elastin and Neoplasm-Metastasis

The extracellular matrix is a fundamental, core component of all tissues and organs, and is essential for the existence of multicellular organisms. From the earliest stages of organism development until death, it regulates and fine-tunes every cellular process in the body. In cancer, the extracellular matrix is altered at the biochemical, biomechanical, architectural and topographical levels, and recent years have seen an exponential increase in the study and recognition of the importance of the matrix in solid tumours. Coupled with the advancement of new technologies to study various elements of the matrix and cell-matrix interactions, we are also beginning to see the deployment of matrix-centric, stromal targeting cancer therapies. This Review touches on many of the facets of matrix biology in solid cancers, including breast, pancreatic and lung cancer, with the aim of highlighting some of the emerging interactions of the matrix and influences that the matrix has on tumour onset, progression and metastatic dissemination, before summarizing the ongoing work in the field aimed at developing therapies to co-target the matrix in cancer and cancer metastasis.

Topics: ADAM Proteins; ADAMTS Proteins; Bone Morphogenetic Protein 1; Cathepsins; Cell Movement; Collagen; Cystatins; Elastin; Extracellular Matrix; Extracellular Matrix Proteins; Fibrillins; Glucuronidase; Glycoproteins; Humans; Hyaluronoglucosaminidase; Matrix Metalloproteinases; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Protein Processing, Post-Translational; Proteoglycans; Serpins; Tissue Inhibitor of Metalloproteinases; Tolloid-Like Metalloproteinases; Tumor Microenvironment

Gastric cancer (GC) is the fifth most frequent cancer in the world and shows the highest incidence in Latin America and Asia. An increasing amount of evidence demonstrates that lysyl oxidase isoforms, a group of extracellular matrix crosslinking enzymes, should be considered as potential biomarkers and therapeutic targets in GC. In this review, we focus on the expression levels of lysyl oxidase isoforms, its functions and the clinical implications in GC. Finding novel proteins related to the processing of these extracellular matrix enzymes might be helpful in the design of new therapies, which, in combination with classic pharmacology, could be used to delay the progress of this aggressive cancer and offer a wider temporal window for clinical intervention.

Topics: Biomarkers, Tumor; Chelating Agents; Collagen; Elastin; Fibrosis; Humans; Neoplasm Metastasis; Protein Isoforms; Protein-Lysine 6-Oxidase; Stomach Neoplasms

This mini-review summarizes our recent experimental and clinical studies on neutrophil elastase (NE) and cancer based on our original view point. Neoplasms metastasize as a result of a complex series of events. This process requires various degradative enzymes including proteases. NE has broad substrate specificity under physiological conditions, and excessive NE results in digestion of not only elastin, but also other extracellular matrix proteins. Several cell lines from human breast cancer and human lung cancer produce immunoreactive NE. The amount of immunoreactive NE in tumor tissue is an independent prognostic indicator of patients with breast cancer and lung cancer. Furthermore, a specific NE inhibitor completely suppressed growth of cancer cells transplanted into severe combined immunodeficiency mice. The use of NE inhibitor would seem to be a promising way to prevent the invasion and metastasis of cancer.

Topics: Animals; Breast Neoplasms; Elastin; Enzyme Inhibitors; Humans; Leukocyte Elastase; Lung Neoplasms; Neoplasm Metastasis; Prognosis

It is now well established that the interaction of tumour cells with elastin is important during invasion and metastasis. This is due to the fact that the elastin receptor complex is widely expressed by tumour cells and is overexpressed in highly metastatic variants. There is evidence that the elastin receptor complex is associated with a signal system involving G proteins, phospholipase C, the phosphoinositol cycle and protein kinase C. Therefore, activation of the elastin receptor system results in activation of protein kinase C-dependent cellular processes such as enzyme secretion and migration. Accordingly, soluble elastin can be used in vivo to interfere with tumour cell dissemination into elastin-rich tissues such as lung, skin or blood vessels. The importance of elastin-tumour cell interactions is emphasized by the observation that the 67 kDa receptor for laminin may well be identical to the 67 kDa elastin receptor of the elastin receptor complex. Interference with the function of this receptor system by the use of both laminin peptides and elastin ligands may provide the basis for a novel and more powerful antimetastatic intervention.

