Biomedical subjects

M Bar-Eli

Publications and source records attributed to M Bar-Eli.

At least 37 records · Page 2Linked to original sources

PubMed1999

Role of interleukin-8 in tumor growth and metastasis of human melanoma.

Expression of interleukin-8 (IL-8) by human melanoma cells correlates with their metastatic potential in vivo. Moreover, UVB irradiation of primary cutaneous melanoma induces IL-8 mRNA and protein production and increases both tumor growth and metastasis in nude mice. Although IL-8 has been shown to be an angiogenic factor, the biological consequences of increased IL-8 production by melanoma cells and the role of IL-8 in the metastatic process remains unclear. The purpose of this review is to determine the role of IL-8 in tumor growth and metastasis of human melanoma. Transfection of nonmetastatic and IL-8-negative melanoma cells with the IL-8 gene rendered them highly tumorigenic and increased their metastatic potential in nude mice. The IL-8-transfected cells displayed upregulation of MMP-2 expression and activity and increased invasiveness through Matrigel-coated filters. Activation of MMP-2 by IL-8 can enhance the invasion of host stroma by the tumor cells and increase angiogenesis and, hence, metastasis. In addition to UVB, IL-8 can also be upregulated by hypoxia conditions, suggesting that the environment plays a major role in regulating IL-8 expression and metastasis. The studies summarized in this review suggest that in melanoma, IL-8 may serve as the angiogenic factor distinguishing benign from malignant cells.

Animals↗

PubMed1999

An examination of mood changes and performance in a professional basketball team.

BACKGROUND: The purpose of this study was to examine the relationship between the Profile of Mood States (POMS) and performance in a professional basketball team. METHODS PARTICIPANTS: seven male professional basketball players playing for the defending champions of the Israel Basketball League participated in this study. EXPERIMENTAL DESIGN: the POMS was administered seven times (T1-T7) during the season. The initial POMS administration was performed three weeks following the start of preseason practice and one day prior to the first basketball game. Each of the other POMS administrations were performed two days following a game and no more than 2 days before the next game. RESULTS: Typical iceberg profiles were observed during T1, T2 and T3, which coincided with successful performance (winning percentages greater than 60% between each POMS administration). Subsequent decreases in performance between T3 and T4 (a 33% winning percentage) resulted in a decrease in vigor and an increase in anger. As team performance improved between T4 and T5 (winning percentage again above 60%), vigor returned to its original level. However, the mood states anger and depression remained elevated, even during successful team play. This may have been related to problems independent of basketball performance (coaching and financial). CONCLUSIONS: These results suggest that the mood state vigor may be reflective of team performance. In addition, mood states appear to be influenced more by performance or experience, rather than performance being influenced by changes in mood states.

Adult↗

PubMed1998

CREB and its associated proteins act as survival factors for human melanoma cells.

cAMP response element-binding protein (CREB) and activating transcription factor 1 (ATF-1), members of the CREB/ATF family, have been implicated in cAMP- and calcium-induced transcriptional activation. We have previously demonstrated that quenching of CREB-associated proteins in metastatic melanoma cells by a dominant-negative CREB (KCREB) that is mutated within its DNA-binding domain decreased their radiation resistance, and their tumorigenic and metastatic potential in nude mice. As the induction of apoptosis by diverse exogenous signals is dependent on the elevation of intracellular Ca2+, the purpose of this study was to determine the role of CREB and its associated proteins in apoptosis using KCREB. We used thapsigargin (Tg), which inhibits endoplasmic reticulum-dependent Ca2+-ATPase and thereby increases cytosolic Ca2+, to induce apoptosis. MeWo human melanoma cells were transfected with the KCREB expression vector and subsequently analyzed for their susceptibility to Tg-induced apoptosis. Here we demonstrate that expression of KCREB in MeWo cells rendered them susceptible to Tg-induced apoptosis. Tg treatment induced phosphorylation of CREB and possibly ATF-1 transcription factors. Treatment with Tg induced CRE-dependent transcription in parental cells, whereas this activation was reduced in the KCREB-transfected cells. In addition, CAT activity driven by the CRE-dependent promoter was inhibited in parental MeWo cells cotransfected with increasing concentrations of KCREB in a dose-dependent manner. We did not observe any changes in Bcl-2 or Bcl-2-related proteins (Bcl-x, Bax, and Bad) in control or KCREB-transfected cells before or after treatment with Tg. Collectively, these data indicate that CREB and its associated proteins act as survival factors for human melanoma cells, and hence contribute to the acquisition of the malignant phenotype.

