New cancer diagnostic technique developed

Washington, Mar 16 - Researchers have devised a new molecular sensor that can detect high levels of lactate - a telltale sign of cancer - in individual cells.

Cancer cells break down sugars and produce the metabolic acid lactate at a much higher rate than normal cells. This phenomenon signals that cancer is present, via diagnostics such as PET scans, and possibly offers an avenue for novel cancer therapies.

Now, a team of Chilean researchers at The Centro de Estudios Cientificos (CECs), with the collaboration of Carnegie’s Wolf Frommer, has devised a molecular sensor that can detect levels of lactate in individual cells in real time.

Prior to this advance, no other measurement method could non-invasively detect lactate in real time at the single-cell level.
The work, published in the journal PLOS ONE, is a boon to understanding how different types of cells go awry when cancer hits.

ÒOver the last decade, the Frommer lab at Carnegie has pioneered the use of Forster Resonance Energy Transfer, or FRET, sensors to measure the concentration and flow of sugars in individual cells with a simple fluorescent colour change,Ó said Alejandro San Martin, lead author of the study.

ÒUsing the same underlying physical principle and inspired by the sugar sensors, we have now invented a new type of sensor based on a transcriptional factor. A molecule that normally helps bacteria to adapt to its environment has now been tricked into measuring lactate for us,Ó Martin said.

ÒStandard methods to measure lactate are based on reactions among enzymes, which require a large number of cells in complex cell mixtures,Ó said Felipe Barros, leader of the project.

ÒThis makes it difficult or even impossible to see how different types of cells are acting when cancerous. Our new technique lets us measure the metabolism of individual cells, giving us a new window for understanding how different cancers operate,Ó Barros said in a statement.

Researchers turned the sensor on in three cell types: normal brain cells, tumour brain cells, and human embryonic cells. The sensor was able to quantify even very low concentrations of lactate, providing an unprecedented sensitivity and range of detection.

The researchers found that the tumour cells produced lactate 3-5 times faster than the non-tumour cells.
ÒThe high rate of lactate production in the cancer cell is the hallmark of cancer metabolism,Ó said Frommer.

Researchers Discover Novel Way to Develop Tumor Vaccines


Researchers at the University of Southern California (USC) have uncovered a new way to develop more effective tumor vaccines by turning off the suppression function of regulatory T cells. The results of the study, titled “A20 is an antigen presentation attenuator, and its inhibition overcomes regulatory T cell-mediated suppression,” will be published in Nature Medicine on March 2, 2008.

“Under normal circumstances, regulatory T cells inhibit the immune system to attack its own cells and tissues to prevent autoimmune diseases. Cancer cells take advantage of regulatory T cells' suppressor ability, recruiting them to keep the immune system at bay or disabling the immune system’s attack provoked by tumor vaccines.” says Si-Yi Chen, M.D., Ph.D., professor of immunology and molecular microbiology at the USC/Norris Comprehensive Cancer Center and the Keck School of Medicine of USC. “Our study provides a new vaccination strategy to overcome the regulatory T cells’ immune suppression while avoiding non-specific overactivation of autoreactive T cells and pathological autoimmune toxicities.”

The study identified a new molecular player called A20, an enzyme that restricts inflammatory signal transduction in dendritic cells. When it is inhibited, the dendritic cells overproduce an array of cytokines and co-stimulatory molecules that triggers unusually strong immune responses that cannot be suppressed by regulatory T cells. The resulting hyperactivated immune responses triggered by A20-deficient dendritic cells are capable of destroying various types of tumors that are resistant to current tumor vaccines in mice.

“Through a series of immunological studies, we have identified A20 as an essential antigen presentation attenuator that prevents the overactivation and excessive inflammation of the dendritic cells, which, in turn, restricts the potency of tumor vaccines,” says Chen.

The immune system’s dendritic cells are the guardian cells of the immune systems and play an important role in activating immune responses to recognize and destroy tumor cells. Tumor vaccines have been designed and developed to incite the immune response to cancer cells so that the immune system can attack and destroy cancer cells. However, discovering A20’s role in restricting immune responses has led to a method for blocking tumors from using regulatory T cells for protection.

“Despite intensive efforts, tumor vaccines have been largely ineffective in causing tumor regression in the clinic,” says Chen. “The vaccination approach we developed inhibits the key inhibitor in tumor antigen-loaded dendritic cells to selectively hyperactivate immune responses and to tip the balance from immune suppression in tumor-bearing hosts or cancer patients to effective antitumor immunity.”

This approach is capable of overcoming the regulatory T cells’ suppression mechanism and will allow for a new generation of tumor vaccines to be developed. The next step is to translate these findings into a human clinical trial, says Chen.

The National Institutes of Health and the Leukemia and Lymphoma Society funded the study.

Xiao-Tong Song, Kevin E. Kabler, Lei Shen, Lisa Rollins, Xue F. Huang, Si-Yi Chen. “A20 is an antigen presentation attenuator, and its inhibition overcomes regulatory T cell-mediated suppression.” Nature Medicine, Mar. 2, 2008. Digital object identifier number 10.1038/nm1721.
(NewsWise)