Matrix Metalloproteinases: Biologic Activity and Clinical Implications

2000 ◽  
Vol 18 (5) ◽  
pp. 1135-1135 ◽  
Author(s):  
Amy R. Nelson ◽  
Barbara Fingleton ◽  
Mace L. Rothenberg ◽  
Lynn M. Matrisian
Keyword(s):  
Matrix Metalloproteinases ◽  
Tumor Growth ◽  
Tumor Progression ◽  
Metastatic Tumor ◽  
The Body ◽  
Genetic Changes ◽  
Biologic Activity ◽  
The Matrix ◽  
Degradative Enzymes

ABSTRACT: Tumor progression is a complex, multistage process by which a normal cell undergoes genetic changes that result in phenotypic alterations and the acquisition of the ability to spread and colonize distant sites in the body. Although many factors regulate malignant tumor growth and spread, interactions between a tumor and its surrounding microenvironment result in the production of important protein products that are crucial to each step of tumor progression. The matrix metalloproteinases (MMPs) are a family of degradative enzymes with clear links to malignancy. These enzymes are associated with tumor cell invasion of the basement membrane and stroma, blood vessel penetration, and metastasis. They have more recently been implicated in primary and metastatic tumor growth and angiogenesis, and they may even have a role in tumor promotion. This review outlines our current understanding of the MMP family, including the association of particular MMPs with malignant phenotypes and the role of MMPs in specific steps of the metastatic cascade. As scientific understanding of the MMPs has advanced, therapeutic strategies that capitalize on blocking the enzymes have rapidly developed. The preclinical and clinical evolution of the synthetic MMP inhibitors (MMPIs) is also examined, with the discussion encompassing important methodologic issues associated with determining clinical efficacy of MMPIs and other novel therapeutic agents.

scholarly journals Cell Plasticity and Prostate Cancer: The Role of Epithelial–Mesenchymal Transition in Tumor Progression, Invasion, Metastasis and Cancer Therapy Resistance

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2795
Author(s):  
Sofia Papanikolaou ◽  
Aikaterini Vourda ◽  
Spyros Syggelos ◽  
Kostis Gyftopoulos
Keyword(s):  
Prostate Cancer ◽  
Cancer Therapy ◽  
Tumor Progression ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Tumor ◽  
Therapy Resistance ◽  
Cellular Process ◽  
Cell Plasticity ◽  
Mesenchymal Transition

Prostate cancer, the second most common malignancy in men, is characterized by high heterogeneity that poses several therapeutic challenges. Epithelial–mesenchymal transition (EMT) is a dynamic, reversible cellular process which is essential in normal embryonic morphogenesis and wound healing. However, the cellular changes that are induced by EMT suggest that it may also play a central role in tumor progression, invasion, metastasis, and resistance to current therapeutic options. These changes include enhanced motility and loss of cell–cell adhesion that form a more aggressive cellular phenotype. Moreover, the reverse process (MET) is a necessary element of the metastatic tumor process. It is highly probable that this cell plasticity reflects a hybrid state between epithelial and mesenchymal status. In this review, we describe the underlying key mechanisms of the EMT-induced phenotype modulation that contribute to prostate tumor aggressiveness and cancer therapy resistance, in an effort to provide a framework of this complex cellular process.

Limited Role of TP53 and TP53-Related Genes in Myxoid Liposarcoma

1998 ◽  
Vol 84 (5) ◽  
pp. 571-577 ◽  
Author(s):  
Silvana Pilotti ◽  
Cinzia Lavarino ◽  
Alessandra Mezzelani ◽  
Gabriella Della Torre ◽  
Fabiola Minoletti ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Chromosomal Translocation ◽  
Myxoid Liposarcoma ◽  
P53 Mutation ◽  
Unexpected Finding ◽  
Genetic Changes ◽  
Molecular Features ◽  
Well Differentiated ◽  
Pleomorphic Liposarcomas

Aims Circumstantial evidence suggests that genetic changes may lead to tumor progression within the myxoid liposarcoma tumors (MLTs) carrying non-random chromosomal translocation t(12;16). Methods To address this subject an immunophenotypic analysis, applying antibodies against proteins encoded by TP53, MDM2 and CDK4 genes, complemented by molecular analysis of eight suitable cases, was performed on 104 consecutive cases. Chromosomal translocations were assessed either by cytogenetic analysis or by RT-PCR in 9 suitable cases and chimeric transcripts were found in all cases but two pleomorphic liposarcomas. Results Based on immunophenotyping and tumor site, the case material consisted of three groups. The first one was made up of 92 non-retroperitoneal cases carrying a null p53, mdm2, cdk4 immunophenotype, which remained unchanged over the time of recurrences and along the gamut of histologic subtypes. The second group was represented by five p53+, mdm2-, cdk4- non-retroperitoneal cases, 4 of which were further analysed by PCR-SSCP for p53 mutation. The im-munophenotipic profile of these cases, complemented by the molecular findings, supported a role of TP53 in tumor progression in three high-grade MLTs. The third group, consisting of 7 retroperitoneal cases, showed a heterogeneous immunophenotype, sharing immunophenotypic and molecular features with the well-differentiated/evoluted (dedifferentiated) liposarcoma group. Conclusions TP53 mutations seem to play a role in tumor progression in a few cases of MLTs (2.8%) showing more aggressive histologic characteristics. The unexpected finding that a number of retroperitoneal LMTs display the immunophenotypic profile of the well differentiated/evoluted (dedifferentiated) liposarcomas, deserves further investigation.