Activating Transcription Factor 1↗

PubMed1998

Loss of AP-2 results in downregulation of c-KIT and enhancement of melanoma tumorigenicity and metastasis.

Expression of the tyrosine kinase receptor, c-KIT, progressively decreases during local tumor growth and invasion of human melanomas. We have previously shown that enforced c-KIT expression in highly metastatic cells inhibited tumor growth and metastasis in nude mice. Furthermore, the ligand for c-KIT, SCF, induces apoptosis in human melanoma cells expressing c-KIT under both in vitro and in vivo conditions. Here we show that loss of c-KIT expression in highly metastatic cells correlates with loss of expression of the transcription factor AP-2. The c-KIT promoter contains three binding sites for AP-2 and EMSA gels demonstrated that AP-2 protein binds directly to the c-KIT promoter. Transfection of wild-type AP-2 into c-KIT-negative A375SM melanoma cells activated a c-KIT promoter-driven luciferase reporter gene, while expression of a dominant-negative AP-2B in c-KIT-positive Mel-501 cells inhibited its activation. Endogenous c-KIT mRNA and expression of proteins were upregulated in AP-2-transfected cells, but not in control cells. In addition, re-expression of AP-2 in A375SM cells suppressed their tumorigenicity and metastatic potential in nude mice. These results indicate that the expression of c-KIT is highly regulated by AP-2 and that enforced AP-2 expression suppresses tumorigenicity and metastatic potential of human melanoma cells, possibly through c-KIT transactivation and SCF-induced apoptosis. Therefore, loss of AP-2 expression might be a crucial event in the development of malignant melanoma.

Animals↗

PubMed1998

Procathepsin-L, a proteinase that cleaves human C3 (the third component of complement), confers high tumorigenic and metastatic properties to human melanoma cells.

We previously demonstrated that highly metastatic human melanoma cells secrete a 41 kDa proteinase that cleaves C3, the third component of complement, and shares antigenic determinants with procathepsin-L. Thus, we herein transfected the nonmetastatic DX-3 melanoma cells with the procathepsin-L cDNA. Three clones expressing and secreting high levels of procathepsin-L were selected. Conditioned medium and whole cell extracts from these clones, but not from control cells, carried a high C3-cleaving activity. The transfected clones displayed up to 60% resistance to complement-mediated lysis. Overexpression of procathepsin-L in melanoma cells increased their tumorigenicity and switched their phenotype from nonmetastatic to highly metastatic cells. This is the first report that demonstrates that enforced expression of procathepsin-L by human melanoma cells arms them with the ability to inactivate complement-mediated lysis and contributes to tumor growth and metastasis.

Animals↗

PubMed1998

Loss of AP-2 results in up-regulation of MCAM/MUC18 and an increase in tumor growth and metastasis of human melanoma cells.