Topics: Amino Acid Sequence; Animals; Elastin; Humans; Lung Neoplasms; Molecular Sequence Data; Neoplasm Metastasis; Neoplasms; Receptors, Cell Surface

Metastasis is a multistep process in which amoeboid chemotaxis plays a key role in the movement of tumor cells into and out of vessels. On a molecular level, much of what is known about amoeboid chemotaxis has been learned through work with Dictyostelium discoideum, a lower eukaryotic amoeboid phagocyte. One of the first and most crucial events to occur in the actin cytoskeleton following chemotactic stimulation is activation of actin nucleation. This is followed by incorporation of specific actin cross-linking proteins into the cytoskeleton, proteins which are implicated in the extension of pseudopods and filopods. Together, these events have been termed the Cortical Expansion Model for amoeboid chemotaxis. Detailed biochemical analysis has implicated a new actin-capping protein and has shown that one of the cross-linking proteins is Elongation Factor 1a, suggesting a link between chemotaxis and growth control. Preliminary data from parallel studies on neoplastic cells are presented.

Topics: Amino Acid Sequence; Animals; Chemotaxis; Dictyostelium; Elastin; Lung Neoplasms; Mice; Molecular Sequence Data; Neoplasm Metastasis; Oligopeptides; Phagocytes

Topics: Cell Movement; Elastin; Humans; Neoplasm Metastasis; Neovascularization, Pathologic

Topics: Animals; Basement Membrane; Breast Neoplasms; Carcinoma; Cell Communication; Collagen; Elastin; Extracellular Space; Humans; Microbial Collagenase; Neoplasm Invasiveness; Neoplasm Metastasis; Receptors, Immunologic; Receptors, Laminin

Topics: Animals; Basement Membrane; Cathepsin B; Cathepsins; Collagen; Connective Tissue; Elastin; Fibronectins; Glycosaminoglycans; Humans; Mast Cells; Microbial Collagenase; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms; Neoplasms, Experimental; Plasminogen Activators; Precancerous Conditions

The invasion of normal tissues and penetration of basement membranes by malignant cells is likely to require the active participation of hydrolytic enzymes. The four major groups of connective tissue proteins, glycoproteins, proteoglycans, collagen and elastin, vary in their quantitative distributions between different tissues. With the exception of elastin, they also vary qualitatively within each class, so that there are no 'typical' connective tissue barriers to tumor cell penetration. The matrix constituents are stabilized and organized by a variety of covalent and noncovalent interactions between the connective tissue proteins. These interactions play important roles in matrix integrity and may alter the susceptibilities of the constituents to degradative enzymes. It is likely that the complete degradation of the matrix will require the action of more than one enzyme because of differing susceptibilities to tissue proteinases. Primary and transplantable tumors produce well-characterized enzymes which may participate in invasion. These enzymes may also be involved in connective tissue turnover in other normal and pathological situations. The use of long-term tumor cell cultures has verified that tumor cells themselves are capable of producing these enzymes. However, there are many potential modulating influences operative in vivo which are absent in culture so that details of actual mechanisms and control of digestion of complex substrates are not well understood. Recent work on the degradation by tumor cells of extracellular matrices previously produced by cultured cells is likely to shed more light on pathways of tissue destruction in vivo. Experiments with tumor cell variants of defined metastatic potentials will also be useful, but invasive and metastatic abilities are not necessarily correlated. It is unlikely that simple correlations can be drawn between the production of one particular degradative enzyme by all tumor cells and the complex biological mechanisms operative during tumor invasion.

