Ephrin-A1 promotes the malignant progression of intestinal tumors in Apcmin/+ mice

Shi, Liang; Itoh, Fumiko; Takahashi, Shigeru; Yamamoto, Masayuki; Kato, Mitsuyasu

doi:10.1038/sj.onc.1210992

Cited by 18 publications

(19 citation statements)

References 31 publications

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“…Normal expression of EphA2, thus, matches closely the differentiation state of the migrating cells in the small intestine. Notably, Paneth cells, another differentiated cell population did not stain positive for EphA2, although we did observe occasional EphA2-positive cells in the mid-crypt regions that may be the same enteroendocrine cells that express ephrin A1 as reported by Shi et al 51 In the large intestine, normal EphA2 expression is confined to the absorptive enterocytes of the intercrypt table. Goblet cells, a differentiated cell type that comprise as many as 60% of cells in the large intestine (and which share a common precursor with Paneth cells) did not express EphA2.…”

Section: Discussionsupporting

confidence: 68%

“…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. 51 Interestingly, in the latter study, mRNA levels of EphA2 were elevated in tumors from the distal small intestine of Apc Min/1 mice, and in both normal small intestine and Apc Min/1 tumors from mice overexpressing EFNA1. These observations are noteworthy because, as we discussed above, several studies indicate that Ephrin-A1 also induces the internalization and degradation of EphA2.…”

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confidence: 62%

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

Bogan

Chen

O’Sullivan

et al. 2008

Intl Journal of Cancer

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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...

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Section: Discussionsupporting

confidence: 68%

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confidence: 62%

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

Bogan

Chen

O’Sullivan

et al. 2008

Intl Journal of Cancer

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“…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.…”

Section: Eph Receptor and Ephrin Signaling In Gastrointestinal Diseasementioning

confidence: 99%

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

White¹,

Getsios

2014

Cell Adhesion & Migration

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Abbreviations: ADAM, a disintegrin and metalloprotease; Apc, adenomatous polyposis coli; Eph, erythropoietin-producing hepatocellular; ER, estrogen receptor; Erk, extracellular signal-regulated kinase; GEF, guanine nucleotide exchange factor; GPI, glycosylphosphatidylinositol; HER2, human epidermal growth factor receptor 2; HGF, hepatocyte growth factor; IBD, inflammatory bowel disease; KLF, Kr€ uppel-like factor; MAPK, mitogen-activated protein kinase; MMTV-LTR, mouse mammary tumor virus-long terminal repeat; MT1-MMP, membrane-type 1 matrix metalloproteinase; PDZ, postsynaptic density protein 95, discs large 1, and zonula occludens-1; PTP, protein tyrosine phosphatase; RTK, receptor tyrosine kinase; SH2, Src homology 2; SHIP2, SH2 inositol phosphatase 2; SLAP, Src-like adaptor protein; TCF, T-cell specific transcription factor; TEB, terminal end bud; TNFa, tumor necrosis factor a:Epithelial cells are tightly coupled together through specialized intercellular junctions, including adherens junctions, desmosomes, tight junctions, and gap junctions. A growing body of evidence suggests epithelial cells also directly exchange information at cell-cell contacts via the Eph family of receptor tyrosine kinases and their membrane-associated ephrin ligands. Ligand-dependent and -independent signaling via Eph receptors as well as reverse signaling through ephrins impact epithelial tissue homeostasis by organizing stem cell compartments and regulating cell proliferation, migration, adhesion, differentiation, and survival. This review focuses on breast, gut, and skin epithelia as representative examples for how Eph receptors and ephrins modulate diverse epithelial cell responses in a context-dependent manner. Abnormal Eph receptor and ephrin signaling is implicated in a variety of epithelial diseases raising the intriguing possibility that this cellcell communication pathway can be therapeutically harnessed to normalize epithelial function in pathological settings like cancer or chronic inflammation.

