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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Data from the literature now indicate that cancer cells can specifically interact with the unique extracellular matrix protein, elastin. The interaction is mediated by two elastin-binding proteins (EBP), S-gal/EBP (organized into the elasin receptor/elastonectin complex) and galectin-3, components of two laminin receptors. Studies revealed that the expression of both EBPs is closely associated to the invasive/metastatic potential of various cancer types. This is due to the fact that elastin-ligation of S-gal/EBP induces motogenic, as well as mitogenic signals and releases various elastases from cancer cells and the induction depends on the metastatic potential. Studies also demonstrated that certain cancer cells can synthesize elastin and express lysyl oxydase, providing explanation for frequent appearance of elastic tissue in tumors such as breast or gastric cancers. Clinico-pathological data suggest some correlation with tumor progression of the presence of the elastic tumor stroma. Since elastic tissue may be a significant reservoir of angiostatic molecule(s) this extracellular matrix protein can also have a role in tumor-induced angiogenesis. Soluble elastin as well as elastin peptides are potent inhibitors of the metastatic process in experimental tumor models. On the other hand, elastin peptides can also be used to design targeted therapies exploiting the unique physicochemical nature of this matrix protein. Altogether, these data suggest a significant role for tumor cell-elastin interactions in tumor progression.
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PMID:Role of elastin-matrix interactions in tumor progression. 1208 51

The microenvironment of cancer cells, composed of extracellular matrix (ECM) macromolecules, plays a pivotal function in tumor progression. ECM preexisting modules or cryptic sites revealed by partial enzymatic hydrolysis positively or negatively regulate matrix metalloproteinase (MMP) expression and activation, further influencing matrix invasion by cancer cells. Pericellular activation of gelatinase A (MMP-2) proceeds via the formation of a complex involving its inhibitor, TIMP-2, its activator(s), MT-MMPs and alphavbeta3 integrin forming a docking system. This proteinase has been invariably linked to cancer cell invasive potential and is often predictive of a poor survival. MMP-2 degrades most ECM macromolecules and appears to act as a main 'decryptase'. ECM modulation of MMP-2 activation pathway thus influences angiogenesis and tumor growth. For instance the noncollagenous domain of alpha3 chain of type IV collagen, through alphavbeta3 integrin binding, inhibits both MT1-MMP and alphavbeta3 integrin expression from melanoma cells and empedes cell migration and proliferation. At the opposite, a particular module in elastin (VGVAPG) with type VIII beta turn conformation stimulates MT1-MMP and proMMP-2 activation through binding to S-gal elastin receptor, and increases the matrix invasive capacity of several cancer cell lines and endothelial cells. Endocytosis emerges as a main mechanism controlling MMP-2, and also other MMPs; it proceeds via the formation of a MMP-thrombospondin(s) complex further recognized by the LRP scavenger receptor. ECM undergoes conspicuous variations with aging linked to alterations of tissue organization and post-translational modifications of matrix constituents that modify cell-matrix interactions and MMP-2 activation pathway.
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PMID:Matrix-directed regulation of pericellular proteolysis and tumor progression. 1208 53

Pericellular proteolysis plays a pivotal function in cell invasion, a hallmark of tumor growth and metastasis. The minidegradome constituted of two matrix metalloproteinases (MMP), i.e. MMP-2 and MT1-MMP, associated with tissue inhibitor of metalloprotease-2 (TIMP-2) and integrin (alpha(v)beta(3)) or CD(44), is mainly involved in such invasive program. It catalyzes matrix degradation but, alternatively, proteolytic exposure of matricryptic sites or matrikines liberation by those enzymes regulates either positively or negatively tumor cell migration. That applies to types I and IV collagens, elastin, laminin 5, as described here, but such phenomenon might be extended to other matrix macromolecules. The development of tumors from epithelium origin is related to aging. Senescent fibroblasts are characterized by increased expression of MMPs, (particularly collagenase-1 (MMP-1) and stromelysin-1 (MMP-3)) and deposited matrix by those aged cells was shown to favor cancer cell growth. Thus, compositional variation of matrix-surrounding tumor cells, with formation of matricryptic sites and matrikines, can be considered as one main epigenetic factor contributing to tumor progression. A matrix-directed pharmacological approach in cancer is now emerging.
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PMID:Proteolyzed matrix as a template for the regulation of tumor progression. 1288 58

