Top

International Journal of Colorectal Disease

Published in:

01-03-2012 | Original Article

Pleiotrophin is a potential colorectal cancer prognostic factor that promotes VEGF expression and induces angiogenesis in colorectal cancer

Authors: Ying Kong, Pei-song Bai, Ke-jun Nan, Hong Sun, Nan-zheng Chen, Xiao-gai Qi

Published in: International Journal of Colorectal Disease | Issue 3/2012

Abstract

Purpose

Pleiotrophin (PTN) is an important developmental secretory cytokine expressed in many types of cancer and involved in angiogenesis and tumor growth; however, the significance of PTN expression in colorectal cancer (CRC) has not been established.

Methods

Immunohistochemistry, western blot, and enzyme-linked immunosorbent assay were used to detect PTN expression in CRC patients. The relationship between PTN expression and clinicopathological characteristics and survival time was statistically analyzed, and the relationship between PTN and vascular endothelial growth factor (VEGF) in tumor angiogenesis was further analyzed.

Results

Of CRC tissues, 74.70% (62/83) stained positive, with a strong positive ratio of 60.24% (50/83). The expression of PTN in CRC tissues was much higher than in normal colorectal tissues. PTN serum levels in CRC patients (mean = 254.59 ± 261.76 pg/ml) were significantly higher than those of normal volunteers (mean = 115.23 ± 79.53 pg/ml; p < 0.001). PTN expression was related to CRC differentiation and TNM staging. High level of PTN is a predictor of a poor prognosis and high expression of PTN is accompanied by high expression of VEGF in CRC patients. Investigation of the relationship between PTN and VEGF revealed that PTN, through the PTN/RPTPβ/ζ signaling pathway, increased tyrosine phosphorylation of β-catenin, leading to an increase in VEGF.

Conclusions

Our study identifies PTN as an essential growth factor for CRC. PTN promotes VEGF expression and cooperates with VEGF in promoting CRC angiogenesis. PTN could serve as a prognostic factor for this cancer. Considering that PTN shows very limited expression in normal tissue, it may represent an attractive new target for CRC therapy.

Li YS, Milner PG, Chauhan AK, Watson MA, Hoffman RM, Kodner CM, Milbrandt J, Deuel TF (1990) Cloning and expression of a developmentally regulated protein that induces mitogenic and neurite outgrowth activity. Science 250(4988):1690–1694PubMedCrossRef

Polykratis A, Delbé J, Courty J, Papadimitriou E, Katsoris P (2004) Identification of Heparin affin regulation peptide domains with potential role on angiogenesis. Int J Biochen Cell Biol 36(10):1954–1966CrossRef

Chang Y, Zuka M, Perez-Pinera P, Astudillo A, Mortimer J, Berenson JR, Deuel TF (2007) Secretion of pleiotrophin stimulates breast cancer progression through remodeling of the tumor microenvironment. Proc Natl Acad Sci USA 104(26):10888–10893PubMedCrossRef

Souttou B, Juhl H, Hackenbruck J, Röckseisen M, Klomp HJ, Raulais D, Vigny M, Wellstein A (1998) Relationship between serum concentrations of the growth factor pleiotrophin and pleiotrophin-positive tumors. J Natl Cancer Inst 90(19):1468–1473PubMedCrossRef

Calvet L, Geoerger B, Regairaz M, Opolon P, Machet L, Morizet J, Joseph JM, Elie N, Vassal G (2006) Pleiotrophin, a candidate gene for poor tumor vasculature and in vivo neuroblastoma sensitivityto irinotecan. Oncogene 25(22):3150–3159PubMedCrossRef

Takahashi Y, Kitadai Y, Bucana CD, Cleary KR, Ellis LM (1995) Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res 55(18):3964–3968PubMed

Lee JC, Chow NH, Wang ST, Huang SM (2000) Prognostic value of vascular endothelial growth factor expression in colorectal cancer patients. Eur J Cancer 36(6):748–753PubMedCrossRef

