Loss of EphA2 receptor tyrosine kinase reduces Apc^min/+ tumorigenesis

Abstract

The Eph receptor A2 (EphA2) is overexpressed in a range of human epithelial cancers, a phenotype that is associated with cancer cell proliferation, progression and angiogenesis. Mouse models of mammary neoplasia have confirmed the role of EphA2 as mice carrying a knockout allele of EphA2 were resistant to breast cancer, a phenotype that was associated with interactions between EphA2 and ErbB2. We investigated in vivo the role of EphA2 in GI cancer. To determine whether EphA2 influences intestinal tumorigenesis, we used qRT-PCR to examine the mRNA expression levels of EphA2 in tumors from the small intestine and colon of Apc Min/1 mice. We found that EphA2 was significantly up-regulated in tumors from both regions when compared with normal control tissues. We then evaluated the spatial expression patterns of EphA2 protein using immunohistochemistry in both the small intestine and colon and found that in normal tissues EphA2 was robustly expressed in highly differentiated cells, such as cells of the villi, but that EphA2 expression was largely absent from the stem cell niche and proliferative zones of intestinal crypts. In contrast, in tumors EphA2 was broadly expressed. Finally, we created a strain of Apc Min/1 mice carrying a genetic knockout of the EphA2 gene. These mice developed significantly fewer and smaller tumors in both the small and large intestine. Overall, our results indicate that EphA2 plays an oncogenic role in the mammalian intestine suggesting that strategies to target EphA2 activity may offer new therapeutic modalities for colorectal cancer. ' 2008 Wiley-Liss, Inc.Key words: colon cancer; receptor tyrosine kinase; EphA2; Apc; Min The Eph receptor tyrosine kinase (RTK) family consists of 16 receptors and 9 ligands that play diverse roles in development, cellular growth, angiogenesis, cell adhesion, cell migration, cell signaling, differentiation and neoplasia, and together constitute the largest family of RTKs in vertebrates. [1][2][3][4][5][6][7][8] Eph RTKs are subdivided into class A and class B molecules based on homology and their ability to bind distinct set of membrane anchored ligands (ephrins). Class A Eph receptors bind to glycosol-phosphatidylinositol-linked class A ephrins, whereas class B Ephs bind to class B ephrins that contain a transmembrane spanning domain. Notably, dysregulation of both class A and B Ephs are implicated in cancer processes in a wide range of mammalian tissues. Eph receptor A2 (EphA2), which maps to human chromosome 1p36.1, is associated with tumor progression, angiogenesis and poor prognosis in breast, pancreatic, ovarian, cervical, mesothelioma, bladder, colon, gastric, lung, melanoma, esophageal, prostate and kidney cancers. 9-15 In mammary cancers, EphA2 promotes adenocarcinoma development and metastatic progression, [16][17][18][19] in some cases by amplifying ErbB2 signaling. 17 Further, in metastatic breast cancer, EphA2 has been reported to be negatively regulated by estrogen and c-Myc, and EphA2 over-expression decreases estrogen dependence; phenotyp...

Clinical relevance of Ephs and ephrins in cancer: Lessons from breast, colorectal, and lung cancer profiling

“…EphA2 and ephrin-A1 expression were also correlated with MVD in human CRC samples [60], suggesting they might regulate neovascularization as well as tumorigenesis. These clinical observations are consistent with data derived from cell culture and animal studies [61–63]. Elevated EphA4 expression was reported for CRCs in the presence of liver metastasis, whereas lower EphB2 levels correlated with liver metastasis [64].…”

Downregulation of EphA2 expression suppresses the growth and metastasis in squamous-cell carcinoma of the head and neck in vitro and in vivo

“…Furthermore, inhibition of EphA2 markedly diminished the tumorigenecity of SCCHN in vivo. This result indicates a critical role of EphA2 in proliferation of SCCHN cancer cells, which is similar to its suggested roles in other reported cancers (Bogan et al 2009;Brantley-Sieders et al 2008;Lu et al 2008;Margaryan et al 2009;Zhou et al 2008). Since EphA2 has long been recognized as an oncogene and a potential tumor marker in tumorigenesis for other carcinomas, it is not surprising to present an association between the expression of EphA2 and proliferation of SCCHN cells.…”

Eph receptor and ephrin function in breast, gut, and skin epithelia

“…Notably, EphA2 and ephrin-A1 differentially impact tumor burden in Apc min/C mice: ephrin-A1 promotes tumorigenesis while loss of EphA2 reduces tumor formation. 118,119 It is therefore possible that an "Eph-switch" from B type to A type receptors contributes to the malignant transformation of gut epithelia.…”