Macrophage activation in nude mice by human malignant melanocytes.
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Animals↗
Biomedical subjects
A Benomar
Publications and source records attributed to A Benomar.
Chemotactic factor and P15E-related chemotaxis inhibitor in human melanoma cell lines with different macrophage content and tumorigenicity in nude mice.
The present study was designed to characterize the production of chemoattractants by human melanoma lines with high (M4Be, M3Da, NTerDa) or low tumorigenic (Doc8, M1Do) potential when heterotransplanted in nude mice. Supernatants from the Doc8 and M1Do cell lines were strongly chemotactic in vitro for mononuclear phagocytes. Chemotactic activity was destroyed by proteolytic enzymes, and upon gel filtration on Sephadex G75, it eluted in the cytochrome c region corresponding to an apparent m.w. of 12,000. Upon chromatofocusing, the Sephadex-separated tumor-derived chemotactic factor (TDCF) showed an isoelectric point of 5.5 to 6. Cell lines with high tumorigenic potential contained low or no detectable chemotactic activity. When culture supernatants of cell lines with modest (M3Da) or no (M4Be) chemotactic activity were exposed to immobilized monoclonal antibodies directed against the retroviral transmembrane protein P15E, appreciable chemotactic activity was detectable (M4Be) or preexisting levels increased (M3Da). The material eluted from Sepharose-bound anti-P15E antibodies inhibited the migration of monocytes in response to chemoattractants. These findings demonstrate the coexistence in some human melanoma cell line supernatants of factors (TDCF and P15E-related inhibitor) with opposite influence on monocyte chemotaxis. That tumor cell products play a pivotal role in regulating the extravasation of monocytes into neoplastic tissues is suggested by the close correlation observed between macrophage levels in melanomas grown in nude mice and levels of chemotactic activity detectable in culture supernatants.
Animals↗
In vivo activation of nude mouse macrophages by human melanoma cells.
Human melanoma cell lines inoculated ip in outbred nude mice were found to activate locally macrophages, which became tumoricidal for the EL 4 target cells in a 48-hour [3H]thymidine cytotoxicity assay. However, the kinetics of this activation largely depended on the tumorigenicity of the cell line used. One week after inoculation with a poorly tumorigenic cell line (PTCL), peritoneal macrophages showed a maximal tumoricidal activity, which then slowly declined to disappear on the 4th week. Macrophages obtained after inoculation of a highly tumorigenic cell line (HTCL) were also activated, but the level of their tumoricidal activity was somewhat lower and decreased more rapidly. Irradiated melanoma cells were also able to activate peritoneal macrophages. The inoculation of a higher number of melanoma cells (less than or equal to 8 X 10(7) cells) resulted in a parallel increase in the cytotoxicity of peritoneal macrophages when activated by PTCL and in a parallel decrease when activated by HTCL. Activated macrophages taken 1 week after tumor cell inoculation and further kept in vitro without additional stimulation progressively lost their tumoricidal activity, within 48 hours after being harvested from PTCL-inoculated mice and within 24 hours after being collected from HTCL-inoculated animals. These data allied to the in vivo capacity of peritoneal cells rich in activated macrophages to prevent the growth of HTCL in nude mice strongly leaned toward the idea that macrophages are involved in the tumor growth control in the absence of a specific immune response. In addition, tumor-macrophage interactions are likely to vary from tumor to tumor and may contribute to the expression of the xenografting capacity of human tumor cells.
Animals↗
Interactions with host macrophages and ability of human melanoma cell lines to grow in nude mice.
The interactions of nude mouse macrophages with five human melanoma cell lines, characterized by their resistance to mouse NK activity and varying in their ability to grow s.c. in nude mice, were investigated. These lines were equally susceptible in vitro to both cytostatic and tumoricidal activities of activated peritoneal macrophages collected from nude mice inoculated 3 days previously with Brucella abortus B19R strains. I.p. injection of a poorly tumorigenic melanoma cell line (PTCL) in nude mice was followed by the local appearance of macrophages able to kill these cells in a 48-hr 3H-thymidine cytotoxicity assay. The level of tumoricidal macrophages was maximum for the first week and then slowly declined to disappear by the 4th week following PTCL inoculation. The use of an HTCL instead of a PTCL also induced macrophages able to kill HTCL cells, but the cytotoxicity level was lower and the activity disappeared more rapidly. In cross-experiments using PTCL-activated macrophages as effectors on HTCL targets, these cells were found to be less sensitive than PTCL cells when macrophages were taken at weeks 2 and 3 following PTCL inoculation. To investigate whether tumoricidal macrophages activated in vivo with human melanoma cells could also act in vivo, we inoculated these s.c. into nude mice, simultaneously with live HTCL cells. Peritoneal cells rich in melanoma-activated macrophages prevented HTCL growth in most recipients, whereas spleen cells from the same donor mice did not modify the tumor take. These data indicate that xenogeneic tumors could activate nude mouse macrophages in vivo and suggest that the ability of human tumors to grow in nude mice could be related to their capacity to activate host macrophages locally and to the susceptibility of human tumor cells to the tumoricidal activity of activated macrophages.