Topics: Animals; Basement Membrane; Cells, Cultured; Collagen; Connective Tissue; Elastin; Extracellular Space; Fibrinolysin; Glycoproteins; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Peptide Hydrolases; Proteoglycans

Collagenases are a family of metalloproteinases which may play a role in facilitating tumor cell invasion of the extracellular matrix. Tumor cells traverse two types of extracellular matrix: basement membranes and interstitial stroma, at multiple stages of the metastatic process. The matrix is a dense meshwork of collagen, proteoglycans, elastin and glycoproteins. Normally the matrix does not contain open spaces large enough for cell movement. Therefore numerous investigators have postulated that collagenolytic proteases, secreted by tumor cells or associated host cells, breakdown the extracellular matrix during tumor cell invasion. A large number of animal and human tumors have been shown to contain collagenase at a higher level than corresponding benign tissues. Separate collagenolytic metalloproteinases have been identified which degrade specific types of collagen. A basement membrane collagenolytic protease was shown to be elevated in a series of metastatic murine tumor cells. Immunologic studies using antibodies specific for collagenase have demonstrated that in vivo, tumor cells can produce collagenase. Therefore identification of collagenase in cultured lines of tumor cells is not an artifact of in vitro cultivation. In some cases, tumor cells may induce host cells to produce collagenase. The best evidence to date that collagenases actually play a role in invasion is derived from experiments in which natural collagenase inhibitors block tumor cell invasion of extracellular matrix in vitro.

Topics: Animals; Basement Membrane; Cell Line; Collagen; Connective Tissue; Elastin; Extracellular Space; Glycoproteins; Humans; Mice; Microbial Collagenase; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Proteoglycans

Cancer stem cell (CSC) inhibitors are a new category of investigational drugs to treat metastasis. Salinomycin (Sali) is one of most studied CSC inhibitors and has reached clinical tests. Several drug carriers have been developed to improve efficacy of Sali. However, Sali has not been shown to inhibit metastasis from orthotopic tumors, the gold standard for metastasis. To fill this gap, we developed an immune-tolerant, elastin-like polypeptide (iTEP)-based nanoparticle (iTEP-Sali-ABA NP) that released 4-(aminomethyl)benzaldehyde-modified Sali (Sali-ABA) under acidic conditions. We found that the NP increased the area under the curve (AUC) of Sali-ABA by 30-fold and the tumor accumulation by 3.4-fold. Furthermore, no metastasis was detected in any of the mice given the NP. However, all the mice died of primary tumor burdens. To overcome primary tumor growth and improve the overall survival, we applied a combination therapy consisting of the iTEP-Sali-ABA NP and iTEP NP-delivered paclitaxel. This therapy effectively retarded primary tumor growth, and most importantly, improved the overall survival. In conclusion, delivery of Sali-ABA by the NP, alone or in combination with paclitaxel, was more effective than free Sali-ABA in decreasing metastasis and increasing survival. This iTEP-Sali-ABA NP represents a novel and clinically promising therapy to combat metastasis.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzaldehydes; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Elastin; Electrophoresis, Polyacrylamide Gel; Female; Humans; Immune Tolerance; Mice, Inbred BALB C; Nanoparticles; Neoplasm Metastasis; Paclitaxel; Peptides; Pyrans; Tissue Distribution

Tumor cell metastasis is a complex, multi-step process that is a major cause of death and morbidity amongst cancer patients. Cell adhesion plays a critical role in the development of metastatic cancer, and it is mediated by interactions between receptors on the cell surface and ligands of the extracellular matrix or other surfaces. Therefore, inhibition of the cell adhesion process appears to be an effective method of preventing metastasis. This work describes a genetically engineered polypeptide with the potential to prevent cell adhesion and inhibit metastasis. We have found that the cell penetrating peptide Tat, fused with elastin-like polypeptide (ELP) inhibited adhesion, spreading, invasion and migration of SKOV-3 ovarian cancer cells in cell culture. Furthermore, we have also confirmed that Tat-ELP has anti-metastatic potential in an experimental ovarian cancer metastasis model in vivo, causing approximately 80% reduction in the tumor burden. Since cell attachment is an important step in tumor cell invasion and metastasis, these results suggest a novel role of Tat-ELP as a therapeutic intervention in cancer metastasis.

