Epidermal Growth Factor Receptor Signaling Is Up-regulated in Human Colonic Aberrant Crypt Foci

Cohen, Guy; Mustafi, Reba; Chumsangsri, Anusara; Little, Nathaniel; Nathanson, Jeff; Cerda, Sonia R.; Jagadeeswaran, Sujatha; Dougherty, Urszula; Joseph, Loren; Hart, John; Yerian, Lisa; Tretiakova, Maria; Yuan, Weiping; Obara, Piotr; Khare, Sharad; Sinicrope, Frank A.; Fichera, Alessandro; Boss, Gerry R.; Carroll, Robert E.; Bissonnette, Marc

doi:10.1158/0008-5472.can-05-0308

Cited by 49 publications

(54 citation statements)

References 43 publications

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“…EGFR is a member of the HER family of receptor tyrosine kinases and is overexpressed in a broad range of tumors, including pancreatic and colon cancer. Like APP, this cell surface receptor plays important roles in growth control, and increased expression has been associated with increased cellular proliferation (71,72). Our results demonstrate that EGFR levels were not altered by treatment with HDAC inhibitors.…”

Section: ␤-Amyloid Precursor Protein Is a Tumor Growth Factormentioning

confidence: 56%

Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein

Venkataramani

Roßner

Iffland

et al. 2010

Journal of Biological Chemistry

107

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The ␤-amyloid precursor protein (APP) represents a type I transmembrane glycoprotein that is ubiquitously expressed. In the brain, it is a key player in the molecular pathogenesis of Alzheimer disease. Its physiological function is however less well understood. Previous studies showed that APP is up-regulated in prostate, colon, pancreatic tumor, and oral squamous cell carcinoma. In this study, we show that APP has an essential role in growth control of pancreatic and colon cancer. Abundant APP staining was found in human pancreatic adenocarcinoma and colon cancer tissue. Interestingly, treating pancreatic and colon cancer cells with valproic acid (VPA, 2-propylpentanoic acid), a known histone deacetylase (HDAC) inhibitor, leads to up-regulation of GRP78, an endoplasmic reticulum chaperone immunoglobulin-binding protein. GRP78 is involved in APP maturation and inhibition of tumor cell growth by down-regulation of APP and secreted soluble APP␣. Trichostatin A, a pan-HDAC inhibitor, also lowered APP and increased GRP78 levels. In contrast, treating cells with valpromide, a VPA derivative lacking HDAC inhibitory properties, had no effect on APP levels. VPA did not modify the level of epidermal growth factor receptor, another type I transmembrane protein, and APLP2, a member of the APP family, demonstrating the specificity of the VPA effect on APP. Small interfering RNA-mediated knockdown of APP also resulted in significantly decreased cell growth. Based on these observations, the data suggest that APP downregulation via HDAC inhibition provides a novel mechanism for pancreatic and colon cancer therapy. ␤-Amyloid precursor protein (APP)2 is a highly conserved single transmembrane protein (type I) with a receptor-like structure and consists of a heterogeneous group of proteins migrating between 110 and 135 kDa (1, 2). The heterogeneity is due to alternative splicing, leading to eight distinct isoforms (namely APP677, APP695, APP696, APP714, APP733, APP751, APP752, and APP770), as well as by a variety of post-translational modifications, including O-and N-glycosylation, sulfation, and phosphorylation. APP isoforms exist as immature (N-glycosylated) and mature (N-and O-glycosylated, tyrosylsulfated) species. Immature APP localizes in the endoplasmic reticulum and cis-Golgi, and the mature APP form preferentially localizes in the trans-Golgi network, secretory and endocytic vesicles, and at the plasma membrane (3, 4).APP695 is the most common isoform in the central nervous system, whereas APP751 and APP770 are predominantly expressed in non-neuronal cells (5). The key event in the pathogenic cascade in Alzheimer disease is the amyloidogenic pathway characterized by subsequent cleavage of APP by the enzyme ␤-secretase and further processing by ␥-secretase, which finally leads to the generation of A␤ peptides. However, the predominant route of APP processing consists of successive cleavages by ␣-and ␥-secretases in non-neuronal cells (6, 7). The cleavage of APP at Lys 16 -Leu 17 bond by ␣-secretase within the A␤ sequence ...

