Platelet-activating factor receptor (PAF-R)-dependent pathways control tumour growth and tumour response to chemotherapy

Abstract Background Phagocytosis of apoptotic cells by macrophages induces a suppressor phenotype. Previous data from our group suggested that this occurs via Platelet-activating factor receptor (PAF-R)-mediated pathways. In the present study, we investigated the impact of apoptotic cell inoculation or induction by a chemotherapeutic agent (dacarbazine, DTIC) on tumour growth, microenvironmental parameters and survival, and the effect of treatment with a PAF-R antagonist (WEB2170). These studies were performed in murine tumours: Ehrlich Ascitis Tumour (EAT) and B16F10 melanoma. Methods Tumour growth was assessed by direct counting of EAT cells in the ascitis or by measuring the volume of the solid tumour. Parameters of the tumour microenvironment, such as the frequency of cells expressing cyclo-oxygenase-2 (COX-2), caspase-3 and galectin-3, and microvascular density, were determined by immunohistochemistry. Levels of vascular endothelium growth factor (VEGF) and prostaglandin E2 (PGE2) were determined by ELISA, and levels of nitric oxide (NO) by Griess reaction. PAF-R expression was analysed by immunohistochemistry and flow cytometry. Results Inoculation of apoptotic cells before EAT implantation stimulated tumour growth. This effect was reversed by in vivo pre-treatment with WEB2170. This treatment also reduced tumour growth and modified the microenvironment by reducing PGE2, VEGF and NO production. In B16F10 melanoma, WEB2170 alone or in association with DTIC significantly reduced tumour volume. Survival of the tumour-bearing mice was not affected by WEB2170 treatment but was significantly improved by the combination of DTIC with WEB2170. Tumour microenvironment elements were among the targets of the combination therapy since the relative frequency of COX-2 and galectin-3 positive cells and the microvascular density within the tumour mass were significantly reduced by treatment with WEB2170 or DTIC alone or in combination. Antibodies to PAF-R stained the cells from inside the tumour, but not the tumour cells grown in vitro. At the tissue level, a few cells (probably macrophages) stained positively with antibodies to PAF-R. Conclusions We suggest that PAF-R-dependent pathways are activated during experimental tumour growth, modifying the microenvironment and the phenotype of the tumour macrophages in such a way as to favour tumour growth. Combination therapy with a PAF-R antagonist and a chemotherapeutic drug may represent a new and promising strategy for the treatment of some tumours.

Factors associated with serum CA19-9 levels among healthy children: a cross-sectional study

Abstract Background CA19-9 is a tumor marker mainly used for biliary tract, pancreas and colorectum. Since the marker applies usually for adults, the normal range of serum CA19-9 among children has been rarely reported. This is the first study reporting the distribution of serum CA19-9 levels among cancer-free children as well as their parents, taking into account the Lewis and secretor gene polymorphism and physical growth. Methods Study subjects were 972 apparently healthy Japanese Brazilians including 476 children aged from 1 to 19 years. Results The comparisons in five-year age groups demonstrated that the mean values of serum CA19-9 was lower in the boys than in the girls, and higher in younger age groups; 22.5 U/ml for 1–4 year-old (n=13), 17.4 U/ml for 5–9 year-old (n=36), 15.5 U/ml for 10–14 year-old (n=96) and 10.2 U/ml for 15–19 year-old (n=74) in boys, and 25.3 U/ml (n=11), 27.1 U/ml (n=50), 17.7 U/ml (n=105) and 13.5 U/ml (n=59) in girls, respectively. The difference in those geometric means was statistically significant among four age groups (p=0.006, ANOVA adjusted for sex). After Lewis and secretor genotypes, which are definitive factors of serum CA19-9, were taken into account, geometric mean of serum CA19-9 was associated with any of BMI (p<0.001), height (p<0.001) and weight (p<0.001) among children excluding those with le/le genotype. The associations were still significant when age was adjusted. Conclusions Serum CA19-9 values were higher among children than among adults, and influenced by sex, height, weight, and BMI even after the adjustment for age as well as Le and Se genotypes.