The term of "matrikines" was coined for designating peptides liberated by partial proteolysis of extracellular matrix macromolecules, which are able to regulate cell activities. Among these peptides, some of them may modulate proliferation, migration, protease production, or apoptosis, which suggest that they can play a significant role in the control of tumor progression. In this introduction, we present the best characterized matrikines, derived from elastin, connective tissue glycoproteins, or collagens.
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PMID:An introduction to matrikines: extracellular matrix-derived peptides which regulate cell activity. Implication in tumor invasion. 1503 60

Extracellular matrix (ECM) has been a central topic in aging research for several years. Cell-matrix interactions extend the interest in this topic both for normal tissue homeostatic regulation as well as for its dysregulation in age-related diseases. A relatively new extension of this ever-increasing field of aging research concerns the recognition of the original biological activities exhibited by proteolytic fragments of matrix macromolecules. A number of such matricryptins were recently identified, some of them endowed with harmful effects for tissue function. Some of the breakdown products exert a positive feedback effect by upregulating the biosynthesis of the original macromolecule synthesis and/or the expression of degrading enzymes. This results in vicious circles which might well be involved in tissue aging. The examples detailed in this review concern fibronectin (FN) and elastin. A number of fibronectin fragments (Fn-fr) were shown to exhibit diverse activities including increasing tissue degradation, inflammation and tumor progression. Elastin degradation products acting as agonists on the elastin-laminin receptor can trigger harmful effects such as up-regulation of proteases and free radical production. Both macromolecules are at the center of autoamplifying vicious circles of potential importance for age-dependent modification of tissue function.
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PMID:Cell-matrix interactions in aging: role of receptors and matricryptins. 1517 57

Elastin peptides (EPs) produced during cancer progression bind to the elastin binding protein (EBP) found at the surface of dermal fibroblasts, leading to the expression of collagenase-1 gene. The production of this enzyme involved in stromal reaction is caused by the sustained activation of the extracellular signal-regulated kinases 1/2 (ERK1/2) pathway via cAMP/protein kinase A (PKA) and phosphatidylinositol 3-kinase (PI3K). However, the mechanism of these signaling events remains unknown. We show that kappa-elastin (kappaE), a commonly used EP, induces maximum phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK)1/2 and ERK1/2 after 30 min. The simultaneous inhibition of PKA and PI3K, by N-(2-(p-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide (H89) and 2-(4-morpholynil)-8-phenyl-4H-1-bemzopyran-4-one (LY294002), respectively, blocked MEK1/2 and ERK1/2 phosphorylation, as did lactose, an EBP antagonist. kappaE induced Raf-1 phosphorylation and activation in a PI3K-dependent manner. In our system, the PI3K p110gamma is expressed and activated by betagamma-derived subunits from a pertussis toxin-sensitive G protein after fibroblast stimulation. Pertussis toxin also blocks the Raf-1/MEK1/2/ERK1/2 phosphorylation cascade. In addition, we found that B-Raf is expressed in dermal fibroblasts and activated in a PKA-dependent manner after kappaE treatment, thereby integrating PKA signals to MEK1/2. It is noteworthy that Ras involvement was excluded because ERK1/2 activation by kappaE was not blocked in RasN17-transfected fibroblasts. Together, our results identify a novel Ras-independent ERK1/2 activation system in which p110gamma/Raf-1/MEK1/2 and PKA/B-Raf/MEK1/2 cooperate to activate ERK1/2. Thus, p110gamma and B-Raf seem to be important modulators of dermal fibroblasts physiology and should now qualify as therapeutic targets in strategies aiming at limiting elastin degradation contribution to cancer progression.
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PMID:Elastin peptides activate extracellular signal-regulated kinase 1/2 via a Ras-independent mechanism requiring both p110gamma/Raf-1 and protein kinase A/B-Raf signaling in human skin fibroblasts. 1565 54

Dermatologists are faced daily with the need to optimize skin repair and excise cutaneous cancers. The extracellular matrix plays a pivotal role in cellular migration, proliferation, and gene regulation during wound healing and progression of melanoma, basal cell carcinoma, and squamous cell carcinoma. Within the last few years, a new class of ligand, the matrikine or matricryptin, has been characterized as subdomains of various ECM proteins capable of signaling to the cell through receptors, such as growth factor receptors. Two classes exist: the "natural" matrikines, which signal directly from the extracellular milieu and "cryptic" matrikines (matricryptins) that require proteolytic processing to reveal the ligand or to release the ligand from its ECM protein. Unlike traditional soluble growth factors, most matrikines possess low binding affinity to their receptors and are often presented in multiple valency that likely increase avidity to receptors. The presentation of these ligands within the ECM can result in unique outcomes. The EGF-like repeats of tenascin-C and laminin-5 signal to EGFR preferentially to upregulate migration during skin repair and tumor progression. Other matrikines in collagen, elastin, decorin, and laminin-1 can promote chemotaxis, mitogenesis, and metastasis in cancers, such as melanoma. Finally, the unique properties of matrikines have been utilized in cancer therapeutics and tissue engineering. Within the next few years, the nature and function of this emerging class of matrikine ligands will have an impact on dermatology, as these proteins are altered in wound repair and skin diseases.
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PMID:Matrikines and matricryptins: Implications for cutaneous cancers and skin repair. 1599 69

