Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The migration of tumor cells through basement membranes and extracellular matrices is an integral component of tumor invasion and metastasis. Laminin and fibronectin are two basement membrane- and extracellular matrix-associated noncollagenous glycoproteins that have been shown to promote both cell adhesion and motility. Purified preparations of laminin and fibronectin stimulated the directed migration of B16 murine metastatic melanoma cells in vitro as assessed in modified Boyden chambers. The stimulation of migration occurred over a concentration range of 1-100 micrograms/ml of laminin or fibronectin, with a peak response occurring between 12.5 and 25 micrograms/ml. The maximal response of these cells was 80-120-fold higher than control migration. Affinity-purified antibody preparations specifically abrogated the migration of these cells in response to the respective proteins. Tumor cells in suspension were preincubated in physiologic levels of plasma fibronectin prior to assay to partially mimic what occurs when a metastasizing cell is in the blood stream. This preincubation with plasma fibronectin had no effect on the subsequent migration of cells in response to either laminin or fibronectin. Furthermore, experiments using filters precoated with fibronectin or laminin indicated that these cells could migrate by haptotaxis to these two proteins. We conclude that tumor cell migration in response to such noncollagenous adhesive glycoproteins could be an important aspect in the invasion and metastasis of certain malignant cell types.
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PMID:Laminin and fibronectin promote the haptotactic migration of B16 mouse melanoma cells in vitro. 671 9

Laminin is a large multidomain protein with diverse biological activities. We previously demonstrated that intact laminin as well as an A chain synthetic peptide (LamA2091-2108) stimulate tissue plasminogen activator (t-PA)-catalyzed plasminogen activation. Here we report that LamA2091-2108 increases t-PA production by the highly metastatic murine melanoma cell line B16F10, with no effect on the parental B16F1 line, which has a low metastatic capacity. Incubation of plasminogen with B16F10-conditioned medium results in direct activation of the zymogen to plasmin. Furthermore, following incubation of B16F10 cells with plasminogen, plasmin is eluted from the cell surface, suggesting that these cells contain binding sites for plasminogen/plasmin in close proximity to t-PA binding sites. Quantitation of t-PA activity using the synthetic substrate Val-Leu-Lys-p-nitroanilide indicates a minimal 10-fold increase in t-PA in the conditioned medium of B16F10 cells grown in the presence of LamA2091-2108, with no increased t-PA activity observed in B16F1-conditioned medium. Similar results were obtained in immunocapture experiments which are specific for t-PA antigen. In addition, B16F10 melanoma-associated t-PA catalyzes the plasminogen-dependent hydrolysis of laminin. Together these data suggest that degradation of basement membrane proteins by metastatic melanoma cells may release fragments (such as LamA2091-2108) which stimulate both the production and activity of metastasis-associated proteinases such as t-PA, providing a mechanism for augmentation of the metastatic capacity of B16F10 melanoma cells.
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PMID:Modulation of murine B16F10 melanoma plasminogen activator production by a synthetic peptide derived from the laminin A chain. 848 2

An altered ability to interact with and degrade extracellular matrix molecules is a common feature of the malignant phenotype. Although changes in the expression of matrix proteins in metastases in vivo are relatively well documented, little is known about the changes in matrix production by malignant cells in culture. Here we have examined the synthesis of the basement membrane components laminin and nidogen (entactin) by low and high metastatic variants of the K-1735 murine melanoma cells. Protein deposition was examined by western blotting as well as immunofluorescence; protein synthesis was examined by immunoprecipitation with specific antibodies. Gene expression was also evaluated by measuring steady-state mRNA levels using cDNA probes on northern and dot-blots. Laminin gamma 1 levels appeared to be similar in both high and low metastatic lines; however, the high metastatic lines had reduced levels of the laminin beta 1 chain. On the contrary, nidogen expression was observed only in the high metastatic lines. Traces of a laminin alpha chain were present only in immunoprecipitates of the low metastatic cells and could not be detected in the high metastatic cells. Both high and low metastatic cells deposited an extracellular matrix of basement membrane components, with laminin deposition decreased in high metastatic cells. Modified expression, production, and deposition of basement membrane components in high metastatic melanoma cells could be involved in their altered interactions with the extracellular matrix.
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PMID:Altered production of laminin and nidogen by high and low metastatic variants of murine melanoma cells. 882 9

Melanocytes arise from the neural crest, migrate to the skin, and can be detected in the basal layer of the epidermis in skin biopsies of human fetuses as early as 11 weeks gestational age. During post-natal life, melanocytes reside at the basal layer of the epidermis, but the ligands to which they attach are unknown. Laminin-5 is a component of anchoring filaments of the lamina lucida of the epidermal basement membrane. In this report we show that human melanocytes adhere to purified laminin-5 to a level comparable with normal human keratinocytes. Blocking antibodies to the 165 kDa subunit of laminin-5 significantly inhibited fetal and neonatal melanocyte attachment to the surface of salt-split skin, which exposes laminin-5 on its surface, suggesting that laminin-5 is a ligand for melanocyte attachment to the basement membrane in vivo. Western blotting of concentrated culture supernatant of fetal and neonatal melanocytes with anti-laminin-5 antibodies demonstrated a single immunoreactive band of the expected size of laminin-5. In contrast, 3 human metastatic melanoma cell lines did not produce laminin-5. Immunofluorescence microscopy with antibodies to each of the three chains of laminin-5 confirmed the presence of laminin-5 in a peri-cellular distribution around melanocytes, but not melanoma cells. Our results suggest that laminin-5 may be a ligand for normal human melanocytes in the basement membrane, and that loss of laminin-5 production by melanoma cells may be a marker for malignant transformation.
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PMID:Melanocytes adhere to and synthesize laminin-5 in vitro. 1038 39

The alpha7beta1 integrin is a laminin-binding receptor that was originally identified in melanoma. Here, we show that, in clonally derived mouse K1735 melanoma variant cell lines with high (M-2) and low (C-23) metastatic potential, elevated expression of alpha7 correlates with reduced cell motility, metastasis, and tumor growth. Both cell lines showed similar beta1 integrin-dependent adhesion to laminin-1 and the E8 laminin fragment. However, the highly metastatic M-2 cells rapidly migrated on laminin, whereas the nonmetastatic C-23 cells were minimally motile. Laminin-binding integrin profiles showed that the M-2 cells expressed moderate amounts of alpha1 and abundant alpha6 but low or undetectable levels of alpha2 and alpha7. By contrast, C-23 cells expressed low or undetectable levels of alpha1, alpha2, and alpha6 but had up-regulated levels of alpha7. Consistent with the protein data, Northern blot analysis showed that levels of alpha7 mRNA were highest in the poorly metastatic variant cells, whereas alpha6 message was not detected; in contrast, alpha6 mRNA was elevated in the highly metastatic cells, whereas alpha7 message was not detected. Forced expression of alpha7 in the M-2 cells suppressed cell motility, tumor growth, and metastasis. Collectively, these results indicate that, during melanoma progression, acquisition of a highly tumorigenic and metastatic melanoma phenotype is associated with loss of the alpha7beta1 laminin receptor.
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PMID:Expression of the alpha7beta1 laminin receptor suppresses melanoma growth and metastatic potential. 1043 16