Call of the riled

Researchers at the University of California, San Diego School of Medicine say a ''stress response'' mechanism used by normal cells to cope with harsh or demanding conditions is exploited by cancer cells, which transmit the same stress signal to surrounding cells, triggering an inflammatory response in them that can aid tumor growth.

An artist's representation shows how stress signals from cancer cells prompt similar signals in neighboring cells, aiding and abetting tumor growth. Left: To survive in a harsh environment (low oxygen, nutrient deprivation), tumor cells produce constant endoplasmic reticulum (ER) stress response. Center: These ER stress signals are transmitted to nearby macrophages – white blood cells charged with recognizing and removing tumor cells and pathogens. The macrophages react with their own ER stress signals, initiating an inflammation response. Right: The resulting macrophage-amplified inflammation encourages more tumor growth.

The findings are reported by Maurizio Zanetti, MD, professor of medicine and director of the Laboratory of Immunology at the UC San Diego Moores Cancer Center, and colleagues, and published in the April 4 early online edition of Proceedings of the National Academy of Sciences.

The endoplasmic reticulum (ER) is the protein-making factory inside all cells. Increased physiological demands or disease conditions can sometimes cause proteins to misfold and accumulate in the ER. Cells typically respond by an ER stress response, which attempts to reset normal ER balance.

For normal cells, the ER stress response is transient. For tumor cells, it's life.  Because they exist in an environment that's invariably difficult (their host is always trying to kill them, and oxygen and nutrient deprivation are frequent), tumor cells produce an on-going ER stress response, which helps them not only to survive, but to thrive. 

According to Zanetti and colleagues, tumor cells generate ''transmissible ER stress.'' Specifically, they induce bystander cells to issue a similar stress response, most notably nearby macrophages – a type of white blood cell employed by the body's immune system to recognize and remove pathogens and cellular debris.

Recently, several laboratories, including some at UC San Diego, have underscored the crucial role of inflammation in promoting cancer growth. A consequence of ''transmissible ER stress'' points to ''receiver'' macrophages as an important source of inflammation, which serves as an environmental cue for cancer development.