In normal and pathological tissues, polymorphonuclear leukocyte proteases (elastase, cathepsin G and proteinase 3) may generate soluble peptides through limited proteolysis of elastin, the main component of mature elastic fibres. Elastin-derived peptides display diverse biological activities including cell migration, differentiation, proliferation, chemotaxis, tumor progression and up-regulation of metalloproteinases. To be biologically active, their structures must adopt a beta-turn conformation which accommodates to the cell surface-located elastin binding protein. In this study, we established that human elastin exon 24-derived peptides are hydrolysed by leukocyte elastase, when the active site is fully occupied (from S(5) to S'(3)). As shown by mass spectrometry analyses, a major cleavage site was demonstrated at a Val-Ala bond and a minor one at Gly-Val bond. For longer peptides, the hydrolysed fragments could themselves be re-hydrolysed. If the shortest fragments do not contain the GxxPG sequence known to stimulate cellular effects, some of the intermediates together with hydrolysis fragments generated by other proteases such as proteinase 3, may possess this motif.
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PMID:Human leukocyte elastase hydrolysis of peptides derived from human elastin exon 24. 1694 64

Lysyl oxidase-like 2 (LOXL2) belongs to an amine oxidase family whose members have been implicated in crosslink formation in stromal collagens and elastin, cell motility, and tumor development and progression. We previously demonstrated the association between increased LOXL2 expression and invasive/metastatic behavior in human breast cancer cells and mouse squamous and spindle cell carcinomas, interaction between LOXL2 and SNAIL in epithelial-mesenchymal transition, and localization of the LOXL2 gene to 8p21.2-21.3, within a minimally deleted region in several cancers, including colon and esophagus. In the present study, we analyzed LOXL2 expression in colon and esophageal tumors, and explored methylation as a regulator of LOXL2 expression. Immunohistochemistry using normal tissues demonstrated intracellular localization of LOXL2 in colonic enteroendocrine cells and esophageal squamous cells at the luminal surface, but not in mitotically active cells. Tissue array analysis of 52 colon adenocarcinomas and 50 esophageal squamous cell carcinomas revealed presence of LOXL2 expression in 83 and 92% of the samples, respectively, and a significant association between increased number of LOXL2-expressing cells and less-differentiated colon carcinomas. We determined that the methylation status of the 1150 bp 5' CpG island may contribute to the regulation of the gene. Loss of heterozygosity studies, using a microsatellite within intron 4 of the LOXL2 gene, revealed that loss of LOXL2 was unlikely to play a major role in either colon or esophageal tumors. These results suggest that increased LOXL2 expression in colon and esophageal cancer may contribute to tumor progression.
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PMID:Lysyl oxidase-like 2 expression is increased in colon and esophageal tumors and associated with less differentiated colon tumors. 1739 33

Lysyl oxidase (LOX) is an extracellular matrix (ECM) enzyme that catalyzes the cross-linking of collagens or elastin in the extracellular compartment, thereby regulating the tensile strength of tissues. However, recent reports have demonstrated novel roles for LOX, including the ability to regulate gene transcription, motility/migration, and cell adhesion. These diverse functions have led researchers to hypothesize that LOX may have multiple roles affecting both extra- and intracellular cell function(s). Particularly noteworthy is aberrant LOX expression and activity that have been observed in various cancerous tissues and neoplastic cell lines. Both down and upregulation of LOX in tumor tissues and cancer cell lines have been described, suggesting a dual role for LOX as a tumor suppressor, as well as a metastasis promoter gene--creating a conundrum within the LOX research field. Here, we review the body of evidence on LOX gene expression, regulation, and function(s) in various cancer cell types and tissues, as well as stromal-tumor cell interactions. Lastly, we will examine putative mechanisms in which LOX facilitates breast cancer invasion and metastasis. Taken together, the literature demonstrates the increasingly important role(s) that LOX may play in regulating tumor progression and the necessity to elucidate its myriad mechanisms of action in order to identify potentially novel therapeutics.
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PMID:Paradoxical roles for lysyl oxidases in cancer--a prospect. 1747 32


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