Animals↗
[Homocysteine, lipoprotein (a): risk factors for coronary heart disease].
Our data suggest that the hyperhomocysteinemia and/or increased plasma level of lipoprotein Lp(a) are risk factors for coronary heart disease. We investigated 178 patients who underwent complete cardiac examination comprising coronary angiography and biological analysis (CT, HDL-c, LDL-c, TG, and apoAI, apoB, homocysteine and Lp(a)). Patients presenting a significant stenosis of the coronary artery ( 50% of the vascular lumen) were considered as cases (113 patients). Those without stenosis or with non-significant stenosis (< 50% of the vascular lumen) were used as controls (65 subjects). Homocysteinemia was significantly higher in cases than in control subjects (8.26 mol/L (2.34 versus 17.85 (2.34, p < 0.001). A strong association between coronary heart disease and homocystein has been found (Eta(2) = 0.76). The OR were 0.16 when homocystein level was lower than 15 mol/L, and 27.78 when homocysteine level was upper than or equal to 15 mol/L. The RR was 5.16 (95% IC = 3.66-6.66, p < 0.001). Even though there was a significant correlation between tabagic impregnation and homocysteinemia (Spermann's rho = 0.37, p < 0.05), there was no interactive effect between these two factors and coronary disease (Wald khi2 = 0.086, p > 0.05). Therefore, no association was found between homocyteinemia and other coronary heart disease risk factors. The Lp(a) levels were significantly higher in cases than in controls subjects (188 (84 mg/L in control subjects versus 590 (199 in cases, p < 0.001). A stronger relationship was noted between coronary heart disease and Lp(a) (Eta (2) = 0.66). The OR were 0.09 when lipoprotein (a) levels were lower than 350 mg/L, and 5,88 when Lp(a) levels were higher than or equal to 350 mg/L. The estimate RR was 6.47 (95% IC = 4.39-8.55, p < 0.001). The level of Lp(a) was positively correlated with the severity of coronary heart disease (Spermann's rho = 0.95, p < 0.001). A weak correlation between Lp(a) and LDL-c was observed (Spermann's rho = 0.12, p = 0.048). But the multivariate analysis didn't show interactive effect between these two factors and coronary disease (khi2 de Wald = 0.264, p > 0.05). No association was noted between Lp(a) and the others risk factors. Moreover, a positive correlation between the levels of homocysteine and those of Lp(a) was found (Spermann's rho = 0.54, p < 0.001). In contrast their effect on coronary heart disease seems to be independant (Wald khi2 = 2.957, p > 0.05). Thus, these two parameters appear as independant risk factors for coronary heart disease.
Case-Control Studies↗
[Apolipoprotein E and angiotensin-converting enzyme gene polymorphisms as risk factors of coronary disease].
The objective of this study was to test the hypothesis that apo E (RFLP, HhaI) and/or angiotensin-converting enzyme (ACE) (ins16del) are associated with higher risk for coronary heart disease. We investigated 250 patients who underwent complete cardiac examination comprising coronary angioplasty and biological analysis (CT, HDLc, LDLc, TG, apo A and apo B). Prevalence of the alleles of apo E and ACE was assessed by molecular analysis. Patients without stenosis or with non-significant stenosis (> 50% of the vascular lumen) were used as reference group (141 patients). Those presenting a significant stenosis of the coronary artery (. 50% of the vascular lumen) were considered as cases (109 patients). The relative frequency of the e 4 allele was significantly higher in cases than in reference group (p > 0.02). A strong association have been found between coronary heart disease and apo E polymorphism (2 = 8.91; p > 0.05). The presence of the e 4 allele increase the risk of atherosclerosis (RR = 2.71; IC95%: 1.25-5.90; p > 0.02) compared to e 3 allele. Also, subjects with D allele were more frequent in cases than in reference group (p > 0.001). A significant association was noted between ACE polymorphism and coronary heart disease (2 = 42.15; p > 0.001). This relationship was positive (rho de Spearman = 0.39; p > 0.01). With D/D homozygotes patients, the RR for coronary heart disease was 19.10 (p > 0.001), while The RR with I/D heterozygotes was 6.91 (p > 0.001) compared to I/I homozygotes. A significant interaction have been shown up between D/D genotype and arterial hypertension (HTA) (2 de Wald = 16.10; p > 0.001). The multivariate analysis showed that the chronic smoking, diabetes, hypoapolipoproteinemia A, interactive effects between D/D and HTA, I/D and obesity, and between D/D and hypertriglyceridemia were the major significant factors to take into consideration in our population. We also note that subjects with both D and e 4 alleles were presenting a high risk to coronary heart disease (RR = 5.93; IC95%: 2.00-17.55; p > 0.01). Thus, those two alleles (4 and D) appears to be important cardiovascular risk factors in the moroccan population.
Apolipoproteins E↗