Prokineticin 2/Bv8 is expressed in Kupffer cells in liver and is down regulated in human hepatocellular carcinoma

Abstract

as expected. In addition, out of all isolated liver cells examined, only Kupffer cells (liver resident macrophages) express significant levels of PK2/Bv8 and its receptors, prokineticin receptor 1 and 2. CONCLUSION:In nor mal l ive r P K2/ B v8 a n d i t s receptors were specifically expressed by Kupffer cells. PK2/Bv8 expression decreased as the liver evolves t o wa r d s c a n c e r a n d d i d n o t c o r r e l a t e w i t h H C C angiogenesis. INTRODUCTIONIn vivo, a solid tumor can not progress beyond a few cubic millimeters without oxygen and nutrients supplied by an adequate vascular support [1] . The creation of novel vascular vessels in the tumor microenvironment resulting from an over expression of pro-angiogenic factors plays a central role in tumor invasion and metastasis [2] . Hepatocellular carcinoma (HCC) present typical neo vascularization [3] . Among the soluble factors responsible for the shift towards tumor neo vascularization, vascular endothelial growth factor (VEGF) is thought to play an important role in HCC. This factor is synthesized essentially during hypoxic stress [4] and promotes the growth, migration, morphogenesis of vascular endothelial cells and increases vascular permeability [5,6] . Furthermore, the VEGF/VEGF receptor system is thought to be closely related to the histological grade of hepatocellular carcinoma [7] and strongly expressed in well differentiated HCC [8] . Several other potent angiogenic factors have been reported to be Abstract AIM:To study the implication of prokineticin 1 (PK1/EG-VEGF) and prokineticin 2 (PK2/Bv8) in hepatocellular carcinoma angiogenesis. METHODS:The gene induction of PK1/EG-VEGF and PK2/Bv8 was investigated in 10 normal, 28 fibrotic and 28 tumoral livers by using real time PCR. Their expression was compared to the expression of VEGF (an angiogenesis marker), vWF (an endothelial cell marker) and to CD68 (a monocyte/macrophage marker). Furthermore, the mRNA levels of PK1/EG-VEGF, PK2/Bv8, prokineticin receptor 1 and 2 were evaluated by real time PCR in isolated liver cell populations. Finally, PK2/Bv8 protein was detected in normal liver paraffin sections and in isolated liver cells by immunohistochemistry and immunocytochemistry.RESULTS: PK2/Bv8 mRNA but not PK1/EG-VEGF was expressed in all types of normal liver samples examined. In the context of liver tumor development, we reported that PK2/Bv8 correlates only with CD68 and showed a significant decrease in expression as the pathology evolves towards cancer. Whereas, VEGF and vWF mRNA were significantly upregulated in both fibrosis and HCC, involved in HCC angiogenesis, notably basic fibroblast growth factor (bFGF) [9,10] , angiopoietin 1 (Ang1) and angiopoietin 2 (Ang2) [11] . Interestingly, inflammatory cytokines like Interleukin 8 (IL-8) and tumor necrosis factoralpha (TNF-α) have also been shown to be implicated in the maintenance of HCC angiogenesis but also in chronic hepatitis [12,13] . P r o k i n e t i c i n 1 , a l s o n a m e d e n d o c r i n e g l a n dvascular endothelial gro...

The immunophenotype of antigen presenting cells of the mononuclear phagocyte system in normal human liver – A systematic review

“…It is postulated that through this interaction they are key in instigating fibrosis following inflammation [93]. CD68+ KCs also co-express prokineticin 2/Bv8, a molecule strongly implicated in angiogenesis [43].…”

Mechanisms of Resistance to Anti-Angiogenic Therapy and Development of Third-Generation Anti-Angiogenic Drug Candidates

“…120 Because Bv8 expression is downregulated in hepatocellular carcinoma as compared to normal liver without correlation between expression levels of Bv8 and angiogenesis, further studies on the role of Bv8 in human cancer are warranted. 121 PlGF has been implicated in the resistance against anti-VEGF therapy. 122 Its levels correlate with clinical outcome in several, though not all human cancers.…”

Cytokine properties of prokineticins

“…We measured the expression of PROK1 and PROK2 in fresh human monocytes obtained from 10 different healthy donors and our results consistently showed very high expression of PROK2 but undetectable expression of PROK1 (data not shown). Furthermore, we recently showed that the resident macrophage population of human liver (called Kupffer cells) was the specific source of PROK2 in liver, whereas PROK1 was weakly expressed [25].…”

“…Recently, we studied the expression of PROKR1 and PROKR2 in fresh human monocytes from 10 different donors at the protein level using flow cytometry and we observed that both receptors were expressed on the monocyte surface (J. Monnier, V. Quillien, C. Piquet‐Pellorce, C. Leberre, L. Preisser, H. Gascan & M. Samson, unpublished data). In addition, we showed that in liver hepatic cells both PROKR1 and PROKR2 mRNA were only expressed at high levels by Kupffer cells [25]. In mice peritoneal macrophages a predominance of PROKR1 transcripts was found, and macrophage cells extracted from PROKR1 knockout mice were unable to respond to PROK2 [29].…”