Immunolocalization of Criptoregulin and Amphiregulin in Rectal-Cancer - Correlation With Prognosis

Gagliardi, G.; Talbot, Ian C.; Northover, John; Warren, A.; Stamp, Gordon; Lalani, El–Nasir; Gullick, William J.; Pignatelli, Massimo

doi:10.3892/ijo.4.4.865

Cited by 7 publications

(13 citation statements)

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“…Staining for TGFa, AR and CR was mostly localized in the cytoplasm, although nuclear staining for AR was occasionally observed (Figure 4a, c and e). Para-nuclear staining of CR was also occasionally found, as previously described (Gagliardi et al, 1994). Staining with these antibodies could be blocked by pre-incubation with the corresponding recombinant protein (data not shown).…”

Section: Resultssupporting

confidence: 81%

“…Furthermore, AR protein is preferentially expressed in well dierentiated human primary colon carcinomas when compared with poorly dierentiated tumors . Nuclear localization of AR has been described in colon and breast carcinoma cell lines and human primary carcinomas (Ciardiello et al, 1991;Saeki et al, 1992;Johnson et al, 1992;Gagliardi et al, 1994;Normanno et al, 1993Normanno et al, , 1994. In this regard, AR possess a nuclear targeting sequence, and it has been shown that exogenously applied AR associates with nuclei in a time and concentration dependent fashion (Shoyab et al, 1989;Modrell et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

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Simultaneous blockade of different EGF-like growth factors results in efficient growth inhibition of human colon carcinoma xenografts

Luca¹,

Arra

D’Antonio

et al. 2000

Oncogene

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A majority of human colon carcinomas coexpress the epidermal growth factor (EGF)-related peptides transforming growth factor a (TGFa), amphiregulin (AR) and CRIPTO-1 (CR). We have synthesized novel, antisense mixed backbone oligonucleotides (AS MBOs) directed against TGFa, AR and CR. We screened the EGFrelated AS MBOs for their ability to inhibit the anchorage independent growth of GEO human colon carcinoma cells. The MBOs that showed a high in vitro ecacy were then used for in vivo experiments. TGFa, AR and CR AS MBOs were able to inhibit the growth of GEO tumor xenografts in nude mice in a dosedependent manner. Furthermore, the AS MBOs were able to speci®cally inhibit the expression of the target mRNAs and proteins in the tumor xenografts. A more signi®cant tumor growth inhibition was observed when mice were treated with a combination of the three AS MBOs as compared to treatment with a single AS MBO. Finally, tumors from mice treated with TGFa, AR and CR AS MBOs showed a signi®cant reduction of microvessel count, as compared with tumors from untreated mice or from mice treated with a single AS MBO. These data suggest that combinations of AS oligonucleotides directed against dierent growth factors might represent a novel, experimental therapy approach of colon carcinomas.

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Section: Resultssupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Simultaneous blockade of different EGF-like growth factors results in efficient growth inhibition of human colon carcinoma xenografts

Luca¹,

Arra

D’Antonio

et al. 2000

Oncogene

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“…CR-1 expression was also detected in 62% of normal colon mucosa specimens from individuals that belong to families with a high incidence of colorectal carcinomas, whereas only 20% of colon mucosa from low-risk patient specimens was positive for CR-1 (De Angelis et al, 1999). In an additional study, expression of CR-1 immunoreactivity in normal rectal mucosa adjacent to carcinoma was associated with an increase in the incidence of bowel wall penetration, lymph node involvement and a recurrence rate of 100% (Gagliardi et al, 1994). Therefore, the gradual increase in CR-1 expression that occurs in the multistage process that evolves from normal mucosa to premalignant lesions, and from premalignant lesions to carcinoma, suggests that CR-1 may be involved in the early events of carcinogenesis in different tissues.…”

