Tumor vasculature is regulated by PHD2-mediated angiogenesis and bone marrow-derived cell recruitment (Cancer Cell, 2009, 15:527-538)

報告日期: 2010/04/23
報告時間: 15:10/16:00
報告學生: 陳柏源
講評老師: 施桂月
附件下載:

http://basicmed.med.ncku.edu.tw/admin/up_img/990416-1.pdf

Tumor Vasculature is Regulated by PHD2-Mediated Angiogenesis and Bone Marrow-Derived Cell Recruitment

Denise A. Chan, Tiara L.A. Kawahara, Patrick D. Sutphin, Howard Y. Chang, Jen-Tsan Chi, and Amato J. Giaccia

Cancer cell 2009 June ; 15: 527-538

 

Student: Po-Yuan Chen

Commentator: Dr. Shi, Guey-Yueh 

Date / Time: April 16th,2010/ PM3:00

Place: Room 601, College of Medicine

 

Abstract

  Tumor angiogenesis, the pathological process that induced by solid tumors encompasses two complementary processes: sprouting angiogenesis and neovascularization. The former is a local response which involved existing blood vessels; the latter is the de novo formation of new blood vessels through the mobilization and recruitment of bone marrow-derived cells (BMDCs). Hypoxia-inducible factors (HIF) which are key regulators of oxygen homeostasis and are composed of an oxygen-labile α subunit and a constitutive b subunit. Previous studies shown that HIF positively correlated with tumor growth while no genetic mutations in any of the HIF subunits affecting the stability or activity of these proteins have been identified. PHD2 is one of three prolyl hydroxylases originally identified as negative regulators of HIF. It has been proposed to be the key oxygen sensor because transiently silencing PHD2 results in stabilization of HIF-1a. The author hypothesized that deregulation of PHD2 might contribute to several types of tumor that have high level of HIF thus contribute to the tumor angiogenesis. The author first investigated the mRNA and protein level of PHD2, they found it decreased in several types of human cancer. Second, they used shRNA to knockdown the PHD2 in colon and pancreatic cancer cell lines and found tumor growth were increased both in vitro and in vivo. Third, they used shRNA to knockdown the HIF and found the tumor growth were not been reduced, thus the author thought tumor suppressor function of PHD2 is HIF-independent. Then they found PHD2 could negatively regulated the BMDCs recruitment in an HIF-independent manner, which is mediated by down stream factors such as NF-kB, IL-8 and angiogenin. This study highlight the importance of HIF-independent pathways in regulating tumor angiogenesis. In particular, inhibiting either ANG or IL-8 may be potential avenues for treatment of tumors that have become resistant to anti-VEGF therapies.

 

Reference

1.  Appelhoff, R.J., Tian, Y.M., Raval, R.R., Turley, H., Harris, A.L., Pugh, C.W., Ratcliffe, P.J., and Gleadle, J.M. (2004). Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. J. Biol. Chem. 279, 38458–38465.