The DRs positive for paracrine factors. Effects of

The main findings of our study are that in pediatricpatients with HLB and HCC (1) the peritumoral DRs positive for paracrinefactors such as VEGF+ DRs, VEGFD + DRs, ANGPT1 + DRs and PDGFC + DRs stainedwith EpCAM are observed in HBL and HCC (2) ANGPT1+ DRs correlates closely withKi67+ DRs in HBL. (3) Angiogenic maker, expression of CD34, in DRs area ispositively correlated with number of CD34+ vessel and area of CD34+ inintratumoral area in pediatric patient with liver tumors. (4) There arepositive correlation within DRs positive for paracrine factors. Effects of age,preoperative chemotherapy and gender of pediatric patients on DRs positive forparacrine factors are identified in this study.

(5) ASfor, relationship between DR+ for PF and tumor grade,  In the course of chronic cholestatic liverdiseases, cholangiocyte proliferation aims to repair and compensate for theanatomic and functional loss of injured ducts. (1) In fact, proliferatingcholangiocytes display enhanced secretory activities by which they compensatefor the impaired function of injured cells. (2-4) Inthese pathologies, HPC activation contributes to DRs. (5, 6) DRsis thought to arise due to a complex interaction between hepatocytes, hepaticprogenitor cells, hepatic stellate cells and extracellular matrix as well asinflammatory cells and endothelial cells. (7) In liver diseasescondition, it is known that DRs occurs in cholestatic diseases, in inflammatorydiseases and in conditions with massive loss of parenchyma. (8, 9) Furthermore,a study suggests an important role of VEGFs in support the expansion of HPCniche by an autocrine and paracrine effects on neighboring cells stimulatingthe proliferation of HPCs and endothelial cells. (11) These aspects couldhave important implication in liver diseases processes and carcinogenesis. Inaddition, It is reported that the positive association of ductular reactionswith poor prognosis of adult HCC.

(12) Basedon these reports, we hypothesized that DRs which express paracrine factors arecorrelated with angiogenesis and tumoral proliferation. According to recent studies, PDGF-C may useparacrine mechanisms to modulate endothelial cells and perhaps othernon-parenchymal cells including hepatic satellite cells by inducing othergrowth factors that act on these liver cells. (13, 14) Ourresults show that PDGFC+ DRs is positively correlated with proliferation oftumor cell in overall liver tumor group while there are no correlations in eachHBL and HCC (Table 3). It remains to be determined whether PDGF-C acts directlyor through paracrine effects to induce progression of tumors in this study. In adults, sustained angiogenesis ispathological and characteristic of malignancy, where the formation of aneovasculature is essential for tumor growth and development. (15-17) Oneof the signals linking ductal and arterial development in the liver is VEGF,which cooperates with ANGPT-1.

(18) Besides, two studies previouslyreported that VEGF-D showed angiogenic activity on endothelial cells, as wellas mitogenic and motogenic activity on tumor-derived cells and suggested VEGF-Dcan be a c-fos effector for tumor malignancy. (19, 20) However,relationships are still not clear among these angiogenic factors+ DRs and livertumors in pediatric patients. In this study, although there are no significantcorrelation between VEGF+ DRs and perspectives of anigiogensis andproliferation of tumor cells, we observed that the group of VEGFD+ DRs above50% show higher the number of vessel with CD34 positive staining in peritumoralarea compared to the group of VEGFD+ DRs below 50%.

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The group of ANGPT-1+ DRs above50% show a greater area of CD34 positive staining in peritumoral area compareto the group of ANGPT-1+ DRs below 50% (Table 6). Moreover, ANGPT-1+ DRs inHCC, the group of ANGPT-1+ DRs above 50% show a greater area of Ki67 positivestaining in intratumoral area compare to the group have ANGPT-1+ DRs below 50%.Nevertheless, the negative correlations betweenANGPT-1+ DRs and area of CD34 positive staining in peritumoral area, betweenANGPT-1+ DRs and area of CD34 positive staining in intratumoral area areidentified as well in this study (Table 4). Although the expression of ANGPTsin intratumoral area was not tested in this study, it also has been reportedthat the expression of ANGPTs is greater in HCC tissues than in noncancerousliver tissues and it is more intense in hypervascular HCC than in HCC that doesnot show hypervascularity. ANGPT-2 expression is upregulated with tumordedifferentiation. These results suggest it is the balance of ANGPT-1 and ANGPT-2expression that regulates the vascular development of HCC.

(21, 22) Therefore,to clarify the relationships among ANGPT-1+ DRs and angiogenesis andproliferation of tumor cell, it is needed to investigate that the level ofANGPT-1 and ANGPT-2 expression in both peritumoral DRs and intratumoral areafor future work.Finally, cholangiocyte proliferation occursvirtually in all pathologic conditions of liver injury where it is associatedwith inflammation, regeneration, and repair, thus conditioning the evolution ofliver damage. Interestingly, proliferating cholangiocytes secrete differentcytokines, growth factors, neuropeptides, and hormones, which representpotential mechanisms for cross talk with other liver cells. (10) Our finding, positivecorrelation between Ki67+ DRs and proliferation in intratumoral area in HBL (Table3), imply these perspective of DRs in status of liver damage including livertumors.In conclusion, our study demonstrates that theperitumoral DRs positive for paracrine factors are observed in HBL and HCC, andpositive correlations within DRs positive for paracrine factors are identified.It is alsosupported that the DRs correlated closely with severity of fibrosis andInflammation in pediatric patients with liver tumor and grade of tumor.l1 Therefore, our results suggest DRs positive for paracrine factors play apotential role in liver diseases and tumor progression as a paracrine manner inpediatric patients with liver tumors.