MCAM/MUC18 is a cell-surface glycoprotein of 113 kDa, originally identified as a melanoma antigen, whose expression is associated with tumor progression and the development of metastatic potential. We have previously shown that enforced expression of MCAM/MUC18 in primary cutaneous melanoma led to increased tumor growth and metastatic potential in nude mice. The mechanism for up-regulation of MCAM/MUC18 during melanoma progression is unknown. Here we show that up-regulation of MCAM/MUC18 expression in highly metastatic cells correlates with loss of expression of the transcription factor AP-2. The MCAM/MUC18 promoter contains four binding sites for AP-2, and electrophoretic mobility shift assay gels demonstrated that the AP-2 protein bound directly to the MCAM/MUC18 promoter. Transfection of AP-2 into highly metastatic A375SM melanoma cells (AP-2-negative and MCAM/MUC18-positive) inhibited MCAM/MUC18 promoter-driven chloramphenicol acetyltransferase reporter gene in a dose-dependent manner. MCAM/MUC18 mRNA and protein expression were down-regulated in AP-2-transfected but not in control cells. In addition, re-expression of AP-2 in A375SM cells inhibited their tumorigenicity and metastatic potential in nude mice. These results indicate that the expression of MCAM/MUC18 is regulated by AP-2 and that enforced AP-2 expression suppresses tumorigenicity and metastatic potential of human melanoma cells, possibly by down-regulating MCAM/MUC18 gene expression. Since AP-2 also regulates other genes that are involved in the progression of human melanoma such as c-KIT, E-cadherin, MMP-2, and p21(WAF-1), we propose that loss of AP-2 is a crucial event in the development of malignant melanoma.

Animals↗

PubMed1998

Molecular changes in human melanoma metastasis.

The molecular changes associated with the transition of melanoma cells from radial growth phase to vertical growth phase (metastatic phenotype) are not well defined. Our recent studies have demonstrated that the two tumor suppressor genes, p53 and p16/CDKN2, do not play a major role in the acquisition of the metastatic phenotype in human melanoma. Mutations in p53 are infrequent and do not correlate with the metastatic potential of human melanoma cells while p16/CDKN2 abnormalities are frequent, but are not pre-requisite for the acquisition of the metastatic phenotype. On the other hand, the tyrosine-kinase receptor c-KIT and the cell adhesion molecule MCAM/MUC-18 play active roles in the progression of human melanoma. Metastatic melanoma cells overexpress MCAM and do not express the c-KIT receptor. Enforced c-KIT expression in metastatic cells significantly inhibited their growth and metastatic potential in nude mice. Furthermore, exposure of c-KIT-positive melanoma cells in vitro and in vivo to stem cell factor (SCF), the ligand for c-KIT, triggered apoptosis of these cells but not of normal melanocytes. Ectopic expression of MCAM into primary cutaneous melanoma cells enhanced their tumorigenicity and metastatic ability in vivo. We found that both genes, c-KIT and MCAM, are regulated by the transcription factor AP-2 and that metastatic melanoma cells do not express AP-2. We therefore propose that loss of AP-2 might be a crucial event in the progression of human melanoma.

Animals↗

PubMed1997

Melanoma progression-associated glycoprotein MUC18/MCAM mediates homotypic cell adhesion through interaction with a heterophilic ligand.

MUC18/MCAM is a cell-surface glycoprotein that is strongly expressed on advanced human melanomas. Transfection of 3 MCAM-negative melanoma cell lines with MCAM cDNA led to cell-surface expression and to a MCAM-dependent homotypic adhesion. This adhesion was independent of divalent cations and was inhibited at 4 degrees C. Mixed aggregation assays with MCAM-expressing and non-expressing cells revealed that MCAM can function as a heterophilic cell adhesion molecule interacting with a non-MCAM ligand. Although MCAM contains a potential glycosaminoglycan-binding site, cell-surface glycosaminoglycans do not appear to be involved in the heterophilic adhesion observed here since these molecules were not able to influence the adhesion. Using a functional adhesion assay, 4/4 melanoma cell lines examined were found to express an MCAM ligand. In contrast, no evidence for an MCAM ligand was found on the 2 carcinoma or 2 hematopoietic cell lines examined. Stable transfection of an MCAM ligand-negative colorectal cell line resulted in MCAM surface expression but not in homotypic adhesion, indicating that homophilic MCAM-MCAM adhesive interactions may not occur. Our results suggest that MCAM expression by melanoma cells is associated with increased homotypic adhesion, an event that may support tumor cell survival and growth in vivo.

Antigens, CD↗

PubMed1997

Dominant-negative CREB inhibits tumor growth and metastasis of human melanoma cells.