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“…For immunofluorescence, the embryos were processed for cryosectioning as described earlier 18 and sectioned at a thickness of 5 mm at À221C. After being blocked, the sections were incubated with anti-PECAM-1 (BD Biosciences; 1:100) and anti-ey-globin (1:200) antibodies (a generous gift from Dr Atsumi) 19 or with Cy3-conjugated antia-smooth muscle actin (SMA) (Sigma Clone 1A4; 1:200) at 41C overnight.…”

Section: Immunofluorescence and Histologymentioning

confidence: 99%

Poor vessel formation in embryos from knock-in mice expressing ALK5 with L45 loop mutation defective in Smad activation

Itoh

Carvalho

Adachi

et al. 2009

Laboratory Investigation

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Transforming growth factor (TGF)-b regulates vascular development through two type I receptors: activin receptor-like kinase (ALK) 1 and ALK5, each of which activates a different downstream Smad pathway. The endothelial cell (EC)-specific ALK1 increases EC proliferation and migration, whereas the ubiquitously expressed ALK5 inhibits both of these processes. As ALK1 requires the kinase activity of ALK5 for optimal activation, the lack of ALK5 in ECs results in defective phosphorylation of both Smad pathways on TGF-b stimulation. To understand why TGF-b signaling through ALK1 and ALK5 has opposing effects on ECs and whether this takes place in vivo, we carefully compared the phenotype of ALK5 knock-in (ALK5 KI/KI ) mice, in which the aspartic acid residue 266 in the L45 loop of ALK5 was replaced by an alanine residue, with the phenotypes of ALK5 knock-out (ALK5 À/À ) and wild-type mice. The ALK5 KI/KI mice showed angiogenic defects with embryonic lethality at E10.5-11.5. Although the phenotype of the ALK5 KI/KI mice was quite similar to that of the ALK5 À/À mice, the hierarchical structure of blood vessels formed in the ALK5 KI/KI embryos was more developed than that in the ALK5 À/À mutants. Thus, the L45 loop mutation in ALK5 partially rescued the earliest vascular defects in the ALK5 À/À embryos. This study supports our earlier observation that vascular maturation in vivo requires both TGF-b/ALK1/ BMP-Smad and TGF-b/ALK5/activin-Smad pathways for normal vascular development. Formation of mature blood vessels requires endothelial cell (EC) proliferation, the construction of a permanent basement membrane, and the recruitment of mural cells such as pericytes and vascular smooth muscle cells (VSMCs). Angiogenesis, the formation of new blood vessels, is controlled in two phases: the activation and the resolution phases. In the activation phase, vascular permeability and basement membrane degradation are increased, which allows ECs to proliferate, invade, and migrate into the extracellular space and form a new capillary lumen. In the resolution phase, ECs can no longer proliferate and migrate but are tightly bound to the extracellular matrix. Mesenchymal cells are then recruited onto the endothelial tube where they differentiate into pericytes or VSMCs surrounding the newly formed vessels. Multiple cytokines, including vascular endothelial growth factor, fibroblast growth factor, plateletderived growth factor, and transforming growth factor (TGF)-b, interplay with one another to regulate EC differentiation, vascular network formation, and the establishment and maintenance of vessel wall integrity.1,2 TGF-b is a multifunctional cytokine that regulates many cellular responses, including proliferation, differentiation, migration, and apoptosis. Aberrant TGF-b signaling is associated with tumorigenicity, cardiovascular abnormality, and anomalies in development of the gastrointestinal tract.

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Ephrin-A1 promotes the malignant progression of intestinal tumors in Apcmin/+ mice

Cited by 18 publications

References 31 publications

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

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

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

Poor vessel formation in embryos from knock-in mice expressing ALK5 with L45 loop mutation defective in Smad activation

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Ephrin-A1 promotes the malignant progression of intestinal tumors in Apcmin/+ mice

Cited by 18 publications

References 31 publications

Loss of EphA2 receptor tyrosine kinase reduces Apcmin/+ tumorigenesis

Loss of EphA2 receptor tyrosine kinase reduces Apcmin/+ tumorigenesis

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

Poor vessel formation in embryos from knock-in mice expressing ALK5 with L45 loop mutation defective in Smad activation

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

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