Carcinoembryonic Antigen Inhibits Anoikis in Colorectal Carcinoma Cells by Interfering with Trail-R2 (DR5) Signaling

Samara, Raed; Laguinge, Luciana M.; Jessup, J. Milburn

doi:10.1158/0008-5472.can-06-4315

Cited by 55 publications

(59 citation statements)

References 46 publications

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“…Elevated serum levels of CEA are clinically associated with induction of metastasis and suppression of anoikis, a form of apoptosis caused by detachment from extracellular matrices, in colorectal carcinomas (28). CEA shows a diffuse-cytoplasmic expression pattern rather than an apicoluminal pattern in more invasive and metastatic neoplastic cells of colorectal tumors (22).…”

Section: Discussionmentioning

confidence: 99%

Differential expression of the LOX family genes in human colorectal adenocarcinomas

Kim

2009

Oncol Rep

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Abstract. Lysyl oxidase (LOX) is an amine oxidase that catalyzes the cross-linking of collage or elastin in the extracellular matrix, regulating the tensile strength and structural integrity of connective tissues. Recently, four paralogues (LOXL, LOXL2, LOXL3 and LOXL4) of LOX have been identified in humans, each containing the functional domains required for the amine oxidase activity toward collagen and elastin. Paradoxical roles of the LOX family members have been reported in various neoplastic tissues as tumor suppressors or promoters depending on tumor status and type. To address expression of the LOX family genes in colorectal adenocarcinomas, we performed real-time PCR analysis with matched tumor/normal tissue specimens from 104 patients. The expression of the LOX family genes was not statistically associated with tumor location, stage, growth type, or differentiation status. However, upregulation of LOX, LOXL2 and LOXL4 was significantly correlated with absence of lymphovascular invasion (P=0.012, 0.014 and 0.005, respectively), suggesting that the oxygen tension in or around the tumors may be an important regulator for the differential expression of LOX, LOXL2 and LOXL4 in colorectal cancer. Additionally, expression of LOX, but not the other LOX family genes, was significantly upregulated in patients with a diffuse cytoplasmic expression pattern of CEA, indicating that LOX upregulation may be associated with increased invasiveness and metastatic potential in colorectal cancer.

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Section: Discussionmentioning

confidence: 99%

Differential expression of the LOX family genes in human colorectal adenocarcinomas

Kim

2009

Oncol Rep

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“…In colorectal cancers in partnership with CEA, hnRNP M may also play a role in the regulation of anoikis a form of apoptosis caused by detachment from the extra-cellular matrix [70][71][72][73]. This may also be a survival mechanism during metastasis.…”

Section: The Cea Receptor (Cear)mentioning

confidence: 99%

“…The mechanism of CEA inhibition of anoikis occurs by CEA binding to the death receptor DR-5 and reducing caspase 8 activity. This binding requires the PELPK sequence and therefore suggests that hnRNP M4 may also be involved though the details of this interaction are not known [73]. HnRNP M4 is a ubiquitous multifunctional protein in mammals and in general is localized to the nucleus: there is also evidence that it can shuttle between the nucleus and cytoplasm carrying RNA [74,75].…”

Section: The Cea Receptor (Cear)mentioning

confidence: 99%

“…Recent studies have shown a direct relationship between CEA and TRAIL-R2 signaling causing a decrease in anoikis. Although the involvement of hnRNP M in this mechanism has not been proven [73]. Using site-directed mutagenesis Samara et al showed that the interaction requires the PELPK signaling motif [73].…”

Section: Cea and Liver Metastasismentioning

confidence: 99%

“…Although the involvement of hnRNP M in this mechanism has not been proven [73]. Using site-directed mutagenesis Samara et al showed that the interaction requires the PELPK signaling motif [73]. Thus the requirement of the PELPK motif suggests that hnRNP M together with CEA interacts with the TRAIL-R2 signaling pathway.…”

Section: Cea and Liver Metastasismentioning

confidence: 99%

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Carcinoembryonic antigen (CEA) and its receptor hnRNP M are mediators of metastasis and the inflammatory response in the liver

