Fueling Prostate Cancer with Stress


In general, stress is not a good thing. Chronic stress can prevent the immune system from working properly and interfere with healing and recovery. Studies have even suggested that chronic stress may stimulate carcinogenesis and prevent response to therapy, but this has not been extensively explored.

Now, researchers led by George Kulik, a biologist at the Wake Forest Baptist Medical Center, are among the first to show that behavioral stress can worsen prostate cancer outcomes.

Kulik and colleagues used two different mouse models of prostate cancer to show that adrenaline-dependent stress can promote prostate cancer progression and reduce the effectiveness of cancer treatment. First, they cleverly subjected mice with implanted human prostate tumors to environmental stress by filling their cage with the scent of a predator. This scent is known to cause a spike in adrenaline in mice. The stressed-out mice did not respond well to treatment with bicalutamide, an androgen deprivation drug that is used to treat prostate cancer. The tumors of the stressed mice were much larger after treatment compared with the tumors of mice that were not exposed to the scent.

In a different approach to induce stress, the mice were directly injected with adrenaline. This group of mice also had a worsened response to treatment with bicalutamide, providing further evidence that the drug does not work as well when the animals are under stress.

The researchers also performed the same experiments in a different mouse model that was genetically modified to develop prostate cancer over time. In these prostate cancer-prone mice, stress induced by adrenaline injections or by exposure to a predator’s scent also prevented effective bicalutamide treatment and resulted in accelerated cancer progression.

In summary, mice treated with bicalutamide without being exposed to a stressful condition (predator smell or adrenaline injections) had shrinkage of their tumors. In contrast, mice that were given bicalutamide, but were repeatedly exposed to stress, did not respond to the treatment.

Next, the researchers demonstrated that adrenaline may inhibit cancer treatment by reducing the efficiency of processes that lead to cell death, or apoptosis. Treatment of both mouse models with a β-blocker (beta-blocker), a selective β2-adrenergic receptor (ADRB2) antagonist, or ICI118,551 inhibited the release of adrenaline and prevented accelerated tumor growth. Similarly, mice with an adrenaline receptor mutation that prevents a normal stress response to adrenaline did not experience accelerated tumor growth.

Studies have previously linked depression, chronic stress, and low social support with worse outcomes and cancer progression in cancer patients. In prostate cancer patients specifically, behavioral stress has been associated with higher prostate-specific antigen (PSA) levels and increased inflammation.

Conversely, β-blockers—adrenaline inhibitors typically prescribed for high blood pressure—have been shown to reduce mortality of different cancers in a number of studies. These include a recently published study led by cancer biologist Anil Sood at the University of Texas MD Anderson Cancer Center in Houston, who also wrote a commentary to the current study.

“It is important to understand which cancers are most affected by these stress pathways,” Sood says. Among the next questions is which patients will most likely benefit from anti-stress interventions such as β-blockers? Sood and others are testing the effect of β-blockers on cancer patient outcomes in an ongoing pilot study. Identifying the markers of chronic stress to test anti-stress therapies are also needed.

“[The mechanisms by which stress impacts cancer outcomes] is an important area to understand. This knowledge will likely inform translational studies,” Sood says.

References:

Armaiz-Pena GN, Allen JK, Cruz A, et al. Src activation by β-adrenoreceptors is a key switch for tumour metastasis. Nat Commun. 2013;4:1403

Hassan S, Karpova Y, Baiz D, et al. Behavioral stress accelerates prostate cancer development in mice. J Clin Invest. 2013;123:874-86

Nagaraja AS, Armaiz-Pena GN, Lutgendorf SK, Sood AK. Why stress is BAD for cancer patients. J Clin Invest.123;2:558-60