Stress-dependent increases in vessel density (top, left to right) and tumor weight and number (bottom) are prevented by VEGF antagonist PTK787.

SOOD/MACMILLAN

Having 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 identified 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 β2 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 stress-mediated 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 significant 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 find a new application in reducing the negative effects of stress on tumor growth.

Reference:

Thaker, P.H., et al.
2006
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Nat. Med.
doi:.