Highlights

Manipulating the milieu

23 Nov 2010

Cancer cells secrete proteins that help them adapt to low-oxygen environments

Fig. 1: Effect of oxygen on human skin cancer cells. (Left) Cancer cells in a normal-oxygen environment. (Right) Cancer cells in a low-oxygen environment, showing the altered distribution of proteins (green) that affect the behavior of tumor cells.

Fig. 1: Effect of oxygen on human skin cancer cells. (Left) Cancer cells in a normal-oxygen environment. (Right) Cancer cells in a low-oxygen environment, showing the altered distribution of proteins (green) that affect the behavior of tumor cells.

© 2010 American Society for Biochemistry and Molecular Biology

Cancer cells can grow even when oxygen and nutrient levels are low. They respond to stress either by manipulating their environment so that they can move to more hospitable locations or by inducing new vessel growth to obtain what they need from blood circulation. Sai Kiang Lim at the A*STAR Institute of Medical Biology and co-workers have now determined that proteins secreted from oxygen-deprived cancer cells may be responsible for changes in cancer cell behavior and proliferation.

By growing human skin cancer cells in cell culture, the researchers found that cancer cells grown in a low-oxygen environment did not stick as well to the culture dish as those grown in a normal-oxygen environment (Fig. 1), and were more prone to migrate through an artificial matrix. They reasoned that oxygen-deprived cancer cells can spread, or metastasize, to other locations in the body because of these changes.

The researchers also found that human skin cancer cells grown in a low-oxygen environment could induce the formation and outgrowth of new blood vessels from the membranes of chicken eggs. As these changes were initiated outside the cancer cells, the researchers suspected that proteins secreted by the cancer cells may be responsible for these changes.

Based on this hypothesis, Lim and her team used proteomics—the sequencing and measurement of the relative abundances of a set of proteins—to compare the differences in protein secretion between cancer cells grown in low- and normal-oxygen environments. They found an increase in the secretion level of protein-cleaving enzymes in human skin cancer cells grown in a low-oxygen environment, which they believe causes the degradation of the matrix that keeps the cells in place, permitting them to migrate and spread. They also observed that human skin cancer cells grown in a low-oxygen environment showed enhanced secretion of proteins involved in blood vessel formation.

Surprisingly, many of the secreted proteins the researchers identified are normally found within the membrane or inside cancer cells. The researchers deduced that the reason for this is because cancer cells were secreting exosomes—small vesicles that can contain proteins.

“Cancer is a leading cause of mortality, causing one in eight deaths worldwide with 90% of these deaths attributable to metastasis. We are now focusing on understanding the mechanisms by which cancer cells make and secrete exosomes to influence their microenvironment,” says Lim. “Once we find out these mechanisms, we can devise therapies to control cancer growth and spread.”

The A*STAR-affiliated researchers contributing to this research are from the Institute of Medical Biology.

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References

Park, J.E. et al. Hypoxic tumor cell modulates its microenvironment to enhance angiogenic and metastatic potential by secretion of proteins and exosomes. Molecular & Cellular Proteomics 9, 1085–1099 (2010). | article

This article was made for A*STAR Research by Nature Research Custom Media, part of Springer Nature