Meng K, Rodriguez-Peña A, Dimitrov T, Chen W, Yamin M, Noda M, Deuel TF (2000) Pleiotrophin signals increased tyrosine phosphorylation of beta-catenin through inactivation of the intrinsic catalytic activity of the receptor-type protein tyrosine phosphatase beta/zeta. Proc Natl Acad Sci USA 97(6):2603–2608PubMedCrossRef

Skurk C, Maatz H, Rocnik E, Bialik A, Force T, Walsh K (2005) Glycogen-Synthase Kinase3beta/beta-catenin axis promotes angiogenesis through activation of vascular endothelial growth factor signaling in endothelial cells. Circ Res 96(3):308–318PubMedCrossRef

10.

Easwaran V, Lee SH, Inge L, Guo L, Goldbeck C, Garrett E, Wiesmann M, Garcia PD, Fuller JH, Chan V, Randazzo F, Gundel R, Warren RS, Escobedo J, Aukerman SL, Taylor RN, Fantl WJ (2003) ß-Catenin regulates vascular endothelial growth factor expression in colon cancer. Cancer Res 63(12):3145–3153PubMed

11.

Héroult M, Bernard-Pierrot I, Delbé J, Hamma-Kourbali Y, Katsoris P, Barritault D, Papadimitriou E, Plouet J, Courty J (2004) Heparin affin regulatory peptide binds to vascular endothelial growth factor (VEGF)and inhibits VEGF-induced angiogenesis. Oncogene 23(9):1745–1753PubMedCrossRef

12.

Gorreta F, Runfola TP, VanMeter AJ, Barzaghi D, Chandhoke V, Del Giacco L (2005) Identification of thioredoxin reductase 1-regulated genes using small interference RNA and cDNA microarray. Cancer Biol Ther 4(10):1079–1088PubMedCrossRef

13.

Muramatsu T (2002) Midkine and pleiotrophin: two related proteins involved in development, survival, inflammation and tumorigenesis. J Biochem 132(3):359–371PubMedCrossRef

14.

Yamakawa T, Kurosawa N, Kadomatsu K, Matsui T, Itoh K, Maeda N, Noda M, Muramatsu T (1999) Levels of expression of pleiotrophin and protein tyrosine phosphatasez are decreased in human colorectal cancers. Cancer Lett 135(1):91–96PubMedCrossRef

15.

Vacherot F, Delbé J, Heroult M, Barritault D, Fernig DG, Courty J (1999) Glycosaminoglycans differentially bind HARP and modulate its biological activity. J Biol Chem 274(12):7741–7747PubMedCrossRef

16.

Isemura M, Sato N, Munakata H, Aikawa J, Ototani N, Yosizawa Z, Sakuma A, Masuda T, Aoyagi Y, Ichida F (1984) Glycosaminoglycans of human colonic mucosa and colonic adenocarcinoma. Tohoku J Exp Med 142(1):89–95PubMedCrossRef

17.

Dai J, Rabie AB (2007) VEGF:an essential mediator of both angiogenesis and endochondral ossification. J Dent Res 86(10):937–950PubMedCrossRef

18.

Vecchiarelli-Federico LM, Cervi D, Haeri M, Li Y, Nagy A, Ben-David Y (2010) Vascular endothelial growth factor—a positive and negative regulator of tumor growth. Cancer Res 70(3):863–867PubMedCrossRef

19.

Novotny WF, Maffi T, Mehta RL, Milner PG (1993) Identification of novel heparin-releasable proteins, as well as the cytokines midkine and pleiotrophin, in human postheparin plasma. Arterioscler Thromb 13(12):1798–1805PubMedCrossRef

20.