The ATF/CREB family of eukaryotic transcription factors contain the bZIP structural motif and mediate their transcriptional activities via heterodimerization with ATF and AP-1 family members. Quenching of CREB-associated proteins by a dominant-negative CREB (KCREB) that is mutated within its DNA-binding domain decreases radiation resistance of human melanoma cells. The purpose of this study was to determine the role of CREB in tumor growth and metastasis of human melanoma using KCREB. Highly metastatic MeWo human melanoma cells were transfected with the KCREB expression vector and subsequently analysed for changes in their tumorigenic and metastatic potential. Expression of KCREB in MeWo human cells decreased their tumorigenic and metastatic potential in nude mice compared with parental and control transfected cells. The KCREB-transfected cells displayed downregulation of 72 kDa collagenase type IV (MMP-2) mRNA expression and activity and decreased invasiveness through Matrigel-coated filters. Moreover, transcriptional activities mediated by the CAT gene driven by the MMP-2 promoter were decreased by 14-45-fold in KCREB-transfected cells. In addition, the cell-surface adhesion molecule MCAM/MUC18 that is involved in metastasis of human melanoma was downregulated in the KCREB-transfected cells. These data indicate that, through their transcriptional activities, CREB and its associated proteins play an important role in the acquisition of the metastatic phenotype of human melanoma cells.

Animals↗

PubMed1997

Expression of MCAM/MUC18 by human melanoma cells leads to increased tumor growth and metastasis.

The cell surface adhesion molecule MCAM (MUC18) is strongly expressed by advanced primary and metastatic melanomas but is weaker and less frequent in nevus cells. Previous studies have shown that MCAM expression correlates with tumor thickness and metastatic potential of human melanoma cells in nude mice. To provide direct evidence that MCAM plays a role in tumor growth and metastasis of human melanoma, the nonmetastatic MCAM-negative primary cutaneous melanoma SB-2 cells were transfected with MCAM cDNA and analyzed subsequently for changes in their tumorigenic and metastatic potential. Enforced expression of MCAM in SB-2 cells rendered them highly tumorigenic and increased their metastatic potential in nude mice as compared with parental and control transfected cells. The transfected cells displayed increased homotypic adhesion, increased attachment to human endothelial cells, decreased ability to adhere to laminin, and increased invasiveness through Matrigel-coated filters. Anti-MCAM monoclonal antibody reversed these functions in the transfected cells but not in control cells. The above changes in function attributed to the expression of MCAM may underlie the contribution of MCAM/MUC18 to the malignant phenotype.

Animals↗

PubMed1997

Molecular mechanisms of melanoma metastasis.

The molecular changes associated with the transition of melanoma cells from radial growth phase to vertical growth phase (metastatic phenotype) are not very well defined. Expression of the tyrosine-kinase receptor c-KIT progressively decreases during local tumor growth and invasion of human melanomas. To provide direct evidence that c-KIT plays a role in metastasis of human melanoma, we transfected the c-KIT gene into c-KIT-negative, highly metastatic human melanoma cells and subsequently analyzed their tumorigenic and metastatic potential in nude mice. Enforced c-KIT expression significantly inhibited tumor growth and metastasis. Exposure of c-KIT-positive melanoma cells in vitro and in vivo to stem cell factor (SCF), the ligand for c-KIT, triggered apoptosis of these cells but not of normal melanocytes. These results suggest that the loss of c-KIT receptor may allow malignant melanoma cells to escape SCF/c-KIT-mediated apoptosis, thus contributing to tumor growth and eventually metastasis. The expression of c-KIT and other genes associated with malignant melanoma (such as MCAM/MUC18) is highly regulated by the transcription factor AP-2. The AP-2 protein is not expressed in malignant melanoma cells. Therefore, loss of AP-2 expression might be a crucial event in the progression of human melanoma.

Animals↗

PubMed1997

Effect of goal difficulty, goal specificity and duration of practice time intervals on muscular endurance performance.

