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• W2079047903 abstract "The lipidic molecule platelet-activating factor (PAF) sparks a wide range of immunoregulatory actions.1 A phospholipase A2 (PLA2)-dependent process on membrane alkyl-acyl-glycerophosphocholines (AAGPC) generates the lyso-PAF precursor, and its subsequent acetylation results in the PAF molecule. Tissue PAF concentrations are physiologically downregulated by a specific PAF acetylhydrolase activity (AHA).2 The PAF receptor (PAF-R) gene produces 3 different species of mRNA (i.e., transcript 1, transcript 2 and an elongated form of the transcript 2), which generate a unique membrane PAF-R.3, 4 During the past decade, in vitro studies and animal models have highlighted a potential role of PAF in cancer and tumor metastasis. Thus, PAF acts on the growth of various human tumor cell lines,5, 6 increases adhesiveness of tumor cells to vascular endothelia,7 enhances oncogene expression8 and can contribute to tumor development by enhancing cell motility and by stimulating the angiogenic response.6, 9 Data report the accumulation of AAGPC in metastatic cells10 and the role of PAF in metastatic diffusion in mice.11 The contribution of PAF in human solid tumors is poorly documented. Its pathophysiologic role has been suggested in breast cancer9, 12 and recently in colorectal carcinoma.13 To improve our knowledge concerning the role of PAF in human tumor metastasis, we have focused our attention on its potential involvement in liver metastasis of colorectal carcinoma. Liver is thus a potentially PAF target since PAF, lyso-PAF, AHA and PAF-R are found in normal liver.14, 15 As reported in Figure 1(a), investigation of 30 patients revealed a 7-fold increase (p = 0.0008) of PAF levels in the tumor tissue (7.30 ± 1.98 pg/mg protein) as compared to the adjacent tissue (0.88 ± 0.24 pg/mg protein). Elevated levels of PAF can result from a lower PAF degradation or a higher PAF production. In agreement with the later hypothesis, amounts of the lyso-PAF precursor (Fig. 1b) were higher (p = 0.0001) in the tumor tissue (5.14 ± 0.84 ng/mg protein) as compared to the adjacent tissue (0.94 ± 0.14 ng/mg protein). This latter result is consistent with the elevated (p = 0.01) PLA2 levels (the enzymatic activity that generated the lyso-PAF precursor; Fig. 1c) in the tumor tissue (3.96 ± 0.15 U/mg protein) as compared with those in the neighboring tissue (2.86 ± 0.52 U/mg protein). It is worth noting that AHA levels (the PAF-degrading enzyme; Fig. 1d) were higher (p = 0.0001) in the tumor tissue (21.05 ± 2.79 fmol/min/mg protein) as compared to the nontumor tissue (8.78 ± 0.74 fmol/min/mg protein). This result might be due to an elevated AHA secretion by Kupffer cells16 and/or by tissue-infiltrated macrophages (as previously suggested to explain the high tumor tissue AHA amounts in human lung cancer).17 Since PAF acts as a local cell-to-cell mediator, an elevated PAF synthesis is only of relevance if PAF-R can be detected at the site of PAF production. PAF acts through specific receptors. As schematized in Figure 2 (top), the PAF-R gene produces 3 different species of mRNA (i.e., transcript 1, transcript 2 and an elongated form of the transcript 2). Two 5′ noncoding exons (exons 1 and 2) are alternatively spliced to a common site on the third exon (exon 3), encoding the functional PAF-R protein. Thus, both transcripts ultimately yield the functional PAF-R.3, 4 PAF-R transcripts 1 and 2 are also named leukocyte type and tissue type, respectively. As shown in Figure 2 (bottom), semiquantitative PCR experiments indicated the presence of similar amounts of PAF-R transcripts 1 in the tumor and nontumor tissue. In contrast, a dramatic increase of PAF-R transcripts 2 (both normal size and spliced variant) was found in the tumor tissue as compared with the nontumor one. Several compounds such as tumor necrosis factor-α, transforming growth factor-β and PAF itself enhance total PAF-R mRNA synthesis in several cell types.18, 19, 20 Transcription of a single gene from multiple promoters provides additional flexibility in the control of gene expression. It is interesting to note that in liver metastasis of colorectal carcinoma, only PAF-R transcripts 2 (the PAF-R tissue type) are upregulated. Such an upregulation of PAF-R transcripts 2 has been previously reported in human umbilical vascular endothelial cells in response to stress21 and in endometrial cells in response to estradiol.22 Whatever molecular signals implicated in these elevated PAF-R transcripts 2 levels (may be hypoxia or PAF itself), the current data strongly argue for a pathophysiologic role of PAF in liver metastasis of colorectal cancer. During the past decade, in vitro data and animal studies have highlighted that PAF is a proangiogenic molecule that mediates vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) effects.23, 24, 25, 26, 27 We thus investigated if tissue PAF values might be correlated with those of VEGF and bFGF; these angiogenic growth factors being detected by specific ELISA assays (DuoSet, R&D Systems Europe, Oxon, U.K.) as previously described.28 Regression analysis highlighted a significant link between PAF values and those of VEGF (r = 0.34; p = 0.009) and