Polytarchou C, Hatziapostolou M, Papadimitriou E (2005) Hydrogen peroxide stimulates proliferation and migration of human prostate cancer cells through activation of activator protein-1 and up-regulation of the heparin affin regulatory peptide gene. J Biol Chem 280(49):40428–40435PubMedCrossRef

21.

Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM, Schumacker PT (2000) Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O₂ sensing. J Biol Chem 275(33):25130–25138PubMedCrossRef

22.

Coothankandaswamy V, Liu Y, Mao SC, Morgan JB, Mahdi F, Jekabsons MB, Nagle DG, Zhou YD (2010) The alternative medicine pawpaw and its acetogenin constituents suppress tumor angiogenesis via the HIF-1/VEGF pathway. J Nat Prod 73(5):956–961PubMedCrossRef

23.

Clark DE, Lord EA, Suttie JM (2006) Expression of VEGF and pleiotrophin in deer antler. Anat Rec A Discov Mol Cell Evol Biol 288(12):1281–1293PubMed

24.

Perez-Pinera P, Zhang W, Chang Y, Vega JA, Deuel TF (2007) Anaplastic lymphoma kinase is activated through the pleiotrophin/receptor protein-tyrosine phosphatase beta/zeta signaling pathway: an alternative mechanism of receptor tyrosine kinase activation. J Biol Chem 282(39):28683–28690PubMedCrossRef

25.

Danilkovitch-Miagkova A, Miagkov A, Skeel A, Nakaigawa N, Zbar B, Leonard EJ (2001) Oncogenic mutants of RoN and MET receptor tyrosine kinases cause activation of the β-catenin pathway. Mol Cell Biol 21(17):5857–5868PubMedCrossRef

26.

Podar K, Anderson KC (2010) A therapeutic role for targeting c-Myc/Hif-1-dependent signaling pathways. Cell Cycle 9(9):1722–1728PubMedCrossRef

27.

Li G, Hu Y, Huo Y, Liu M, Freeman D, Gao J, Liu X, Wu DC, Wu H (2006) PTEN deletion leads to up-regulation of a secreted growth factor pleiotrophin. J Biol Chem 281(16):10663–10668PubMedCrossRef

28.

Gu D, Yu B, Zhao C, Ye W, Lv Q, Hua Z, Ma J, Zhang Y (2007) The effect of pleiotrophin signaling on adipogenesis. FEBS Lett 581(3):382–388PubMedCrossRef

29.

Tian Q, He XC, Hood L, Li L (2005) Bridging the BMP and Wnt pathways by PI3K/AKT and 14-3-3zeta. Cell Cycle 4(2):215–216PubMedCrossRef

Title: Pleiotrophin is a potential colorectal cancer prognostic factor that promotes VEGF expression and induces angiogenesis in colorectal cancer
Authors: Ying Kong
Pei-song Bai
Ke-jun Nan
Hong Sun
Nan-zheng Chen
Xiao-gai Qi
Publication date: 01-03-2012
Publisher: Springer-Verlag
Published in: International Journal of Colorectal Disease / Issue 3/2012
Print ISSN: 0179-1958
Electronic ISSN: 1432-1262
DOI: https://doi.org/10.1007/s00384-011-1344-z

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Pleiotrophin is a potential colorectal cancer prognostic factor that promotes VEGF expression and induces angiogenesis in colorectal cancer

Abstract

Purpose

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 3/2012

Endoscopic stenting and elective surgery versus emergency surgery for left-sided malignant colonic obstruction: a prospective randomized trial

Computer-generated surface and tone enhancements to distinguish neoplastic from non-neoplastic colon polyps less than 1 cm in diameter

Long-term risk of adenocarcinoma post-ileal pouch–anal anastomosis for ulcerative colitis: report of two cases and review of the literature

HPV and precancerous lesions of anal canal in women: systematic review

Determinants of short- and long-term outcome in patients undergoing simultaneous resection of colorectal cancer and synchronous colorectal liver metastases

The effects of tacrolimus on colonic anastomotic healing in rats