogenic and immunotherapy targeting TAMs/monocyte whose effects are briefly discussed in the last part of this review.

scholarly journals Epithelial–mesenchymal transition: role in cancer progression and the perspectives of antitumor treatment

Acta Naturae ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 4-23
Author(s):  
A. V. Gaponova ◽  
S. Rodin ◽  
A. A. Mazina ◽  
P. V. Volchkov
Keyword(s):  
Epithelial Cells ◽  
Tumor Progression ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Malignant Tumors ◽  
The Body ◽  
Epithelial Tissue ◽  
Mesenchymal Transition ◽  
Tumor Dissemination

About 90% of all malignant tumors are of epithelial nature. The epithelial tissue is characterized by a close interconnection between cells through cellcell interactions, as well as a tight connection with the basement membrane, which is responsible for cell polarity. These interactions strictly determine the location of epithelial cells within the body and are seemingly in conflict with the metastatic potential that many cancers possess (the main criteria for highly malignant tumors). Tumor dissemination into vital organs is one of the primary causes of death in patients with cancer. Tumor dissemination is based on the so-called epithelialmesenchymal transition (EMT), a process when epithelial cells are transformed into mesenchymal cells possessing high mobility and migration potential. More and more studies elucidating the role of the EMT in metastasis and other aspects of tumor progression are published each year, thus forming a promising field of cancer research. In this review, we examine the most recent data on the intracellular and extracellular molecular mechanisms that activate EMT and the role they play in various aspects of tumor progression, such as metastasis, apoptotic resistance, and immune evasion, aspects that have usually been attributed exclusively to cancer stem cells (CSCs). In conclusion, we provide a detailed review of the approved and promising drugs for cancer therapy that target the components of the EMT signaling pathways.

scholarly journals Human Lung Microbiome on the Way to Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-6 ◽  
Author(s):  
Olga V. Kovaleva ◽  
Daniil Romashin ◽  
Irina B. Zborovskaya ◽  
Mikhail M. Davydov ◽  
Murat S. Shogenov ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Helicobacter Pylori ◽  
Tumor Progression ◽  
Microbial Communities ◽  
Cancer Progression ◽  
Human Lung ◽  
Lung Microbiome ◽  
Long Time ◽  
Underlying Mechanisms ◽  
Proinflammatory Factors

Recent research on cancer-associated microbial communities led to the accumulation of data on the interplay between bacteria, immune and tumor cells, the pathways of bacterial induction of carcinogenesis, and its meaningfulness for medicine. Microbial communities that have any kind of impact on tumor progression and microorganisms associated with tumors have been defined as oncobiome. Over the last decades, a number of studies were dedicated to Helicobacter pylori and its role in the progression of stomach tumors, so this correlation can be regarded as proven. Involvement of bacteria in the induction of lung cancer has been largely ignored for a long time, though some correlations between this type of cancer and lung microbiome were established. Despite the fact that in the present the microbial impact on lung cancer progression has many confirmations, the underlying mechanisms are poorly understood. Microorganisms can contribute to tumor initiation and progression through production of bacteriotoxins and other proinflammatory factors. The purpose of this review is to organize the available data on lung cancer microbiome and its role in malignant tumor progression.

Cysteine cathepsins in human cancer

2004 ◽  
Vol 385 (11) ◽  
pp. 1017-1027 ◽  
Author(s):  
Christopher Jedeszko ◽  
Bonnie F. Sloane
Keyword(s):  
Serine Proteases ◽  
Human Cancer ◽  
Cysteine Proteases ◽  
Matrix Metalloproteases ◽  
Surrounding Tissue ◽  
Cysteine Cathepsins ◽  
Endogenous Inhibitors ◽  
Tumor Tissues ◽  
Expression Activity ◽  
Diagnostic And Prognostic Value

Abstract Proteases play causal roles in the malignant progression of human tumors. This review centers on the roles in this process of cysteine cathepsins, i.e., peptidases belonging to the papain family (C1) of the CA clan of cysteine proteases. Cysteine cathepsins, most likely along with matrix metalloproteases (MMPs) and serine proteases, degrade the extracellular matrix, thereby facilitating growth and invasion into surrounding tissue and vasculature. Studies on tumor tissues and cell lines have shown changes in expression, activity and distribution of cysteine cathepsins in numerous human cancers. Molecular, immunologic and pharmacological strategies to modulate expression and activity of cysteine cathepsins have provided evidence for a causal role for these enzymes in tumor progression and invasion. Clinically, the levels, activities and localization of cysteine cathepsins and their endogenous inhibitors have been shown to be of diagnostic and prognostic value. Understanding the roles that cysteine proteases play in cancer could lead to the development of more efficacious therapies.

scholarly journals Evaluation of novel cathepsin-X inhibitors in vitro and in vivo and their ability to improve cathepsin-B-directed antitumor therapy

