Proteomics and Cancer

by National Cancer Institute

Key Points

Proteomics is the study of the proteins in a cell, tissue or organism.

Only a small percentage of the thousands of proteins in human cells have been sequenced or identified.

Proteomics technology is being explored for potential use in cancer diagnosis and treatment. This research involves searching for proteins that may serve as biomarkers of early disease, responsiveness to therapy, or the likelihood of relapse after treatment.

A high priority of current research efforts is the application of proteomics technology to improving patient care.

There is no validated proteomic technology currently available for the clinic.

1. What is proteomics?

The term 'proteome' was first coined in 1994, and refers to all the proteins in a cell, tissue, or organism. Proteomics refers to the study of the proteome. Because proteins are involved in almost all biological activities, the proteome is a rich source of biological information.

Protein scientists have diverse interests. These include determining the function and amino acid sequence of proteins; their three-dimensional structure; how the addition of sugar, phosphate, or fat affects protein function; and how proteins interact with other molecules, including other proteins. Some researchers are focused on the proteins present in particular parts of the cell such as the outer cell membrane, the nucleus, the cytoplasm (the region of the cell outside the nucleus), or the nuclear membrane; others are analyzing protein-protein interactions in a particular cell or organism; some are studying the differences between the proteins present in diseased vs. healthy cells.

2. How does studying the proteome compare to studying the genome? What are some of the challenges in proteomics research?

The total number of proteins in human cells is estimated to be between 250 to 500 thousand, and only a small percentage have been sequenced or identified. The complete proteome has not been characterized for any organism. In contrast, the genome or the entire set of genes for several organisms has been sequenced, including humans. The human genome is estimated to contain about 35,000 protein-encoding genes.

Besides the difference in quantity, another important difference between the genome and proteome is that the genome is static and relatively unchanged from day to day. Cellular proteins, on the other hand, are continually moving and undergoing changes such as binding to a cell membrane, partnering with other proteins, gaining or losing a chemical group such as a sugar, fat, or phosphate, or breaking into two or more pieces. Proteins play a central role in the complex communication network within and between cells and are constantly responding to the needs of the organism.

Several other properties of proteins add to their complexity:

• Proteins and/or modified proteins may vary among individuals, between cell types, and even within the same cell under different stimuli or different disease-states.

• One gene can produce more than one protein and one protein can be modified in multiple ways, which may change its behavior. This can happen when the cell uses a single gene DNA template to produce several different messenger RNAs, which are then used as templates to make different proteins, or it may happen when a protein is modified by cellular processes after it is created. The result is that instead of one gene producing one protein, one gene can produce as many as 1,000 different proteins. On average, however, a gene produces five to ten different proteins from its messenger RNAs.

• The quantity of different proteins can vary greatly. For example, in human blood, the concentration of the protein albumin is more than a billion times greater than another protein, interleukin-6.

• There is no laboratory amplification technique for proteins like there is for amplifying genes. This means that it is not possible to make copies of proteins that are present in very small amounts.

3. What are the approaches used in the development of clinical proteomics?

The goal of clinical proteomics is to develop proteomics technology for the benefit of patient care. This new research technology is now being used in clinical research studies ranging from cancer to cardiovascular disease and organ transplants. Researchers are searching for proteins that can be used as early biomarkers of disease, or that may predict response to therapy or the likelihood of relapse after treatment in blood, urine, or diseased tissue.

Ovarian Cancer

Ovarian cancer is a major focus of early biomarker discovery because it is usually diagnosed at an advanced stage with a five-year survival rate of about 20 percent. To evaluate the potential use of proteomics as a diagnostic tool, a group of researchers from the National Cancer Institute (NCI) in Bethesda, Md., collected serum from 50 ovarian cancer patients and 50 controls and used a computer algorithm to search for the protein patterns that distinguished cancer from non-cancer. When they tested this pattern with a set of blinded serum samples, the test pattern correctly identified all 50 patients with cancer, and was able to discriminate them from 63 out of 66 patients who were unaffected or had benign disease. Using the same approach, two other groups reported similar results.

Prostate cancer

A similar proteomic analysis of prostate cancer patients vs. healthy controls was carried out by looking for differences in protein patterns between the two groups. Using blood samples from 167 prostate cancer patients, 77 patients with benign prostate hyperplasia and 82 healthy men, the computer was able to develop a classification system that correctly classified 96 percent of the samples as either prostate cancer or non-cancer (benign prostate hyperplasia/healthy men). Another proteomic approach is to determine whether the changes in specific phosphoproteins (proteins with phosphate groups attached) believed to be important in cellular signaling events and cancer progression in prostate cancer patients can serve as a biomarker of early disease.

Breast Cancer

A combination of three candidate proteins in the blood were found to be useful in discriminating between 169 patients at various stages of breast cancer compared to women with benign breast disease and healthy controls. In three other studies, nipple aspirate fluid was used to identify tumor marker candidates. Nipple aspirate fluid has a higher concentration of breast specific proteins than blood. Mammary ducts are thin tubes that lead to the nipples and are where 70 percent to 80 percent of breast cancers originate.

Lung and Bladder

Several laboratories have successfully analyzed tumor tissue from patients with lung and bladder cancer and discovered protein patterns that could discriminate diseased from healthy tissue. Likewise, preliminary results using a proteomic approach to detect bladder cancer have been promising.

Future Use

At this point, none of the above described proteomics analyses is mature enough to be used in the clinic as a screening tool. However, these exploratory studies point to the promise of proteomics as a diagnostic marker. Validation in clinical trials in large groups of patients is necessary before proteomics patterns can be used routinely in the clinic as biomarkers for early disease.

About the Author

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