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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Regulation of a number of adhesion molecules during neural crest cell migration was studied. The neural crest, a transient embryonic neural epithelium structure, undergoes mesenchymal transformation (epithelial-mesenchymal transition). The cells then migrate, giving rise to a variety of elements including the peripheral nervous system and melanocytes. During migration, neural crest cells do not express functional cell Adhesion Molecules but interact specifically with cell-binding domains in fibronectin molecules. A rat bladder carcinoma cell line was used as an in vitro model to study conversion of epithelial cells to a migratory fibroblast-like state. Conversion can be induced by culture on collagen or exposure to acidic Fibroblast Growth Factor (aFGF). Furthermore, constitutive fibroblast-like transformation can be induced by transfection with cDNA encoding aFGF. Growth factor-producing clones exhibit increased invasive and metastatic properties as compared with non-FGF-producing control cells. This model may provide increased understanding of the role of the different adhesion molecules in processes involving cell remodeling, such as tumor spread and development of metastases.
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PMID:[Adhesion and mobility of embryonic and tumoral cells]. 128 12

Neoplastic cells require an appropriate pericellular environment and new formation of stroma and blood vessels in order to constitute a solid tumor. Tumor progression also involves degradation of various extracellular matrix (ECM) constituents. In this review we have focused on the possible involvement of ECM-resident growth factors and enzymes in neovascularization and cell invasion. We demonstrate that the pluripotent angiogenic factor, basic fibroblast growth factor (bFGF) is an ECM component required for supporting cell proliferation and differentiation. Basic FGF has been identified in the subendothelial ECM produced in vitro and in basement membranes of the cornea and blood vessels in vivo. Despite the ubiquitous presence of bFGF in normal tissues, endothelial cell (EC) proliferation in these tissues is usually very low, suggesting that bFGF is somehow sequestered from its site of action. Our results indicate that bFGF is bound to heparan sulfate (HS) in the ECM and is released in an active form when the ECM-HS is degraded by cellular heparanase. We propose that restriction of bFGF bioavailability by binding to ECM and local regulation of its release, provides a novel mechanism for regulation of capillary blood vessel growth in normal and pathological situations. Heparanase activity correlates with the metastatic potential of various tumor cells and heparanase inhibiting molecules markedly reduce the incidence of lung metastasis in experimental animals. Heparanase may therefore participate in both tumor cell invasion and angiogenesis through degradation of the ECM-HS and mobilization of ECM-resident EC growth factors. The subendothelial ECM contains also tissue type- and urokinase type- plasminogen activators (PA), as well as PA inhibitor which may regulate cell invasion and tissue remodeling. Heparanase and the ECM-resident PA participate synergistically in sequential degradation of HS-proteoglycans in the ECM. These results together with similar observations on the properties of other ECM-immobilized enzymes and growth factors, suggest that the ECM provides a storage depot for biologically active molecules which are thereby stabilized and protected. This may allow a more localized, regulated and persistent mode of action, as compared to the same molecules in a fluid phase.
Cancer Metastasis Rev 1990 Nov
PMID:Extracellular matrix-resident growth factors and enzymes: possible involvement in tumor metastasis and angiogenesis. 170 86

During the natural history of a tumor, cancer cells become more and more aggressive and their increasing malignancy leads usually to the patient's death. The expression of malignant properties by tumor cells is manifested by the occurrence of metastases and is the result of an overexpression of molecules that are normally or barely non expressed by the normal cell progenitors. These molecules can be involved in cell attachment (receptor to the extracellular matrix), in proteolysis (collagenases), in angiogenesis (b FGF), in adhesion to endothelial cells, in resistance to the immune system. The genetic instability of tumor cells favors the amplification, mutation and gene translocation events, resulting in the activation of some genes or/and oncogenes which might direct the expression of the malignant properties. Finally, metastatic cells have been shown to have a growth advantage over non metastatic cells, so that metastatic cell population becomes ultimately numerously dominant in the primary tumor. The current knowledge about the malignant cell properties allow us to begin to understand how a cancer cell becomes metastatic and how the metastatic dissemination is usually an ineluctable process.
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PMID:[Metastatic dissemination of cancer cells]. 171 92