The aims of this study were to explore the relationships between goal specificity, goal difficulty and performance, and to determine if setting unrealistic goals would produce decreases in performance. The subjects were high school students from 15 schools and an attempt was made to control for the effects of social comparison. The schools were randomly assigned to one of 15 conditions representing five levels of goal conditions-namely, 'do' (no goals), 'do your best', 'improve by 10%' (easy), 'improve by 20%' (difficult/ realistic) and 'improve by 40%' (improbable/unattainable)-and three levels of practice duration (4, 6 and 8 weeks). This design consisted of nesting goal difficulty within practice duration, which enabled an examination of the goal specificity and goal attainability/difficulty hypotheses proposed by Locke and Latham (1985). A 5 x 3 factorial ANCOVA was applied to the post-baseline sit-up gain scores. The results indicated that all specific groups performed better than all non-specific groups. In addition, across practice durations the difficult/realistic group exhibited the greatest increase in performance, followed by the easy group. The performance gains of the improbable/unattainable group were substantially less compared with the difficult/ realistic group after 4 and 6 weeks, but not after 8 weeks of practice. These results are in line with both the goal specificity and goal difficulty hypotheses derived from the application of Locke's goal-setting theory to sport.

Adolescent↗

PubMed1997

Expression of five selected human mismatch repair genes simultaneously detected in normal and cancer cell lines by a nonradioactive multiplex reverse transcription-polymerase chain reaction.

Abnormalities in at least 1 of 5 mismatch repair (MMR) genes (hMSH2, hMLH1, hPMS1, hPMS2 and GTBP/hMSH6) are found in hereditary nonpolyposis colon cancer and sporadic colon cancers. We used a single-reaction multiplex reverse transcription (RT)-polymerase chain reaction (PCR), with the beta-actin gene as an internal control, to simultaneously evaluate expression of these 5 known human MMR genes in normal and tumor cell lines with known or uncharacterized mutations in MMR genes. The relative quantitation of the transcripts is demonstrated by controlling the number of PCR cycles and titrating cDNA with a dose-curve. The 13 normal cell lines tested were derived from normal lymphocytes, skin, thymus, breast, lung, colon, liver and kidney. The 26 cancer cell lines were derived from melanoma and cancers of the brain, breast, lung, colon, pancreas and prostate. All 5 MMR genes were ubiquitously expressed in all normal cell lines tested, suggesting their housekeeping roles. Aberrant MMR gene expression was only observed in the colon cancer cell lines. Two previously uncharacterized colon cancer cell lines did not express hMLH1. These data suggest that this nonradioactive multiplex RT-PCR assay for MMR gene expression may be useful for fast screening for genetic alterations that may affect gene expression and so may aid molecular analysis of MMR-related colon cancer.

Adaptor Proteins, Signal Transducing↗

PubMed1997

Expression of interleukin-8 by human melanoma cells up-regulates MMP-2 activity and increases tumor growth and metastasis.

Expression of interleukin-8 (IL-8) by human melanoma cells correlates with their metastatic potential. Moreover, UV-B irradiation of primary cutaneous melanoma cells induces IL-8 mRNA and protein production and increases both tumor growth and metastasis in nude mice. Although IL-8 has been shown to be an angiogenic factor, the biological consequences of increased IL-8 production by melanoma cells and the role of IL-8 in the metastatic process remains unclear. The purpose of this study was to determine the role of IL-8 in tumor growth and metastasis of human melanoma cells. Nonmetastatic SB-2 melanoma cells with negligible levels of IL-8 were transfected with IL-8 cDNA and subsequently analyzed for changes in their tumorigenic and metastatic potential. Enforced expression of IL-8 rendered the melanoma cells highly tumorigenic and increased their metastatic potential as compared with parental and control transfected cells. The IL-8-transfected cells displayed up-regulation in M(r) 72,000 collagenase type IV (MMP-2) mRNA and collagenase activity and increased invasiveness through Matrigel-coated filters. Moreover, when the MMP-2 promoter was linked upstream of the chloramphenicol acetyltransferase (CAT) reporter gene, CAT activity was up-regulated in IL-8 but not in control transfected cells, suggesting that IL-8 is involved in MMP-2 gene transcription. Activation of type IV collagenase by IL-8 can enhance the invasion of host stroma by the tumor cells and increase angiogenesis and, hence, metastasis.