bFGF (r = 0.49; p = 0.0001). VEGF and bFGF are important angiogenic growth factors that enhance the metastatic potential of cancer cells.29, 30, 31 PAF that mediates bFGF- and VEGF-induced actions might be an interesting therapeutic target in order to overcome their effects in liver metastases. Strengthening such hypothesis, several in vivo studies have still highlighted that a variety of specific PAF receptor antagonists have been proven to reduce tumor metastasis,11, 32 tumor growth,32 tumor vascularization6 and inflammation-induced carcinogenesis33 in several animal models of cancer. Recently, low levels of PAF were found in Dukes' stage C and D colorectal cancer patients as compared to Dukes' A and B.13 It is thus intriguing to note a low level of PAF in the primary tumor and an increased level in the liver metastasis. One explanation might be linked to the level of VEGF receptors (VEGFR). VEGF effects are mediated through several receptor tyrosine kinases (VEGFR-1, −2 and −3). Reduced levels of mRNA VEGFR were found in stage C patients as compared to stages A and B.34 We may thus suggest that reduced VEGFR levels in Dukes' stage C and D patients lead to a lower VEGF stimulation, thus inducing lower PAF release as compared to Dukes' A and B patients. In contrast, high levels of VEGFR are fond in liver metastasis,35 suggesting an efficient VEGF stimulation and thus PAF formation. Quantification of PAF (a), lyso-PAF (b), PLA2 (c) and AHA (d) levels in liver metastasis of colorectal cancer. The procedure of the present study followed the rules edited by the French National Ethics. Thirty patients were investigated (15 men and 15 women with a median age of 64 years). Specimens for the tumor and the tissue close to the tumor were obtained during the surgical procedure. PLA2, lyso-PAF, PAF and AHA levels were investigated as previously described.13 Briefly, tissue samples were ethanol-extracted (80% final), purified using thin-layer chromatography and assayed for PAF (pg/mg protein) by aggregation of washed rabbit platelets. Lyso-PAF was measured (ng/mg protein) in ethanolic extracts of tissue samples after its chemical acetylation into PAF. PLA2 levels were assessed (U/mg protein) by enzyme-linked immunosorbent assay according to the manufacturer's recommendations (R&D Systems Europe). AHA was determined (fmol/min/mg protein) by investigating degradation of [3H]-labeled PAF. Tissue protein concentration was determined with a Bio-Rad kit according to the manufacturer's recommendations (Bio-Rad, Marnes-la-Coquette, France). Results are presented as mean ± SEM. A paired Student's t-test was used to analyze intragroup differences. A p-value of < 0.05 was considered significant. Detection of PAF-R transcripts in liver metastasis of colorectal cancer. Reverse transcriptase-polymerase chain reaction (RT-PCR) experiments were performed on total RNA as previously described.4 Products were analyzed on a 2% agarose gel stained with ethidium bromide. The 3 PAF-R mRNA transcripts were schematized in the top. The dotted line is not present in the spliced mRNA. Only exon 3 encodes the functional protein. Expected sizes of amplified products were PAF-R transcript 1, 225 bp; PAF-R transcript 2, 269 bp; spliced variant of PAF-R transcript 2, 351 bp; glyceraldehyde-3-phosphate dehydrogenase (GAPDG, a positive control of PCR amplification), 439 bp. The PAF-R transcript 1 sense primer (P1) was 5′-GACAGCATAGAGGCTGAGGC-3′; the PAF-R transcript 2 sense primer (P2) was 5′-CCTGAGCTCCCCGAGAAGTCA-3′; and the PAF-R transcript anti-sense primer (P3) was 5′-TAGCCATTAGCAATGACCCC-3′. The GADPH sense and antisense primers were 5′-GGCTGAGAACGGGAAGCTTG-3′ and 5′-GGATGATGTTCTGGAGAGCC-3′. Semiquantitative assessment of PAF-R transcripts was obtained by assaying in parallel serial dilutions of each cDNA (undiluted, diluted 1/4, diluted 1/16). Sizes of PCR products and DNA size ladder are indicated by arrows. One representative experiment (in duplicate) out of 3 is shown. In conclusion, the present study reports that elevated levels of PAF and PAF-R transcripts are present in human liver metastasis of colorectal carcinoma. PAF, which is present in the tumor, may have pathophysiologic functions and might account at least in part for the bFGF- and VEGF-induced neoangiogenic activity occurring in human liver metastases. Results on the beneficiated use of PAF-R antagonists in tumor growth and metastatic diffusion in animal studies are sufficiently provocative to merit that clinical studies now investigate this issue. An alternative approach to the use of PAF-R antagonists might be the use of recombinant PAF AHA. Strengthening this hypothesis, the inactivation of PAF by local expression of the PAF AHA reduces tumor vascularization, growth, neoangiogenesis and tumor cell motility in mice.36 Yours sincerely, Yves Denizot, Bernard Descottes, Véronique Truffinet, Denis Valleix, François Labrousse, Muriel Mathonnet." @default.
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• W2079047903 date "2004-09-28" @default.
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• W2079047903 title "Platelet-activating factor and liver metastasis of colorectal cancer" @default.
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