The growth of human prostate cancer and its relationship to the surrounding stroma are controlled by complex mechanisms that are incompletely understood. Clearly, peptide growth factors appear to have crucial roles in these processes. One of these factors, TGF-beta, and its family members are notable for their wide spectrum of biological effects. In terms of growth, TGF-beta inhibits the growth of prostate cancer cells in a cytostatic fashion while stimulating the growth of critical stromal cells, such as fibroblasts. Since the inhibitory effects of TGF-beta on prostate cancer cells appear to diminish as the process of transformation progresses towards less differentiated states, the net effect on prostate tumour growth may be positive. Recent evidence suggests that the inhibitory effects of TGF-beta on growth, at least, might be mediated through the RB tumour suppressor gene product and the proto-oncogene c-myc. Beyond its direct growth effects, TGF-beta also alters the response of prostate cancer cells to positive mitogenic factors, such as members of the EGF and FGF families, suggesting that growth control is a delicate balance between positive and negative influences. Non-mitogenic responses to TGF-beta by prostate cancer cells, the immune system, the stroma and the vascular system provide evidence that TGF-beta might also be important in the processes of carcinogenesis, tumour establishment and metastases. In addition, TGF-beta appears to influence metabolic pathways important to drug metabolism and steroidogenesis. In vivo, limited evidence suggests that TGF-beta can alter the growth and differentiation of some tumour types but appears to be very toxic when administered in high doses. A better understanding of the response of prostate cancer cells to members of the TGF-beta family may open new avenues of treating and controlling this disease.
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PMID:Response of prostate cancer cells to peptide growth factors: transforming growth factor-beta. 184 49

Epithelium-to-mesenchyme transformation plays a key role in tissue remodelling in embryos since it allows cells from the primitive epithelia to migrate to other sites where they participate in the formation of new structures. A similar phenomenon may be involved in the detachment of malignant cells from neighboring primary tumor cells, which is a prerequisite to the invasion of neighboring tissues or the development of metastases. To test this hypothesis, an in vitro model using a rat bladder carcinoma cell line was developed. Cells exhibited epithelial features under standard culture conditions. After exposure to a soluble inducer (acidic FGF) or the specific extracellular matrix components (collagens), the cells acquired a fibroblastic phenotype, separated from one another, and started to move freely on the substrate. Inducers were found to act synergistically on the fibroblastic transformation of carcinoma cells and to promote the penetration of these cells into collagen gels.
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PMID:[Modulation of epithelial differentiation of cultured rat bladder carcinoma]. 229 Jun 98

Basic FGF (bFGF) and acidic FGF (aFGF) are multipotential factors that stimulate and support proliferation, migration and differentiation. Both bFGF and aFGF are non-secreted growth factors consistent with the lack of a signal peptide. However, bFGF and aFGF are deposited in extracellular matrix (ECM) suggesting that an alternative mechanism for FGF release exists. Four oncogenes, int-2, hst/K-fgf, FGF-5 and FGF-6 have been isolated that are highly homologous to aFGF and bFGF. Unlike bFGF and aFGF, they possess signal peptides and are secreted. These oncogenes transform cells and induce tumors, ostensibly via an autocrine mechanism. The involvement of bFGF and aFGF in autocrine transformation has been clarified by studies using FGF cDNA transfection. NIH-3T3 cells transfected with native bFGF cDNA and expressing 20 to 100 times as much bFGF as parental 3T3 cells acquire an enhanced proliferation rate and higher saturation density. NIH cells transfected with a construct in which bFGF cDNA is altered by addition of a signal peptide, undergo autocrine transformation and exhibit morphological and biochemical alterations characteristic of highly transformed cells. Injection of cells expressing native bFGF even at levels 100 times greater than parental 3T3 cells fails to induce tumors or lung metastasis in syngeneic mice. Signal peptide bFGF-transected cells on the other hand, acquire a high tumorigenic and metastatic potential with tumor incidence and numbers comparable to those induced by ras transformed cells. Acquisition of a signal peptide converts bFGF into a transforming protein analogous to FGF-related oncogenes which naturally have signal peptide sequences.
Cancer Metastasis Rev 1990 Nov
PMID:Autocrine regulation of cell growth and transformation by basic fibroblast growth factor. 229 36

Chemotherapeutic assays, using nitrosoureas, performed on tumor bearing rats have shown a regression of local tumor, accompanied with an amplification of pulmonary metastases, demonstrating that the treatment of metastasis differs from the treatment of a local tumor. Cells organizing a tumor are heterogeneous for their drug resistance, and for a series of properties including their ability to form metastasis. Metastatic cells have to leave the tumoral tissue, to traverse biological barriers, to resist to immune system, to implant and growth in the target tissue. An experimental model has been used to characterize metastatic cells. Metastatic potential has been defined as the ability to invade lungs. Highly metastatic cloned cell lines, such as subline 6, were strongly stimulated to proliferate by EGF, expressed fibronectin, actively degraded the extracellular matrix, rapidly attached to endothelial vascular cells, and resisted to natural killer lymphocytes. Inversely, weakly metastatic lines, such as subline 8, were preferentially stimulated by FGF and EDGF, poorly expressed fibronectin, did not degrade extracellular matrix, slowly attached to vascular cells, and were killed by NK lymphocytes. Studies on a large series of clones showed a diversity between them, and that no one property was determinant. Modulation of these characters by growth factors, hormones and immune state of the host is discussed, and leads to conclude that the expression of metastatic potential of a tumor depends on genetically defined characters and also on influences excerted by the host.
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PMID:[Experimental study of cancer metastasis]. 639 21