Section: In Vivo Tumorigenesis Induced By Cripto-1mentioning

confidence: 85%

Cripto-1: a multifunctional modulator during embryogenesis and oncogenesis

et al. 2005

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It is increasingly evident that genes known to perform critical roles during early embryogenesis, particularly during stem cell renewal, pluripotentiality and survival, are also expressed during the development of cancer. In this regard, oncogenesis may be considered as the recapitulation of embryogenesis in an inappropriate temporal and spatial manner. The epidermal growth factor-Cripto-1/FRL1/cryptic family of proteins consists of extracellular and cell-associated proteins that have been identified in several vertebrate species. During early embryogenesis, epidermal growth factor-Cripto-1/FRL1/ cryptic proteins perform an obligatory role as coreceptors for the transforming growth factor-beta subfamily of proteins, which includes Nodal. Cripto-1 has also been shown to function as a ligand through a Nodal/Alk4-independent signaling pathway that involves binding to glypican-1 and the subsequent activation through src of phosphoinositol-3 kinase/Akt and ras/mitogen-activated protein kinase intracellular pathways. Expression of Cripto-1 is increased in several human cancers and its overexpression is associated with the development of mammary tumors in mice. Here, we review the role of Cripto-1 during embryogenesis, cell migration, invasion and angiogenesis and how these activities may relate to cellular transformation and tumorigenesis. We also briefly discuss evidence suggesting that Cripto-1 may be involved in stem cell maintenance.

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“…CR-1 immunoreactivity has been detected in 71% of primary rectal carcinomas and in 37% of normal rectal mucosa adjacent to carcinoma (Gagliardi et al 1994). Interestingly, tumors with CR-1 immunoreactivity extending to the adjacent normal mucosa showed an increase in the incidence of bowel wall penetration, lymph node involvement and a recurrence rate of 100%, suggesting a correlation between CR-1 immunoreactivity in the normal adjacent colon mucosa and prognosis and survival of rectal tumors.…”

Section: Rectal Cancermentioning

confidence: 99%

The EGF-CFC family: novel epidermal growth factor-related proteins in development and cancer.

Saloman

Bianco

Ebert

et al. 2000

Endocrine-Related Cancer

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112

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The EGF-CFC gene family encodes a group of structurally related proteins that serve as important competence factors during early embryogenesis in Xenopus, zebrafish, mice and humans. This multigene family consists of Xenopus FRL-1, zebrafish one-eyed-pinhead (oep), mouse cripto (Cr-1) and cryptic, and human cripto (CR-1) and criptin. FRL-1, oep and mouse cripto are essential for the formation of mesoderm and endoderm and for correct establishment of the anterior/ posterior axis. In addition, oep and cryptic are important for the establishment of left-right (L/R) asymmetry. In zebrafish, there is strong genetic evidence that oep functions as an obligatory co-factor for the correct signaling of a transforming growth factor-β (TGFβ)-related gene, nodal, during gastrulation and during L/R asymmetry development. Expression of Cr-1 and cryptic is extinguished in the embryo after day 8 of gestation except for the developing heart where Cr-1 expression is necessary for myocardial development. In the mouse, cryptic is not expressed in adult tissues whereas Cr-1 is expressed at a low level in several different tissues including the mammary gland. In the mammary gland, expression of Cr-1 in the ductal epithelial cells increases during pregnancy and lactation and immunoreactive and biologically active Cr-1 protein can be detected in human milk. Overexpression of Cr-1 in mouse mammary epithelial cells can facilitate their in vitro transformation and in vivo these Cr-1-transduced cells produce ductal hyperplasias in the mammary gland. Recombinant mouse or human cripto can enhance cell motility and branching morphogenesis in mammary epithelial cells and in some human tumor cells. These effects are accompanied by an epithelial-mesenchymal transition which is associated with a decrease in β-catenin function and an increase in vimentin expression. Expression of cripto is increased several-fold in human colon, gastric, pancreatic and lung carcinomas and in a variety of different types of mouse and human breast carcinomas. More importantly, this increase can first be detected in premalignant lesions in some of these tissues. Although a specific receptor for the EGF-CFC proteins has not yet been identified, oep depends upon an activin-type RIIB and RIB receptor system that functions through Smad-2. Mouse and human cripto have been shown to activate a ras/raf/MAP kinase signaling pathway in mammary epithelial cells. Activation of phosphatidylinositol 3-kinase and Akt are also important for the ability of CR-1 to stimulate cell migration and to block lactogenic hormone-induced expression of β-casein and whey acidic protein.In mammary epithelial cells, part of these responses may depend on the ability of CR-1 to transactivate erb B-4 and/or fibroblast growth factor receptor 1 through an src-like tyrosine kinase.

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Immunolocalization of Criptoregulin and Amphiregulin in Rectal-Cancer - Correlation With Prognosis

Cited by 7 publications

References 0 publications

Simultaneous blockade of different EGF-like growth factors results in efficient growth inhibition of human colon carcinoma xenografts

Simultaneous blockade of different EGF-like growth factors results in efficient growth inhibition of human colon carcinoma xenografts

Cripto-1: a multifunctional modulator during embryogenesis and oncogenesis

The EGF-CFC family: novel epidermal growth factor-related proteins in development and cancer.

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