Separate primary and validating clinical studies concur that tumor VEGF level is the most important prognostic parameter among several markers of tumor angiogenesis and proteolysis.
In order to examine whether the expression of calcium-binding proteins of the S100 family may correlate with the transformation grade of human mammary-tumor cells, we studied the expression patterns of 4 members of this family (CACY, CAPL, S100L, S100 alpha/beta) in human breast-cancer cell lines. Each S100 protein is shown to be individually regulated in the human breast-cancer cell lines we studied, but it appears that the expression levels of S100 proteins do not strictly correlate with prognostic factors or the tumorigenicity of the cells. However, 2 aggressive cell lines, MDA-MB-231 and HS-578T, show elevated expression of CAPL. We show that methylation may account for partial regulation of the S100 genes, whereas neither genomic rearrangements in the S100 gene cluster region nor gene dosis effects seem to influence their expression pattern in MDA-MB-231 and MCF-7 cells. On the basis of our genomic analyses, we can localize the gene for S100L within 5 kb upstream of S100E, thus extending the S100 gene cluster by one gene. A series of primary breast tumors was collected and tested for expression of CAPL, CACY and S100 alpha/beta. The results show that all human breast-cancer tissues tested express CACY, whereas the presence of CAPL is more restricted. There is a significant correlation between enhanced expression of CAPL and presence of the invasivity marker urokinase-type plasminogen activator (uPA). This observation suggests that CAPL may play an important role in the acquisition of metastatic potential of human mammary epithelial cells.
Human peripheral blood neutrophils are primed, or enabled to respond to formyl peptide, by prior exposure to bacterial lipopolysaccharide (LPS). The activity of LPS and the size of its aggregates are altered by plasma constituents such as high density lipoprotein (HDL) and the recently discovered acute phase reactant lipopolysaccharide binding protein (LBP) Tobias et al.: J. Exp. Med. 164,777, 1986]. The ability of LPS, LPS-LBP, and LPS-HDL complexes to activate a number of cellular responses have been compared. LPS-LBP and LPS-HDL were prepared using LBP and HDL from rabbit serum. LPS from Salmonella minnesota Re595 and its LPS-LBP and LPS-HDL complexes differed in their ability to prime PMN O2- production in response to formyl peptide (f-Nle-Leu-Phe-Nle-Tyr-Leu [FNLPNTL]). Human PMN prepared under conditions in which O2- production is minimal (less than 1 nmol O2-/10(6) PMN/10 min) after exposure to 10(-7) M FNLPNTL can be primed with 0.1-100 ng/ml LPS in a dose- and time-dependent manner to produce up to 12 nmol O2-/10(6) PMN/10 min. LBP complexation accelerated the priming induced by LPS, whereas HDL complexation retarded it. Priming was accompanied by a parallel two- to threefold increase in formyl peptide receptor number as determined by FACS analysis of fluoresceinated FNLPNTL binding and SDS-PAGE autoradiographic analysis of photoaffinity ligand binding. Thus binding of LPS to plasma proteins changes the response of the PMS to LPS and may represent one way in which the response of the PMN is regulated during infection. Since LBP concentrations change during an acute phase response, complexation of LPS with LBP is a mechanism that may regulate neutrophil responses in vivo during inflammation.
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