How chronic stress exacerbates cancer

476 A reas of negative charge come and go on the plasma membrane, report Tony Yeung, Sergio Grinstein (Hospital for Sick Children, Toronto, Canada), and colleagues. Loss of the charged areas correlates with the loss of certain signaling proteins from the membrane and inactivation of related downstream activity. Attraction based on charge is well established for sequence-specifi c protein–protein interactions. But the Toronto group documented an electrostatic switch that was evident with many different probes, with many different anionic lipids, and on liposomes that lacked any proteins. The probes were modeled on fragments of the K-Ras protein and combined polycationic sequences with a hydrophobic anchor to keep the probe in the plasma membrane rather than interacting with the anionic nucleoplasm. The probes were displaced from the intracellular face of the plasma membrane by three different conditions: an infl ux of calcium; fl ipping out of negatively charged phosphatidylserine (PS); and the later stages of phagocytosis. Rac1 dissociated from phagosomes with similar kinetics, even if locked in a GTP-bound form. During phagocytosis, signaling results in hydrolysis of negatively charged membrane-localized PIP2 to form uncharged diacylglycerol and cytoplasmic IP3. Inhibition of PIP2 hydrolysis reduced the loss of the probes from phagosomes. The Toronto group suggests that charge-dominated attachment may be reversed downstream of calcium elevation, PS fl ipping, and PIP2 hydrolysis for a wide range of biological pathways. “If it is happening in other contexts [such as around individual receptor kinases] it would be much harder to tell,” says Grinstein, because of the smaller surface areas involved. But Grinstein will be looking next at endocytosis, based on evidence that endosomes and plasma membranes differ in their charge. Reference: Yeung, T., et al. 2006. Science. 313:347–351. A probe detecting surface charge (red) is depleted during phagocytosis. G RI N ST EI N / A A A S How chronic stress exacerbates cancer H aving cancer is stressful enough without the knowledge that stress itself promotes tumor growth. But Premal Thaker, Liz Han, Aparna Kamat, Anil Sood (University of Texas M.D. Anderson Cancer Center, Houston, TX), and colleagues have found just that: human ovarian carcinoma cells injected into mice form tumors that grow more when the mice are exposed to chronic stress. Drugs that block stress responses may therefore be appropriate for certain cancer patients. Humans and mice have two major responses to stress. The adrenal gland responds by producing glucocorticoids, and the sympathetic nervous system by producing catecholamines, which bind to the β adrenergic receptors ADRB1 and ADRB2. The Texan group identifi ed a pathway leading from ADRB2 to protein kinase A (PKA) and the production of VEGF. VEGF is known to induce angiogenesis (the growth of new blood vessels) and thus to aid tumor growth. The group had earlier found that patients with greater distress had higher levels of VEGF, and that catecholamines but not glucocorticoids were clearly linked in vitro to increased production of VEGF by cancer cells. In the current study with the injected mice, they found that social isolation, 2 hours of immobilization daily, or a β 2 agonist caused tumor nodule number and mean tumor weight to approximately double or triple. Levels of VEGF and mean vessel density in the tumors were both increased. All of these stressmediated increases were blocked by reducing the levels of ADRB2 (but not ADRB1) or by antagonizing PKA or VEGF. Only tumors that express ADRB2 will be susceptible to this particular stress pathway. It is not clear how large this universe is, as there have not been large-scale surveys of ADRB2 expression in different tumor types. Patients with tumors that express high levels of ADRB2, and who have signifi cant stressors such as surgery or lack of social support, would be the best candidates for a trial of β blockers as potential cancer therapeutics. These adrenergic receptor antagonists are widely used for hypertension, but may fi nd a new application in reducing the negative effects of stress on tumor growth. Reference: Thaker, P.H., et al. 2006. Nat. Med. doi:10.1038/nm1447.