Eph Receptor Tyrosine Kinases in Tumor and Tumor Microenvironment

Brantley-Sieders, Dana M.; Schmidt, Sonja; Parker, Monica A.; Chen, Jin

doi:10.2174/1381612043383160

Cited by 103 publications

(93 citation statements)

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“…Whereas c-myc loss had no significant effect on proliferation or apoptosis in embryonic stem cells, tumor formation was markedly reduced due to dysregulation of angiogenic factors (14). Thus, we next examined the expression of VEGF as well as several other factors involved in angiogenesis, including Eph receptor tyrosine kinases, which are deregulated in many human cancers, and their respective ligands, the ephrins (24,25). We first examined the expression of VEGF in the whole animal using serum isolated from retroorbital eye bleeds.…”

Section: Reduction In C-myc Levels Correlates With a Decrease In The mentioning

confidence: 99%

Inhibition of Intestinal Polyposis with Reduced Angiogenesis in ApcMin/+ Mice Due to Decreases in c-Myc Expression

Yekkala

Baudino

2007

Molecular Cancer Research

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The c-myc oncogene plays an important role in tumorigenesis and is frequently deregulated in many human cancers, including gastrointestinal cancers. In humans, mutations of the adenomatous polyposis coli (Apc) tumor suppressor gene occur in most colorectal cancers. Mutation of Apc leads to stabilization of B-catenin and increases in B-catenin target gene expression (c-myc and cyclin D1), whose precise functional significance has not been examined using genetic approaches. Apc Min/+ mice are a model of familial adenomatous polyposis and are heterozygous for an Apc truncation mutation. We have developed a model for examining the role of c-Myc in Apc-mediated tumorigenesis. We crossed c-myc +/À mice to Apc Min/+ to generate Apc Min/+ c-myc +/À animals. The compound Apc Min/+ c-myc +/À mice were used to evaluate the effect of c-myc haploinsufficiency on the Apc Min/+ phenotype. We observed a significant reduction in tumor numbers in the small intestine of Apc Min/+ c-myc +/À mice compared with control Apc Min/+ c-myc +/+ mice. In addition, we observed one to three polyps per colon in Apc Min/+ c-myc +/+ mice, whereas only two lesions were observed in the colons of Apc Min/+ mice that were haploinsufficient for c-myc. Moreover, reduction in c-myc levels resulted in a significant increase in the survival of these animals. Finally, we observed marked decreases in vascular endothelial growth factor, EphA2, and ephrin-B2 expression as well as marked decreases in angiogenesis in intestinal polyps in Apc Min/+ c-myc +/À mice. This study shows that c-Myc is critical for Apc-dependent intestinal tumorigenesis in mice and provides a potential therapeutic target in the treatment of colorectal cancer. (Mol Cancer Res 2007;5(12):1296 -303)

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Section: Reduction In C-myc Levels Correlates With a Decrease In The mentioning

confidence: 99%

Inhibition of Intestinal Polyposis with Reduced Angiogenesis in ApcMin/+ Mice Due to Decreases in c-Myc Expression

Yekkala

Baudino

2007

Molecular Cancer Research

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“…The Eph family of receptors constitutes the largest known family of tyrosine kinase receptors comprising not less than 14 members (Kullander and Klein, 2002;Poliakov et al, 2004). Expression of Eph receptors is highly tissue specific and modulated in various pathological situations including cancer (Brantley-Sieders et al, 2004;Surawska et al, 2004). To the best of our knowledge, a role of Eph receptors in leukemia cell differentiation has not yet been established.…”

Section: Arbitrary Unitmentioning

confidence: 99%

A survey of the signaling pathways involved in megakaryocytic differentiation of the human K562 leukemia cell line by molecular and c-DNA array analysis

et al. 2005

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The K562 cell line serves as a model to study the molecular mechanisms associated with leukemia differentiation. We show here that cotreatment of K562 cells with PMA and low doses of SB202190 (SB), an inhibitor of the p38 MAPK pathway, induced a majority of cells to differentiate towards the megakaryocytic lineage. Electronic microscopy analysis showed that K562 cells treated with PMA þ SB exhibited characteristic features of physiological megakaryocytic differentiation including the presence of vacuoles and demarcation membranes. Differentiation was also accompanied by a net increase in megakaryocytic markers and a reduction of erythroid markers, especially when both effectors were present. PMA effect was selectively mediated by new PKC isoforms. Differentiation of K562 cells by the combination of PMA and SB required Erk1/2 activation, a threshold of JNK activation and p38 MAPK inhibition. Interestingly, higher concentrations of SB, which drastically activated JNK, blocked megakaryocytic differentiation, and considerably increased cell death in the presence of PMA. c-DNA microarray membranes and PCR analysis allow us to identify a set of genes modulated during PMAinduced K562 cell differentiation. Several gene families identified in our screening, including ephrins receptors and some angiogenic factors, had never been reported so far to be regulated during megakaryocytic differentiation.

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“…It is now clear that the Eph molecules also play a role in adult tissues under physiological conditions and in disease states such as cancer. Eph RTKs and their ligands, the ephrins, are frequently overexpressed in different types of cancer (reviewed in Nakamoto and Bergmann, 2002;Brantley-Sieders et al, 2004b;Ireton and Chen, 2005). One family member in particular, the EphA2 receptor, has been linked to breast, prostate, lung and colon cancer, as well as melanoma (Ogawa et al, 2000;Walker-Daniels et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

A kinase-dependent role for EphA2 receptor in promoting tumor growth and metastasis

et al. 2005

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Receptor tyrosine kinases of the Eph family are upregulated in several different types of cancer. One family member in particular, the EphA2 receptor, has been linked to breast, prostate, lung and colon cancer, as well as melanoma. However, mechanisms by which EphA2 contributes to tumor progression are far from clear. In certain tumor cell lines, EphA2 receptor is underphosphorylated, raising the question of whether ligandinduced receptor phosphorylation and its kinase activity play a role in oncogenesis. To test directly the role of EphA2 receptor phosphorylation/kinase activity in tumor progression, we generated EphA2 receptor variants that were either lacking the cytoplasmic domain or carrying a point mutation that inhibits its kinase activity. Expression of these EphA2 mutants in breast cancer cells resulted in decreased tumor volume and increased tumor apoptosis in primary tumors. In addition, the numbers of lung metastases were significantly reduced in both experimental and spontaneous metastasis models. Reduced tumor volume and metastasis are not due to defects in tumor angiogenesis, as there is no significant difference in tumor vessel density between wild-type tumors and tumors expressing EphA2-signaling-defective mutants. In contrast, tumor cells expressing the EphA2 mutants are defective in RhoA GTPase activation and cell migration. Taken together, these results suggest that receptor phosphorylation and kinase activity of the EphA2 receptor, at least in part, contribute to tumor malignancy.

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Eph Receptor Tyrosine Kinases in Tumor and Tumor Microenvironment

Cited by 103 publications

References 0 publications

Inhibition of Intestinal Polyposis with Reduced Angiogenesis in ApcMin/+ Mice Due to Decreases in c-Myc Expression

Inhibition of Intestinal Polyposis with Reduced Angiogenesis in ApcMin/+ Mice Due to Decreases in c-Myc Expression

A survey of the signaling pathways involved in megakaryocytic differentiation of the human K562 leukemia cell line by molecular and c-DNA array analysis

A kinase-dependent role for EphA2 receptor in promoting tumor growth and metastasis

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