2022 ◽  
Vol 79 (1) ◽  
Author(s):  
Ana Mitrović ◽  
Janja Završnik ◽  
Georgy Mikhaylov ◽  
Damijan Knez ◽  
Urša Pečar Fonović ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Mouse Models ◽  
Cancer Progression ◽  
Cathepsin B ◽  
Cancer Resistance ◽  
Antitumor Therapy ◽  
Cysteine Cathepsins ◽  
Cathepsin X

AbstractNew therapeutic targets that could improve current antitumor therapy and overcome cancer resistance are urgently needed. Promising candidates are lysosomal cysteine cathepsins, proteolytical enzymes involved in various critical steps during cancer progression. Among them, cathepsin X, which acts solely as a carboxypeptidase, has received much attention. Our results indicate that the triazole-based selective reversible inhibitor of cathepsin X named Z9 (1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-((4-isopropyl-4H-1,2,4-triazol-3-yl)thio)ethan-1-one) significantly reduces tumor progression, both in vitro in cell-based functional assays and in vivo in two independent tumor mouse models: the FVB/PyMT transgenic and MMTV-PyMT orthotopic breast cancer mouse models. One of the mechanisms by which cathepsin X contributes to cancer progression is the compensation of cathepsin-B activity loss. Our results confirm that cathepsin-B inhibition is compensated by an increase in cathepsin X activity and protein levels. Furthermore, the simultaneous inhibition of both cathepsins B and X with potent, selective, reversible inhibitors exerted a synergistic effect in impairing processes of tumor progression in in vitro cell-based assays of tumor cell migration and spheroid growth. Taken together, our data demonstrate that Z9 impairs tumor progression both in vitro and in vivo and can be used in combination with other peptidase inhibitors as an innovative approach to overcome resistance to antipeptidase therapy.

The effect of dipeptidyl nitrile derivatives on pancreatic ductal adenocarcinoma cells in vitro

2021 ◽  
Vol 15 ◽  
Author(s):  
Sabrina Mendes Botelho ◽  
Fernanda dos Reis Rocho ◽  
Lorenzo Cianni ◽  
Carlos A. Montanari ◽  
Andrei Leitão
Keyword(s):  
Cancer Progression ◽  
Anticancer Agents ◽  
Combined Therapy ◽  
Cysteine Proteases ◽  
Development Project ◽  
In Vitro Assays ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells ◽  
Cysteine Cathepsins

Aims: This study aims to evaluate the bioactivity of dipeptidyl nitrile inhibitors of human cysteine cathepsins that could work as anticancer agents in a drug discovery and development project. Background: Human lysosomal cysteine proteases promote cancer progression, migration, and metastasis, targeted by inhibitors. Objective: Here, 19 cysteine protease inhibitors known as dipeptidyl nitriles were tested using MIA PaCa-2 pancreatic cancer cells and Balb/3T3 clone A31 non-tumoral mouse fibroblasts. Method: In vitro assays evaluated cell migration, colony formation, inhibition of the enzymatic activity in cell lysates, and combination therapy with gemcitabine. Result: There were mixed results; the inhibitors reduced the number of colonies but did not affect the total area. Cells migrated despite enzyme inhibition by Neq0709 and Neq0712. As expected, the compounds were non-cytotoxic; they improved the potency of gemcitabine in the combined therapy assay, especially for Neq0707. Conclusion: In summary, our findings revealed the complexity of dealing with the translation from biochemical to cell-based assays in the hit-to-lead step.

scholarly journals An Epigenetic Perspective on Intra-Tumour Heterogeneity: Novel Insights and New Challenges from Multiple Fields

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4969
Author(s):  
Sven Beyes ◽  
Naiara Garcia Bediaga ◽  
Alessio Zippo
Keyword(s):  
Drug Resistance ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Tumour Progression ◽  
Tumour Microenvironment ◽  
Genetic Alterations ◽  
Epigenetic Changes ◽  
Multiple Cancer ◽  
Tumour Heterogeneity

Cancer is a group of heterogeneous diseases that results from the occurrence of genetic alterations combined with epigenetic changes and environmental stimuli that increase cancer cell plasticity. Indeed, multiple cancer cell populations coexist within the same tumour, favouring cancer progression and metastatic dissemination as well as drug resistance, thereby representing a major obstacle for treatment. Epigenetic changes contribute to the onset of intra-tumour heterogeneity (ITH) as they facilitate cell adaptation to perturbation of the tumour microenvironment. Despite being its central role, the intrinsic multi-layered and reversible epigenetic pattern limits the possibility to uniquely determine its contribution to ITH. In this review, we first describe the major epigenetic mechanisms involved in tumourigenesis and then discuss how single-cell-based approaches contribute to dissecting the key role of epigenetic changes in tumour heterogeneity. Furthermore, we highlight the importance of dissecting the interplay between genetics, epigenetics, and tumour microenvironments to decipher the molecular mechanisms governing tumour progression and drug resistance.

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