Regression of Early and Intermediate Stages of Colon Cancer by Targeting Multiple Members of the EGFR Family with EGFR-Related Protein

Schmelz, Eva M.; Hu, Xu; Sengupta, Radha; Du, Jianhua; Banerjee, Sanjeev; Sarkar, Fazlul H.; Rishi, Arun K.; Majumdar, Adhip P.N.

doi:10.1158/0008-5472.can-07-0536

Cited by 20 publications

(13 citation statements)

References 44 publications

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“…Unlike blocking of EGFR signaling, ERBB3 deficiency in mice results in a significant reduction in the average size of the remaining tumors. Our results, albeit more striking, are similar to the concomitant reduction in tumor number and size by treatment with EGFR-related protein (ERRB), which is thought to function as a pan-ERBB inhibitor (37), suggesting that ERBB3 may be the important target for ERRB.…”

Section: Discussionsupporting

confidence: 75%

Tumor-specific apoptosis caused by deletion of the ERBB3 pseudo-kinase in mouse intestinal epithelium

Lee¹,

Yu²,

Lee³

et al. 2009

J. Clin. Invest.

109

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Pharmacologic blockade of EGFR or the closely related receptor ERBB2 has modest efficacy against colorectal cancers in the clinic. Although the upregulation of ERBB3, a pseudo-kinase member of the EGFR/ERBB family, is known to contribute to EGFR inhibitor resistance in other cancers, its functions in normal and malignant intestinal epithelium have not been defined. We have shown here that the intestinal epithelium of mice with intestine-specific genetic ablation of Erbb3 exhibits no cytological abnormalities but does exhibit loss of expression of ERBB4 and sensitivity to intestinal damage. By contrast, intestine-specific Erbb3 ablation resulted in almost complete absence of intestinal tumors in the Apc Min mouse model of colon cancer. Unlike nontransformed epithelium lacking ERBB3, intestinal tumors lacking ERBB3 had reduced PI3K/ AKT signaling, which led to attenuation of tumorigenesis via a tumor-specific increase in caspase-3-mediated apoptosis. Consistent with the mouse data, which suggest that ERBB3-ERBB4 heterodimers contribute to colon cancer survival, experimentally induced loss of ERBB3 in a KRAS mutant human colon cancer cell line was associated with loss of ERBB4 expression, and siRNA knockdown of either ERBB3 or ERBB4 resulted in elevated levels of apoptosis. These results indicate that the ERBB3 pseudo-kinase has essential roles in supporting intestinal tumorigenesis and suggest that ERBB3 may be a promising target for the treatment of colorectal cancers.

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Section: Discussionsupporting

confidence: 75%

Tumor-specific apoptosis caused by deletion of the ERBB3 pseudo-kinase in mouse intestinal epithelium

Lee¹,

Yu²,

Lee³

et al. 2009

J. Clin. Invest.

109

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“…Interestingly, in mammalian cell culture, ERRP negatively regulates EGFR cell proliferation activity (Yu et al, 2001) and can be an effective therapeutic agent for prostate (Marciniak et al, 2004) and colon cancer models, the latter of which is suggested to occur via sequestration of EGFR ligand TGF-α (Schmelz et al, 2007). There is no clear human ERRP homolog (Reiter et al, 2006), but, by analogy to C. elegans studies, a protein functionally related to mouse ERRP or fly Argos might influence the maintenance of aging tissues in other organisms.…”