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Section: ␤-Amyloid Precursor Protein Is a Tumor Growth Factormentioning

confidence: 56%

Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein

Venkataramani

Roßner

Iffland

et al. 2010

Journal of Biological Chemistry

107

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“…Our laboratory has previously shown that EGFR signals are up-regulated in human ACF, the earliest microscopically detectable premalignant lesions in the colon (2). More recently, we showed that EGFR signals promote premalignant progression in azoxymethane-treated mice (9).…”

Section: Discussionmentioning

confidence: 73%

“…Growing lines of evidence have also emphasized the importance of EGFR signals in colonic carcinogenesis (1,2,9). Signals from this receptor are known to regulate many biological processes, including cell survival, growth, differentiation, motility, and angiogenesis (4).…”

Section: Discussionmentioning

confidence: 99%

“…Up-regulations of EGFRs and ligands have been described in many tumors, including colon cancers (1). Recently, we reported that EGFR signals were up-regulated in human aberrant crypt foci (ACF) identified in situ using image magnification chromoendoscopy (2). ACF are the earliest identifiable lesions in experimental colonic carcinogenesis and dysplastic ACF are believed to be precursors of colon cancer (3).…”

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confidence: 99%

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Epidermal Growth Factor Receptor Controls Flat Dysplastic Aberrant Crypt Foci Development and Colon Cancer Progression in the Rat Azoxymethane Model

Dougherty

Sehdev

Cerda

et al. 2008

Clinical Cancer Research

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Purpose: Colonic carcinogenesis deranges growth-regulating epidermal growth factor receptors (EGFR). We previously showed that EGFR signals were up-regulated in human aberrant crypt foci (ACF), putative colon cancer precursors. The azoxymethane model of colon cancer recapitulates many aspects of human colonic tumors. Recent studies indicate that flat dysplastic ACF with increased h-catenin are tumor precursors in this model. We asked, therefore, if EGFR signals are required for flat dysplastic ACF development and cancer progression. Experimental Design: Rats received azoxymethane or saline, and standard chow or chow supplemented with gefitinib, an EGFR inhibitor, for 44 weeks. EGFR signals were quantified in normal colon, flat ACF, and tumors by computerized analysis of immunostains and Western blots. K-ras mutations were assessed by PCR and mRNA for egfr ligands by quantitative real-time PCR. Results: EGFR inhibition with gefitinib decreased the incidence of flat dysplastic ACF from 66% to 36% and tumors from 71% to 22% (P < 0.05). This inhibitor also reduced the overexpressions of cyclin D1 and Cox-2 in flat ACF. Furthermore, in flat ACF, EGFR blockade decreased the upregulation of c-Jun, FosB, phosphorylated active signal transducers and activators of transcription 3, and CCAAT/enhancer binding protein-h, potential regulators of cyclin D1 and Cox-2. In colonic tumors, EGFR blockade significantly decreased angiogenesis, proliferation, and progression while also increasing apoptosis (P < 0.05). Gefitinib also inhibited the activations of extracellular signal^regulated kinase, Src, and AKT pathways in tumors. Conclusions: We have shown for the first time that EGFR promotes the development of flat dysplastic ACF and the progression of malignant colonic tumors. Furthermore, we have mechanistically identified several transcription factors and their targets as EGFR effectors in colonic carcinogenesis.Colonic carcinogenesis is characterized by the accumulation of activating mutations in proto-oncogenes and inhibiting mutations in tumor suppressor genes. These mutations dysregulate pathways, including epidermal growth factor receptor (EGFR) signals that control cell growth, maturation, and cell death. Up-regulations of EGFRs and ligands have been described in many tumors, including colon cancers (1). Recently, we reported that EGFR signals were up-regulated in human aberrant crypt foci (ACF) identified in situ using image magnification chromoendoscopy (2). ACF are the earliest identifiable lesions in experimental colonic carcinogenesis and dysplastic ACF are believed to be precursors of colon cancer (3).EGFR (ErbB1) is a member of the ErbB family of receptor tyrosine kinases which also includes ErbB2, ErbB3, and ErbB4 (4). Ligand binding induces a conformational change, causing receptors to dimerize and activating the receptor's intrinsic tyrosine kinase. ErbB2 is unique in that it has no identified ligand, but is the preferred heterodimeric partner for other members. EGFR signals activate multiple pathways i...

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“…However, a major criticism of this approach is that EGFR activation might accelerate tumorigenesis (29). Indeed, EGFR is widely considered a tumor promoter; its expression or activation is increased in many colonic precancerous lesions and tumors (30)(31)(32), and EGFR is implicated in animal models of gastrointestinal tumorigenesis (25,(33)(34)(35)(36). Moreover, EGFR monoclonal antibodies are approved for metastatic colorectal cancer treatment (cetuximab and panitumumab) (37).…”

Section: Introductionmentioning

confidence: 99%

Epidermal growth factor receptor inhibits colitis-associated cancer in mice

Dubé¹,

Yan²,

Punit³

et al. 2012

J. Clin. Invest.

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Epidermal Growth Factor Receptor Signaling Is Up-regulated in Human Colonic Aberrant Crypt Foci

Cited by 49 publications

References 43 publications

Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein

Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein

Epidermal Growth Factor Receptor Controls Flat Dysplastic Aberrant Crypt Foci Development and Colon Cancer Progression in the Rat Azoxymethane Model

Epidermal growth factor receptor inhibits colitis-associated cancer in mice

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