Singapore - Cancer biology: All tumor cells are not created equal

The identification of a molecular pathway essential for the development and maintenance of tumor-initiating cells may prove invaluable to cancer treatment

Tumor-initiating cells (TICs) are cells from a cancer that can multiply and form a tumor when transplanted into an experimental animal model such as the mouse. As TICs divide and multiply to form a tumor, many of the cells lose their property of being a TIC.

Clinicians are realizing that killing these TICs is the real goal of chemotherapy; if even one is left after a course of treatment, it can regenerate a tumor. Yet the identification of which tumor cells are TICS has been a challenge. Bing Lim and co-workers at the A*STAR Genome Institute of Singapore, Singapore Bioimaging Consortium and the Institute of Molecular and Cell Biology1 have now shown that a metabolic enzyme involved in synthesizing amino acids is necessary and sufficient for the formation of TICs in non-small cell lung cancer.

In normal cells, glucose is degraded to pyruvate (a process called glycolysis), which is then shunted into the mitochondria, where it proceeds to generate energy for the cell through the Krebs cycle. In the absence of oxygen — for example, in muscle cells undergoing prolonged exercise — pyruvate skips the Krebs cycle and is instead degraded into lactate in a much less energy-efficient process. This happens in cancer cells as well, even in the presence of oxygen. Some researchers suspect that this metabolic difference is a cause of cancer, while others believe that it might be just an effect. However, because the process is so energy-inefficient, the benefits it confers on cancer cells have remained unclear.

To unravel this mystery, Lim and co-workers isolated the rare TICs from primary non-small cell lung cancers at different clinical stages. They noticed that these TICs had very high levels of glycine decarboxylase (GLDC), an enzyme that degrades the amino acid glycine. Next they went on to show that active GLDC is required to make cells cancerous, and that it can do so on its own. They also found that GLDC promotes glycolysis and the accumulation of some of the nucleic acids used to build DNA and RNA, which explains why it is essential in TICs, as well as why cancer cells have an altered metabolism — the energy efficiency is not as important for them as attaining raw materials for their out-of-control growth.

High levels of GLDC are correlated with high mortality in lung cancer patients, and are also found in other cancers. The finding suggests that drugs targeting GLDC such as methotrexate might be effective chemotherapeutic agents.

The A*STAR-affiliated researchers contributing to this research are from the Genome Institute of Singapore, the Singapore Bioimaging Consortium and the Institute of Molecular and Cell Biology

References

1. Zhang, W. C. et al. Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis. Cell 148, 259–272 (2012). | article