Molecular regulation of cellular invasion— role of gelatinase A and TIMP-2

1996 ◽  
Vol 74 (6) ◽  
pp. 823-831 ◽  
Author(s):  
Anita E. Yu ◽  
Robert E. Hewitt ◽  
David E. Kleiner ◽  
William G. Stetler-Stevenson
Keyword(s):  
Extracellular Matrix ◽  
Matrix Metalloproteinases ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Gelatinase A ◽  
Cellular Mechanisms ◽  
Cell Matrix ◽  
Matrix Interactions ◽  
The Matrix ◽  
Cell Matrix Interactions

Extracellular matrix (ECM) turnover is an event that is tightly regulated. Much of the coordinate (physiological) or discoordinate (pathological) degradation of the ECM is catalyzed by a class of proteases known as the matrix metalloproteinases (MMPs) or matrixins. Matrixins are a family of homologous Zn atom dependent endopeptidases that are usually secreted from cells as inactive zymogens. Net degradative activity in the extracellular environment is regulated by specific activators and inhibitors. One member of the matrixin family, gelatinase A, is regulated differently from other MMPs, suggesting that it may play a unique role in cell–matrix interactions, including cell invasion. The conversion from the 72 kDa progelatinase A to the active 62 kDa species may be a key event in the acquisition of invasive potential. This discussion reviews some recent findings on the cellular mechanisms involved in progelatinase A activation and, in particular, the role of tissue inhibitor of matrix metalloproteinases-2 (TIMP-2) and transmembrane containing metalloproteinases (MT-MMP) in this process.Key words: tissue inhibitors of metalloproteinases, metalloproteinase, gelatinases, extracellular matrix, activation.

scholarly journals Role of mTOR and VEGFR Inhibition in Prevention of Metastatic Tumor Growth in the Spine

2020 ◽  
Vol 10 ◽  
Author(s):  
Tobias Kratzsch ◽  
Andras Piffko ◽  
Thomas Broggini ◽  
Marcus Czabanka ◽  
Peter Vajkoczy
Keyword(s):  
Tumor Growth ◽  
Metastatic Tumor

scholarly journals The role of effective energy restriction on metastatic tumor growth

2018 ◽  
Vol 32 (S1) ◽  
Author(s):  
Tapasree Roy Sarkar ◽  
Nathalie Sphyris ◽  
Emily Schmitt ◽  
Garhett Wyatt ◽  
Steven Wall ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Metastatic Tumor ◽  
Energy Restriction ◽  
Effective Energy

scholarly journals Role of matrix metalloproteinase in the aneurismatic aortic disease

2004 ◽  
Vol 62 (3) ◽  
Author(s):  
Nicola Troisi ◽  
Alfredo Mazza ◽  
Felice Mazza ◽  
Gabriele Iannelli
Keyword(s):  
Matrix Metalloproteinases ◽  
Aortic Disease ◽  
Endothelial Damage ◽  
Matrix Proteins ◽  
Tissue Destruction ◽  
The Matrix ◽  
Drug Inhibition ◽  
Atherosclerotic Aneurysm ◽  
Aneurysm Diameter

The aorta is involved in a large variety of diseases and the atherosclerotic aneurysms represent the most common type of these. Recent reports have attempted to clarify the mechanisms, that cause the formation and the progression of the atherosclerotic aneurysms, caused not only by the atherosclerosis. One of the features of this disease is the extensive proteolytic destruction of structural matrix proteins in the aortic wall realized by the matrix metalloproteinases. The atherosclerotic aneurysm can be considered a disease caused by an imbalance between connective tissue destruction and its repair. Knowledge of the role played by matrix metalloproteinases in the formation process of the aneurysms has made the inhibition of these proteins a logical therapeutic strategy. Once completed the aneurysm treatment, surgical or endovascular, the endothelial damage must disappear; the persistence of this damage, after endovascular procedure, is the cause of the formation of the endoleaks. The preoperative matrix metalloproteinases plasmatic levels are related to the aneurysm diameter and after endovascular treatment these values come back normal, except in the case of presence of an endoleak, that don’t make possible the reduction of these values. In spite of that, obscure points still remain, above all about the dosage of these proteins and their inhibition through drugs with clear metalloproteinases- inhibiting properties. The aim of this study is to clarify further on the mechanisms of the formation of the aneurysms with particular care to the matrix metalloproteinases, their dosage and their drug inhibition.

