Correlation of EPHA2 overexpression with high microvessel count in human primary colorectal cancer

Abstract

Evidence suggests that the erythropoietin-producing hepatocellular (EPH) receptor tyrosine kinases (RTKs) and their ephrin (EFN) ligands are involved in human carcinogenesis. Expression of two of them, EFNA1 ligand and its receptor, EPHA2, has been proposed to contribute to tumor-induced neovascularization. Colorectal cancers were examined for expressions of EPHA2 and its ligand EFNA1 by semi-quantitative RT-PCR, and double-immunostained for EPHA2 and CD34. Microvessels in the tumors were counted. Double-staining was also performed in 25 cases of adenoma with focal cancer for comparison. Trends of overexpression of both EPHA2 and EFNA1 was found in tumor tissue compared to the corresponding normal tissue in the same specimen [22/37 (59.5%) and 25/37 (67.5%), respectively; P = = = =0.100 for EPHA2 and eceptor tyrosine kinases (RTKs), which are often the products of transforming oncogenes, have been widely implicated in the generation and progression of common human tumors.1) The erythropoietin-producing hepatocellular (EPH) receptors represent the largest known family of RTKs and they are activated by interaction with cell-surface ligands, termed ephrins (EFNs). EPH receptors have been classified into two subfamilies, EPHA and EPHB, according to their preference for either glycosylphosphatidylinositol (GPI)-anchored EFNA ligands or transmembrane EFNB ligands, and 14 receptors and eight ligands have been identified in vertebrates thus far. The EPH family receptor kinases and their EFN ligands are well known to be involved in fundamental developmental processes of the nervous system, including axon guidance, 2) axon fasciculation,3) neural crest cell migration, 4) acquisition of brain subregional identity, 5) and neuronal cell survival. 6) Evidence has suggested that one member of the EPH family, EPHA2, and one of its ligands EFNA1, are associated with tumorigenesis and tumor neovascularization. 7,8) For example, forced overexpression of EPHA2 causes tumorigenesis by mammary epithelial cells in vitro, and its ligand, EFNA1, has been found to involved in TNF-α-induced angiogenesis.7, 9) A recent paper reported that EFNA1 ligand and its receptor, EPHA2, are expressed by human breast cancer cells and human Kaposi's sarcoma cells during tumor neovascularization. 10) However, expression of EPH receptors and EFNs in gastrointestinal tract tumors has seldom been documented.In this study, we investigated the expression of EPHA2 and its ligand, EFNA1, in colorectal cancer specimens by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis and we counted CD34-positive microvessels surrounding the tumors to identify the relation between colorectal cancer and the EPHA2/EFNA1 system in terms of microvessel induction. Materials and MethodsTissues. RT-PCR samples of human colorectal cancer specimens and corresponding normal tissue were obtained from surgical resections performed at the Hamamatsu University School of Medicine between 1999 and 2002. The clinicopathological characteristics of 37 colorect...

Downregulation of EphA7 by hypermethylation in colorectal cancer

“…The upregulation of the expression of several members of the Eph family of receptor tyrosine kinases has been reported (Easty et al, 1999;Liu et al, 2002;Miyazaki et al, 2003;Fox and Kandpal, 2004). We previously reported that EPHB2 is overexpressed in gastric cancer (Kiyokawa et al, 1994;Kataoka et al, 2002) and that EphA2 is overexpressed in colorectal cancer (Kataoka et al, 2004).…”

“…They also play a role in angiogenesis (Favre et al, 2003;Sullivan and Bicknell, 2003). In recent years, some of the Eph genes have been found to be overexpressed in human tumors, including neuroblastoma (Tang et al, 1999), lung carcinoma (Tang et al, 1999), gastric cancer (Kiyokawa et al, 1994;Kataoka et al, 2002), esophageal cancer (Miyazaki et al, 2003), breast cancer (Wu et al, 2004), and colorectal cancer (Stephenson et al, 2001;Liu et al, 2002Liu et al, , 2004Kataoka et al, 2004). Among the Eph family genes, relatively less attention has been directed toward EphA7 in human tumors, and the potential role of EphA7 in human oncology has not been addressed.…”

“…Among the Eph family genes, relatively less attention has been directed toward EphA7 in human tumors, and the potential role of EphA7 in human oncology has not been addressed. Recently, we noticed a loss of expression of EphA7 during an investigation on alterations in the expression of Eph family genes in human digestive cancers (Kataoka et al, 2002(Kataoka et al, , 2004. EphA7, previously known as Mdk1, Hek11, Ehk-3, Ebk, and Cek11, was originally isolated from adult mouse brain (Ciossek et al, 1995;Valenzuela et al, 1995).…”

EphA2 overexpression promotes ovarian cancer growth

“…1,5,6 For oncology applications, interest in EphA2 has grown recently due to its increased expression in most cancers including lung, breast, ovary, prostate, colorectal, skin and esophagus. [7][8][9][10][11][12][13] Interestingly, EphA2 is located on chromosome 1p36.1, which is a hotspot for rearrangements in many human cancers including ovarian cancer. [14][15][16] We have previously demonstrated that EphA2 is overexpressed in 76% of epithelial ovarian cancers.…”

Loss of EphA2 receptor tyrosine kinase reduces Apcmin/+ tumorigenesis

“…45,46 In intestinal neoplasia, EphA2 has been reported to be up-regulated in human colorectal cancers, and EPHA2 overexpression correlates with colon cancer metastasis and high microvessel count in primary human colorectal cancers. [47][48][49] Ephrin A1 is also implicated in intestinal cancer. EFNA1 antisense oligonucleotides inhibited the growth of HT29 colon carcinoma cells, 50 and overexpression of murine Ephrin-A1 enhanced tumor multiplicity and tumor progression in Apc Min/1 mice.…”