Animals↗

PubMed1996

Enforced c-KIT expression renders highly metastatic human melanoma cells susceptible to stem cell factor-induced apoptosis and inhibits their tumorigenic and metastatic potential.

Expression of the tyrosine-kinase receptor encoded by the c-KIT proto-oncogene progressively decreases during local tumor growth and invasion of human melanomas. To provide direct evidence that c-KIT plays a role in metastasis of human melanoma, we transfected the c-KIT gene into the c-KIT negative highly metastatic human melanoma cell line A375SM and subsequently analysed its tumorigenic and metastatic potential. A375SM parental cells, A375SM-NOT (neo, control), and A375SM-KIT-positive cells were injected s.c. and i.v. into nude mice. A375SM-KIT cells produced significantly slower growing s.c. tumors and fewer lung metastases than control cells. Exposure of c-KIT-positive melanoma cells in vitro and in vivo to stem cell factor (SCF), the ligand for c-KIT, triggered apoptosis of these cells but not of c-KIT-negative melanoma cells or normal melanocytes. Since SCF is produced by keratinocytes and other dermal cells in the skin, these results suggest that the loss of c-KIT receptor expression may allow malignant melanoma cells to escape SCF/c-KIT-mediated apoptosis, hence contributing to tumor growth and eventually metastasis. The antitumor and antimetastatic properties of SCF may be useful in treating human melanomas in early stages.

Animals↗

PubMed1996

A cysteine proteinase, which cleaves human C3, the third component of complement, is involved in tumorigenicity and metastasis of human melanoma.

The DM-4 human melanoma cell line, which is highly metastatic in nude mice, expresses a C3-cleaving activity that proteolyzes labeled as well as unlabeled human C3. This C3-cleaving activity is a cysteine proteinase characterized by a M(r) 41,000. The p41 proteinase shares antigenic determinants with murine p39 procathepsin-L and human procathepsin-L. Preincubation of DM-4 cells with anti-p39 F(ab')2 induced up to 45% decrease in their complement resistance. Pretreatment of DM-4 cells with anti-p39 Ab strongly inhibited their tumorigenicity and significantly decreased their metastatic potential in nude mice. Thus, the p41 C3-cleaving proteinase contributes to tumorigenicity and metastasis of human melanoma DM-4 cells.

Animals↗

PubMed1996

External conditions and disposition--behaviour congruity as determinants of perceived personal causation among exercise adherers and non-adherers.

The aim of this study was to investigate the extent to which perceptions of external conditions, such as physical proximity to the exercise area and disposition--behavior congruity, affects observers' perceptions of personal causation of exercise adherers and non-adherers with regard to physical activity. The hypothetical scenario technique was used, with 120 adherers and 120 non-adherers, to investigate attributions of freedom, choice, control and responsibility. The results revealed that these attributions were significantly affected by perceived external conditions, and by the question of whether behavioural alternatives to be chosen were perceived as being congruent with an actor's disposition. Similar attributional patterns were revealed on all dimensions of personal causation, for the adherers and non-adherers. The implications of these findings for attributional research in the area of exercise adherence are discussed.

Adolescent↗

PubMed1996

Crisis-related observations in competition: a case study in basketball.

This study presents a unique observational approach to basketball, based on the theory of psychological performance crisis in competition. The approach used takes into account the responses of a player' s actions to significant social factors such as team-mates, spectators, the coach and the referees. The contribution of this approach beyond traditional observational techniques is discussed. In our investigation, a single case design was used, in which a professional basketball player was observed during 10 home and 3 away games of the regular season. The relations between the observations and the crisis concept are discussed in detail. In addition, some relevant methodological and applied aspects are presented.

Adaptation, Psychological↗