Dysadherin: A new player in cancer progression

doi:10.1016/j.canlet.2007.02.018

Cancer Letters

Volume 255, Issue 2, 8 October 2007, Pages 161-169

https://doi.org/10.1016/j.canlet.2007.02.018 Get rights and content

Abstract

Dysadherin is a cancer-associated cell membrane glycoprotein that promotes experimental cancer metastasis. Here we review recent work that has provided insights into possible mechanisms of action of this newly recognized player in the cancer progression process. Dysadherin modulates cell phenotype in a number of ways, including down-regulation of E-cadherin-mediated cell adhesion, and up-regulation of chemokine production. In this way, expression of dysadherin in a tumor can influence both the tumor cell itself and the stromal compartment, so as to create conditions that are more permissive for metastatic spread. Dysadherin expression is also an independent prognostic indicator of metastasis and survival for many different types of human cancer. Thus, dysadherin may represent a new molecular target for the visualization, prevention or treatment of advanced cancer.

Introduction

One major goal of cancer research is to identify molecules that are differentially expressed in tumors compared with normal tissues. If these molecules are causally involved in sustaining or promoting tumorigenesis, they represent potential molecular targets for the development of novel therapeutics. If they are merely associated with the tumorigenic process rather than driving it, differentially expressed molecules on the surface of the cancer cell can still be exploited for directing therapeutics or imaging agents specifically to the tumor cell. Dysadherin is a cell surface molecule that was recently identified as the target of a monoclonal antibody that was developed to selectively react with a wide variety of cancer cells, but relatively few normal cells [1]. In this original study, dysadherin was found to promote experimental metastasis, and dysadherin expression correlated with poor prognosis in a small cohort of breast cancer patients, suggesting a causal role for the newly discovered molecule in tumor progression. The aim of the present review is to discuss recent evidence implicating dysadherin as a key player in cancer progression, to address likely mechanisms of action, and to discuss the clinical significance of dysadherin expression in different types of cancer.

Section snippets

Dysadherin structure, distribution and regulation

Dysadherin was originally identified by immunoscreening of a cDNA expression library to find the molecular target of a monoclonal antibody, NCG-3G10, that bound primarily to cancer and not to normal cell lines [1]. Sequence analysis showed that human dysadherin was closely related to the mouse gene RIC (related to ion channels). Dysadherin is now known to be identical to FXYD5 (Fxyd domain containing ion transport regulator 5), the human homolog of RIC. FXYD5 is a structurally divergent member

The role of dysadherin in cancer progression: experimental evidence

Following the cloning of dysadherin, preliminary functional analysis showed that transfection of a liver cancer cell line with the cDNA of dysadherin resulted in reduced cell–cell adhesiveness in vitro and enhanced the formation of intrahepatic metastases following intrasplenic injection of the transfectants in vivo[1]. Similarly, overexpression of dysadherin in Capan-1 human pancreatic cells promoted metastasis [8], while knockdown of dysadherin in the MDA-MB-231 human breast cancer cell line

Pathological studies

E-cadherin plays a critical role in establishing and maintaining the polarity and histological structure of cells, and dysfunction of the E-cadherin-mediated cell adhesion system results in progression of the relatively benign tumor to invasive, metastatic carcinoma [18]. In the original paper describing the discovery of dysadherin as a regulator of E-cadherin and promoter of metastasis, dysadherin expression correlated with poor survival in a small cohort of patients with stage II breast

Unsolved issues in dysadherin biology

From this promising beginning, there is still much to be learned about the role of dysadherin in cancer progression. Currently we need more information on (1) what proteins interact with dysadherin, (2) whether dysadherin can propagate signals within the cell, (3) the detailed molecular mechanisms by which dysadherin regulates E-cadherin, CCL2 and other players that modify the metastatic phenotype, and (4) the regulation of dysadherin expression, including the possible role of

Conclusions and perspectives for the future

Collectively, both clinical and experimental data suggest that overexpression of dysadherin may contribute causally to tumor progression and metastasis, and dysadherin is an independent prognostic indicator of metastasis and/or poor survival in many different cancer types. The expression of dysadherin on normal tissues is somewhat broader than originally anticipated, with significant expression in the kidney, lung and duodenum, as well as in advanced cancers. Thus, while dysadherin is

Acknowledgements

We thank Ethan A. Kohn for critical reading of the manuscript. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute.

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The fifth member of the family, the FXY5, is also called dysadherin (cell surface molecule) because of the identical cDNA sequence. In scientific literature, dysadherin is commonly called FXYD5/dysadherin and is a unique member of the FXYD family with an extended extracellular O-glycosylated domain [99,100] (Table 1). FXYD5/dysadherin is expressed in normal cells and cancer cells associated with worse prognosis and metastatic cancers [101,102].
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Published by Elsevier Ireland Ltd.

Mini-reviewDysadherin: A new player in cancer progression

Abstract

Introduction

Section snippets

Dysadherin structure, distribution and regulation

The role of dysadherin in cancer progression: experimental evidence

Pathological studies

Unsolved issues in dysadherin biology

Conclusions and perspectives for the future

Acknowledgements

J. Biol. Chem.

Semin. Cancer Biol.

Blood

Am. J. Pathol.

J. Thorac. Cardiovasc. Surg.

Lancet

Cancer Cell

J. Biol. Chem.

J. Biol. Chem.

Dysadherin, a cancer-associated cell membrane glycoprotein, down-regulates E-cadherin and promotes metastasis

Proc. Natl. Acad Sci. USA

FXYD proteins: new regulators of Na-K-ATPase

Am. J. Physiol. Renal Physiol.

Aberrant O-glycosylation inhibits stable expression of dysadherin, a carcinoma-associated antigen, and facilitates cell–cell adhesion

Glycobiology

E2a-Pbx1 induces aberrant expression of tissue-specific and developmentally regulated genes when expressed in NIH 3T3 fibroblasts

Mol. Cell Biol.

Oncogenic pathway signatures in human cancers as a guide to targeted therapies

Nature

Global genechip profiling to identify genes responsive to p53-induced growth arrest and apoptosis in human lung carcinoma cells

Cancer Biol. Ther.

Dysadherin expression facilitates cell motility and metastatic potential of human pancreatic cancer cells

Cancer Res.

Chemokine (C–C motif) ligand 2 mediates the prometastatic effect of dysadherin in human breast cancer cells

Cancer Res.

Establishment of two cell lines from human gastric scirrhous carcinoma that possess the potential to metastasize spontaneously in nude mice

Cancer Sci.

Cell adhesion system and human cancer morphogenesis

Cancer Sci.

Mini-review
Dysadherin: A new player in cancer progression