Section: Perspectivesmentioning

confidence: 99%

EGF signaling comes of age: Promotion of healthy aging in C. elegans

Yu¹,

Driscoll²

2011

Experimental Gerontology

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More than 400 genes have been noted to modulate C. elegans longevity. Recent studies testing the role of proposed secreted insulin binding proteins unexpectedly revealed a potent role for the EGF signaling pathway in promoting healthy aging and longevity in C. elegans. Activation of EGF receptor LET-23 is associated with increased mean and maximum lifespan, maintained pharyngeal pumping, extended locomotory function, and low lipofuscin and advanced glycation end product accumulation. Conversely, reducing the activity of the EGF pathway is associated with system-wide evidence of progeria. The EGF pathway appears to work in a manner largely independent of the insulin/IGF-like pathway, in that effects are additive with reduction of DAF-2/InsR activity and are not affected by DAF-16/FOXO transcription factor deficiency. Two novel regulators of EGF signaling, called HPA-1 and HPA-2 (for the high performance in old age locomotory phenotypes that their disruption confers), negatively regulate EGF action, possibly by binding and sequestering EGF. Interestingly, whereas HPA-1 appears to control aging of the animal overall, HPA-2 exerts an effect primarily on locomotory aging. As such, HPA-2 is an example of a protein with an effect on healthspan but not lifespan, a gene class that may have been missed in screens focused on longevity endpoint. To date, roles for EGF signaling in adult maintenance (particularly in non-dividing tissues) have not been addressed in other organisms—should EGF signaling exert a conserved impact on healthy aging, testing this hypothesis could hold implications for anti-aging therapies.

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“…In general, the molecular mechanisms that control CRC progression are related to the altered expression of different proto-oncogenes, tumor suppressor genes, cytokines and their receptors, including Ras, Src, p27 kip1 , p16 ink4a , interleukin (IL) and the epidermal growth factor receptor (EGFR). [1][2][3][4][5][6][7] Notably, these abnormalities involve the signal transducers and activators of transcription (STAT) signaling pathway, specifically STAT3 and STAT5 signaling, although very few studies have reported the abnormal expression or activation of STAT proteins in colorectal cancer. 8 Understanding the molecular mechanisms of STATs may further the development of novel therapies targeted in CRC treatment.…”

mentioning

confidence: 99%

Inhibition of STAT5 induces G1 cell cycle arrest and reduces tumor cell invasion in human colorectal cancer cells

Xiong

Liang

et al. 2009

Laboratory Investigation

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Abnormalities in the signal transducer and activator of transcription (STAT) pathway are involved in the oncogenesis of several cancers. However, the mechanism by which dysregulated STAT5 signaling contributes to the progression of human colorectal cancer (CRC) has not been elucidated. To investigate the role of STAT5 in CRC progression, we depleted STAT5 with a small interfering RNA (siRNA). Our results demonstrate that STAT5 is involved in CRC cell growth, cell cycle progression, invasion and migration through regulation of gene expression, such as Bcl-2, p16 ink4a , p21 waf1/cip1 , p27 kip1 , E-cadherin, the focal adhesion kinase (FAK), vascular endothelial growth factor (VEGF) and matrix metalloproteinases. In addition, immunohistochemical staining reveals upregulation of STAT5 during CRC tumorigenesis. Moreover, phospho-STAT5 (pSTAT5) is predominantly localized in the cytoplasm of adenomas cells and colon adenocarcinoma cells, but primarily presented in the nucleus of normal colonic epithelium cells. Thus, pSTAT5 protein is shuttled from the nucleus to the cytoplasm in the oncogenesis of CRC, suggesting that activated STAT5 may also have cytoplasmic functions. In support of this hypothesis, we found that STAT5 formed a complex with p44/42 MAPK and SAPK/JNK in CRC cells, suggesting cross talk between STAT5 signaling and the MAPK pathway in the development of human CRC. Our findings illustrate the biological significance of STAT5 signaling in CRC progression, and provide novel evidence that intervention in STAT5 signaling may have potential therapeutic value in the prevention of human colorectal cancer.

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Regression of Early and Intermediate Stages of Colon Cancer by Targeting Multiple Members of the EGFR Family with EGFR-Related Protein

Cited by 20 publications

References 44 publications

Tumor-specific apoptosis caused by deletion of the ERBB3 pseudo-kinase in mouse intestinal epithelium

Tumor-specific apoptosis caused by deletion of the ERBB3 pseudo-kinase in mouse intestinal epithelium

EGF signaling comes of age: Promotion of healthy aging in C. elegans

Inhibition of STAT5 induces G1 cell cycle arrest and reduces tumor cell invasion in human colorectal cancer cells

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