Angiogenesis of human melanomas has been the focus of intense interest since it was shown that the spread and prognosis of primary tumors is correlated with their vascularization (N. Weidner, J. P. Semple, W. R. Welch, and J. Folkman, N. Engl. J. Med., 324: 1-8, 1991). Basic fibroblast growth factor (bFGF) and its high-affinity receptor FGFR-1 have been implicated in melanoma growth and angiogenesis (R. Halaban, Y. Funasaka, J. Lee, J. Rubin, D. Ron, and D. Birnbaum, Fibroblast Growth Factors in Normal and Malignant Melanocytes, pp. 232-243. New York: The New York Academy of Sciences, 1991). We have studied the expression of the Tie endothelial cell receptor tyrosine kinase mRNA in skin and primary cutaneous melanomas as well as in their skin and brain metastases by in situ hybridization. The Tie probe hybridized very weakly with the vascular endothelium of capillaries of normal skin, while it was detected in larger arteries and veins as well as in capillaries around sweat glands. However, capillaries and medium-sized vessels within cutaneous and brain metastases of melanoma were strongly positive for Tie mRNA. In contrast, endothelial cells contained very little or no FGFR-1 transcripts, whereas abundant FGFR-1 mRNA was present in melanoma tumor cells and in fibrovascular stroma. In agreement with these findings, a Tie-specific amplified cDNA band was obtained by reverse transcription-polymerase chain reaction from melanoma metastases but not from normal skin. These results suggest a role for the Tie receptor in the angiogenesis associated with melanoma metastases.
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PMID:Enhanced expression of the tie receptor tyrosine kinase mesenger RNA in the vascular endothelium of metastatic melanomas. 798 57

Basic fibroblast growth factor (bFGF) has been detected in body fluids of patients with various malignancies including renal cancer. Cytoplasmatic expression of bFGF in primary renal cell carcinoma cells has been reported recently to correlate with an impaired patient survival. In the present study, we analysed the statistical association of spontaneous serum bFGF levels in 23 patients with advanced renal cell carcinoma and progressive metastasis in different organ sites. Increased bFGF serum levels (>90% percentile for healthy donors i.e., > 14 pg/ml) were found in eight patients (35%) with a mean of 24.1 pg/ml. All patients in this subgroup presented with progressive pulmonary metastases at the time of sample collection (p < or = 0.007). In a total of fifteen patients exhibiting progressive pulmonary metastasis, bFGF serum levels were found to be significantly higher when compared to patients lacking progressive lung lesions (p < or = 0.0006). Of fifteen patients with bFGF levels lower than 14 pg/ml, six showed bone metastases at the time of sample collection (p < or = 0.04). Our results suggest that increased serum bFGF levels may be associated with a higher frequency of progressive pulmonary metastases. Interactions between soluble angiogenic factors and components of the extracellular matrix or basement membranes in remote sites of metastasis will be subject to further experiments.
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PMID:Increased serum levels of basic fibroblast growth factor (bFGF) are associated with progressive lung metastases in advanced renal cell carcinoma patients. 857 47

To elucidate the phenotype of the blood vessels and the expression of the growth factors involved in angiogenesis in metastatic liver cancers, we carried out an immunohistochemical study of 57 surgically resected livers with metastatic cancer. Blood vessels in the metastatic liver cancers frequently expressed von Willebrand factor (vWF), Ulex europaeus agglutinin I (UEA I)-binding sites, alpha-smooth muscle actin (alpha-SMA), type IV collagen and laminin. Sinusoidal endothelial cells around the metastatic liver cancers were positive for vWF in 33.3% of the specimens examined and for UEA I in 28.1%. alpha-SMA-positive perisinusoidal cells accumulated in the vicinity of the metastatic liver cancers in 68.4% of the specimens. Type IV collagen was detected in the perisinusoidal space close to the metastatic cancers as well as distant from them (91.2%). Laminin was detected in the perisinusoidal space in only one specimen (1.8%). Tumour cells of the metastatic liver cancers were positive for vascular endothelial growth factor, basic fibroblast growth factor (bFGF), and acidic fibroblast growth factor (aFGF) in 78.9%, 38.4% and 7.0% of the specimens, respectively. Hepatocytes close to the metastatic liver cancers expressed bFGF more strongly than those distant from the metastatic liver cancers, and their expression of bFGF was more intense than that in the tumour cells. These results suggest that: (1) tumour vessels in metastatic liver cancers consist of endothelium, basement membrane and pericytes, (2) the sinusoids adjacent to tumours undergo capillarization, and (3) vascular endothelial growth factor may contribute to angiogenesis in metastatic liver cancer. Basic fibroblast growth factor may be responsible for the sinusoidal capillarization and the peritumoral fibrosis.
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PMID:An immunohistochemical study of tumour vessels in metastatic liver cancers and the surrounding liver tissue. 881 92


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