Topics: Animals; Cell Adhesion; Cell Movement; Elastin; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Transplantation; Ovarian Neoplasms; Peptides; Recombinant Fusion Proteins; tat Gene Products, Human Immunodeficiency Virus; Transplantation, Heterologous

Cancer cell motility has been associated with metastatic potential of sublines of the Dunning R-3227 rat prostatic adenocarcinoma model. However, three sublines of high motility lacked the capacity for metastasis. In all previous works, motility has been studied upon plastic and only upon attached cells at least 18 h after gravity plating. We studied two highly motile sublines; MAT-LyLu metastasizes to lungs and lymph nodes whereas PIF-1 metastasizes rarely. We compared the motility and attachment capability of cells from the Dunning model in serum-free media upon plastic, glass, laminin, type IV collagen, fibronectin, and elastin to determine whether study upon more physiological surfaces could better explain the discrepancy in metastatic capability observed in vivo. In the high-motility low-metastatic PIF-1 and high-motility high-metastatic MAT-Lylu sublines, membrane ruffling, pseudopodal extension, and cellular translation upon plastic in serum-free media were reduced (P less than 0.0001) by 33 and 31, 70 and 60, and 77 and 65%, respectively. When returned to serum-containing media, biological characteristics (histology, chromosomal number, growth rate, host survival, and metastatic potential) were unchanged. Motility was affected by substrate (analysis of variance, P less than 0.05); however, no consistent pattern of enhancement or detriment occurred in any substrate across both sublines. When motility was compared between sublines, membrane ruffling and cellular translation were relatively unaffected by substrate, whereas pseudopodal extension was altered significantly by different substrates. However, upon individual substrates, no significant differences in motility existed between the two sublines to resolve the inconsistency of high-motility but low-metastatic potential in the PIF-1 subline. Therefore, we examined cell attachment, since in order for a metastatic cell to be motile upon substrate, it must first attach to it. Percentage of 10(5) cells attached was determined in serum-free media with the use of a cell counter after 1, 2, 4, 8, and 16 h on plastic and plastic coated with laminin, fibronectin, elastin, or type IV collagen. Cell attachment increased with time (P less than 0.05) on all substrates for MAT-LyLu (r = 0.95) and PIF-1 (r = 0.98). Attachment of MAT-LyLu cells was impaired by fibronectin and enhanced by elastin, laminin, and type IV collagen compared to plastic at all time points.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adenocarcinoma; Animals; Cell Adhesion; Cell Movement; Collagen; Culture Media, Serum-Free; Elastin; Fibronectins; Laminin; Male; Neoplasm Metastasis; Prostatic Neoplasms; Rats; Tumor Cells, Cultured

Interactions between the extracellular matrix macromolecules and tumor cells are critical in the process of metastasis formation. We show here that elastins (both mature insoluble elastin and a 75-kDa soluble peptide: K-elastin) adhere rapidly to two cell lines with high metastatic capacities: a metastatic lung carcinoma cell line (3LL-HM) and a human amelanotic melanoma cell line (A-2058); by contrast the low-metastatic Lewis lung carcinoma cell line variant as well as a rhabdomyosarcoma cell line with a low metastatic potential bind to elastins to a much lower extent. 3H-labelled K-elastin was used in order to study elastin--3LL-HM interaction. It was found to be saturable (2 ng 3H-labelled K-elastin/10(6) cells), with one class of high-affinity binding sites having Kd equal to 1.3 nM and 16,000 sites/cell. The binding of K-elastin to 3LL-HM cells at its receptor triggered several cell responses; (a) increase of intracellular Ca2+ concentration; (b) induction of 3LL-HM chemotaxis toward the K-elastin gradient; (c) stimulation of the adherence of mature insoluble elastin. In contrast to non-transformed cells such as fibroblasts and smooth muscle cells, the adhesion kinetics of insoluble elastin to 3LL-HM did not exhibit a lag period; the rapid binding of insoluble elastin to the tumor cells was followed by its slow detachment from the cells, which lasted for 6 h. 3LL-HM cells but not human skin fibroblasts were shown to secrete elastinolytic activity inhibitable by metal-chelating agents. In vivo studies were performed in order to evaluate the influence of K-elastin binding to 3LL-HM cells on their ability to form lung colonies in mice. It was shown that pretreatment of 10(4) 3LL-HM cells with 10 microM K-elastin and the simultaneous i.v. injection into mice of 750 micrograms K-elastin together with the highly metastatic cells was able to reduce the number of lung colonies by more than 70% after 12 days.