Thomas

Forse

Bajenova

2011

Clin Exp Metastasis

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This article discusses the role of carcinoembryonic antigen (CEA) as a facilitator of the inflammatory response and its effect on colorectal cancer hepatic metastasis. Colorectal cancer accounts for 11% of all cancers in the United States and the majority of deaths are associated with liver metastasis. If left untreated, median survival is only six to 12 months. Resection of liver metastases offers the only chance for cure. Of the small number of patients who have operable cancer most will have further tumor recurrence. The molecular mechanisms associated with colorectal cancer metastasis to the liver are largely unknown. However CEA production has been shown both clinically and experimentally to be a factor in an increased metastatic potential of colorectal cancers to the liver. CEA also has a role in protecting tumor cells from the effects of anoikis and this affords a selective advantage for tumor cell survival in the circulation. CEA acts in the liver through its interaction with its receptor (CEAR), a protein that is related to the hnRNP M family of RNA binding proteins. In the liver CEA binds with hnRNP M on Kupffer cells and causes activation and production of pro- and anti-inflammatory cytokines including IL-1, IL-10, IL-6 and TNF-α. These cytokines affect the up-regulation of adhesion molecules on the hepatic sinusoidal endothelium and protect the tumor cells against cytotoxicity by nitric oxide (NO) and other reactive oxygen radicals. HnRNP M signaling in Kupffer cells appears to be controlled by beta-adrenergic receptor activation. The cells will respond to the β-adrenergic receptor agonist terbutaline resulting in reduced TNF-α and increased IL-10 and IL-6 production following CEA activation. This has implications for the control of tumor cell implantation and survival in the liver.

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A focused immune response targeting the homotypic binding domain of the carcinoembryonic antigen blocks the establishment of tumor foci in vivo

Abdul-Wahid

Huang

et al. 2012

Intl Journal of Cancer

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Metastatic forms of cancers remain the main cause of death in cancer patients. In this study, we demonstrate that directing a sustained antibody response towards the homotypic binding function of CEA interferes with the implantation and development of tumor foci in CEA-expressing transgenic (CEA.Tg) mice. Specifically, vaccinating CEA.Tg mice with a recombinant, altered self-form of the CEA Ig V-like N domain led to the production of circulating IgG1 and IgG2a antibodies that inhibited CEAmediated adhesion of murine carcinoma expressing CEA (MC38.CEA) and mediated antibody-dependent lysis of tumor cells. Moreover, vaccinated CEA.Tg mice were resistant to the development of tumor nodules in the lungs and the peritoneal cavity, suggesting that mounting a focused antibody response to the CEA N domain may represent a simple therapeutic strategy to control the establishment of metastatic foci in cancer patients.There remains a strong need to develop therapies aimed at blocking or preventing the formation of metastatic tumor foci in cancer patients, in light of the fact that most cancer deaths are accounted for by patients with metastatic disease. Aberrantly expressed surface antigens, involved in intercellular adhesion, represent suitable targets for developing antiadhesive or antiaggregative therapies. One such surface marker is the carcinoembryonic antigen (CEA, CEACAM5 and CD66e), a GPI-linked glycoprotein linked to cell transformation and metastasis. CEA is frequently over-expressed on epithelial carcinomas of the intestinal and respiratory tracts, as well as cancers of the breast, pancreas, stomach and ovary. [1][2][3][4][5] From a clinical perspective, high preoperative serum concentrations of CEA correlate with metastasis, treatment failure and poor overall prognosis.6-10 Specifically, a recent prospective study of CEA levels in the serum of 2,062 breast cancer patients has revealed that a CEA level >7.5 lg/L is associated with a high probability of subclinical metastases and a significant reduction in disease free and overall survival rates. 11The association of CEA with cancer progression has led to its use as an immunogen in designing anticancer vaccines. 2,5 Mechanistically, the intercellular homophilic binding property of CEA correlates with cancer invasion and metastasis. 5,[12][13][14] CEA is composed of seven extracellular Ig-like domains

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Carcinoembryonic Antigen Inhibits Anoikis in Colorectal Carcinoma Cells by Interfering with Trail-R2 (DR5) Signaling

Cited by 55 publications

References 46 publications

Differential expression of the LOX family genes in human colorectal adenocarcinomas

Differential expression of the LOX family genes in human colorectal adenocarcinomas

Carcinoembryonic antigen (CEA) and its receptor hnRNP M are mediators of metastasis and the inflammatory response in the liver

A focused immune response targeting the homotypic binding domain of the carcinoembryonic antigen blocks the establishment of tumor foci in vivo

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