Plasma Membrane Proteomics and Its Application in Clinical Cancer Biomarker Discovery

Henrik J Ditzel,Rikke R Lund,Rikke Leth-Larsen

doi:10.1074/mcp.r900006-mcp200

Henrik J Ditzel, Rikke R Lund + Show 1 more

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https://doi.org/10.1074/mcp.r900006-mcp200

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Abstract

Plasma membrane proteins that are exposed on the cell surface have important biological functions, such as signaling into and out of the cells, ion transport, and cell-cell and cell-matrix interactions. The expression level of many of the plasma membrane proteins involved in these key functions is altered on cancer cells, and these proteins may also be subject to post-translational modification, such as altered phosphorylation and glycosylation. Additional protein alterations on cancer cells confer metastatic capacities, and some of these cell surface proteins have already been successfully targeted by protein drugs, such as human antibodies, that have enhanced survival of several groups of cancer patients. The combination of novel analytical approaches and subcellular fractionation procedures has made it possible to study the plasma membrane proteome in more detail, which will elucidate cancer biology, particularly metastasis, and guide future development of novel drug targets. The technical advances in plasma membrane proteomics and the consequent biological revelations will be discussed herein. Many of the advances have been made using cancer cell lines, but because the main goal of this research is to improve individualized treatment and increase cancer patient survival, further development is crucial to direct analysis of clinically relevant patient samples. These efforts include optimized specimen handling and preparation as well as improved proteomics platforms. Identification of potentially useful proteomics-based biomarkers must be validated in larger, well defined retrospective and prospective clinical studies, and these combined efforts should result in identification of biomarkers that will greatly improve early detection, prognosis, and prediction of treatment response.

Highlights

Plasma membrane proteins that are exposed on the cell surface have important biological functions, such as signaling into and out of the cells, ion transport, and cell-cell and cell-matrix interactions
We focus on the most recent proteomics developments in the cancer biomarker discovery area with a particular focus on plasma membrane (PM) proteins
In a recent quantitative proteomics study of PM protein alterations associated with the ability of disseminated breast tumor cells to establish lung metastasis, we demonstrated that integrin ␤1, ␣v, and ␣6 were more highly expressed on cells capable of generating metastasis

Summary

Introduction

Plasma membrane proteins that are exposed on the cell surface have important biological functions, such as signaling into and out of the cells, ion transport, and cell-cell and cell-matrix interactions. Many of the advances have been made using cancer cell lines, but because the main goal of this research is to improve individualized treatment and increase cancer patient survival, further development is crucial to direct analysis of clinically relevant patient samples. These efforts include optimized specimen handling and preparation as well as improved proteomics platforms. Classification of disease subtypes, prediction of treatment response, and identification of potential targets for drug therapy For most of these applications, a single marker is likely insufficient for stratification, and a panel of markers, the socalled molecular profiles or biosignatures, can be more informative. Winsløwsvej 25.3 and §Department of Oncology, Odense University Hospital, Søndre Boulevard 29, 5000 Odense C, Denmark

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