scholarly journals Immunoediting: evidence of the multifaceted role of the immune system in self-metastatic tumor growth

2012 ◽  
Vol 9 (1) ◽  
pp. 31 ◽  
Author(s):  
Heiko Enderling ◽  
Lynn Hlatky ◽  
Philip Hahnfeldt
Keyword(s):  
Immune System ◽  
Tumor Growth ◽  
Metastatic Tumor

scholarly journals Steroid Sulfatase: Molecular Biology, Regulation, and Inhibition

2005 ◽  
Vol 26 (2) ◽  
pp. 171-202 ◽  
Author(s):  
M. J. Reed ◽  
A. Purohit ◽  
L. W. L. Woo ◽  
S. P. Newman ◽  
B. V. L. Potter
Keyword(s):  
Tumor Growth ◽  
Prognostic Significance ◽  
Dehydroepiandrosterone Sulfate ◽  
The Body ◽  
Biologically Active ◽  
Steroid Sulfatase ◽  
Estrone Sulfate ◽  
Estrogenic Properties ◽  
Hydrolysis Of

Steroid sulfatase (STS) is responsible for the hydrolysis of aryl and alkyl steroid sulfates and therefore has a pivotal role in regulating the formation of biologically active steroids. The enzyme is widely distributed throughout the body, and its action is implicated in physiological processes and pathological conditions. The crystal structure of the enzyme has been resolved, but relatively little is known about what regulates its expression or activity. Research into the control and inhibition of this enzyme has been stimulated by its important role in supporting the growth of hormone-dependent tumors of the breast and prostate. STS is responsible for the hydrolysis of estrone sulfate and dehydroepiandrosterone sulfate to estrone and dehydroepiandrosterone, respectively, both of which can be converted to steroids with estrogenic properties (i.e., estradiol and androstenediol) that can stimulate tumor growth. STS expression is increased in breast tumors and has prognostic significance. The role of STS in supporting tumor growth prompted the development of potent STS inhibitors. Several steroidal and nonsteroidal STS inhibitors are now available, with the irreversible type of inhibitor having a phenol sulfamate ester as its active pharmacophore. One such inhibitor, 667 COUMATE, has now entered a phase I trial in postmenopausal women with breast cancer. The skin is also an important site of STS activity, and deficiency of this enzyme is associated with X-linked ichthyosis. STS may also be involved in regulating part of the immune response and some aspects of cognitive function. The development of potent STS inhibitors will allow investigation of the role of this enzyme in physiological and pathological processes.

scholarly journals Leveling Up the Controversial Role of Neutrophils in Cancer: When the Complexity Becomes Entangled

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2486
Author(s):  
Ronit Vogt Sionov
Keyword(s):  
Tumor Growth ◽  
Tumor Cell ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Immune Cell ◽  
Neutrophil Function ◽  
The Body ◽  
Cathepsin G ◽  
Metastatic Sites

Neutrophils are the most abundant immune cell in the circulation of human and act as gatekeepers to discard foreign elements that have entered the body. They are essential in initiating immune responses for eliminating invaders, such as microorganisms and alien particles, as well as to act as immune surveyors of cancer cells, especially during the initial stages of carcinogenesis and for eliminating single metastatic cells in the circulation and in the premetastatic organs. Since neutrophils can secrete a whole range of factors stored in their many granules as well as produce reactive oxygen and nitrogen species upon stimulation, neutrophils may directly or indirectly affect carcinogenesis in both the positive and negative directions. An intricate crosstalk between tumor cells, neutrophils, other immune cells and stromal cells in the microenvironment modulates neutrophil function resulting in both anti- and pro-tumor activities. Both the anti-tumor and pro-tumor activities require chemoattraction towards the tumor cells, neutrophil activation and ROS production. Divergence is seen in other neutrophil properties, including differential secretory repertoire and membrane receptor display. Many of the direct effects of neutrophils on tumor growth and metastases are dependent on tight neutrophil–tumor cell interactions. Among them, the neutrophil Mac-1 interaction with tumor ICAM-1 and the neutrophil L-selectin interaction with tumor-cell sialomucins were found to be involved in the neutrophil-mediated capturing of circulating tumor cells resulting in increased metastatic seeding. On the other hand, the anti-tumor function of neutrophils was found to rely on the interaction between tumor-surface-expressed receptor for advanced glycation end products (RAGE) and Cathepsin G expressed on the neutrophil surface. Intriguingly, these two molecules are also involved in the promotion of tumor growth and metastases. RAGE is upregulated during early inflammation-induced carcinogenesis and was found to be important for sustaining tumor growth and homing at metastatic sites. Cathepsin G was found to be essential for neutrophil-supported lung colonization of cancer cells. These data level up the complexity of the dual role of neutrophils in cancer.

Sign in / Sign up

Export Citation Format

Share Document