Topics: Adult; Amino Acid Sequence; Animals; Cell Adhesion; Chemotaxis; Elastin; Female; Fibroblasts; Humans; Kinetics; Lung Neoplasms; Mice; Mice, Nude; Molecular Sequence Data; Neoplasm Metastasis; Pancreatic Elastase; Receptors, Cell Surface; Tumor Cells, Cultured

Artificial blood vessel walls constructed by the addition of bovine arterial endothelial cells to multilayers of rat smooth muscle cells were used as substrates for the human fibrosarcoma cell line HT1080. The extracellular matrix proteins elaborated by the smooth muscle cells were prelabeled with [3H]-proline; therefore, their subsequent digestion could be followed by the appearance of radioactivity in the culture medium. The fibrosarcoma cells rapidly hydrolyzed smooth muscle multilayers in the absence of endothelial cells, but an endothelial layer markedly retarded the destructive ability of the tumor cells. The protective effect of the endothelium was not due to a lack of penetration of this cell layer, since HT1080 cells were observed by light and electron microscopy to be in the subendothelial area 24 hr after plating. Subsequently, the tumor cells multiplied in the region between the endothelial and smooth muscle layers and, although their degradative ability was retarded, they were ultimately capable of destroying the structure. Endothelial cells also inhibited hydrolysis of the smooth muscle layers if added simultaneously or up to 1 week after HT1080 cells, but the degree of inhibition was not as great as that seen with a preestablished endothelial layer. Measurable inhibition of tumor cell degradative activity was observed at fibrosarcoma:endothelial cell ratios of 25:1, demonstrating the potency of endothelial cells in modulating this aspect of the invasive phenotype. Although the HT1080 cells only slowly degraded the preexisting matrix proteins in artificial vessel wall cultures, they interfered with the production of new connective tissue proteins which occurred in control cultures. These experiments therefore suggest that endothelial cells have profound effects on tumor cell proteolytic activity, and the significance of these observations to tumor cell extravasation in vivo is discussed.

Topics: Animals; Cell Communication; Cell Line; Collagen; Elastin; Endothelium; Fibrosarcoma; Humans; Mice; Models, Biological; Muscle, Smooth, Vascular; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplastic Cells, Circulating; Proline

Duct elastosis was studied in 219 patients subjected to radical mastectomy for infiltrating carcinoma of the breast, with a 10-year follow-up. Duct elastosis is a frequent finding in infiltrating breast cancer (65% of our cases). It develops in tumors of all three grades of malignancy, but it is more frequent in tumors of low grade malignancy (76% and 74% in grades I and II, respectively, and 47% in grade III tumors). In spite of their greater incidence in low malignancy tumors, the elastotic cases have a greater metastatic ratio than the non-elastotic cases (66% vs 45%). The elastotic cases also contain a significantly greater proportion of scirrhous tumors than the non-elastotic cases (86% vs. 32%). Duct elastosis and scirrhous reaction are two processes which develop in parallel, but are not related etiologically. They seem to be correlated with more advanced stages of the neoplastic disease. The influence of duct elastosis upon the ten year survival of the patients is unfavorable. this influence is not direct, and it is particularly evident in the metastatic cases. It seems to be related to the greater duration of the neoplastic disease and to the slow clinical course of tumors of low degree of malignancy.

Topics: Breast Neoplasms; Elastin; Female; Humans; Life Expectancy; Mastectomy; Neoplasm Metastasis; Prognosis