New Light on the Link Between Chronic Stress and Ovarian Cancer Tumorigenesis
Abstract & Commentary
By Robert L. Coleman, MD, Associate Professor, University of Texas; M.D. Anderson Cancer Center, Houston. Dr. Coleman is on the speaker's bureau for GlaxoSmithKline, Bristol-Myers Squibb, and Ortho Biotech.
Synopsis: Blocking ADRB-mediated angiogenesis could have therapeutic implications for the management of ovarian cancer.
Source: Thaker PH, et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med. 2006;12:939-944.
While stress has well documented effects on immune, neurochemical and endocrinological function, its role in cancer progression is less well understood. It is appreciated, in preclinical studies, that stress can affect the growth of some tumors through modulation of the immune response to tumor cells. However, regulation in solid tumors, like ovarian cancer, is less certain. The hypothesis that the stress mediators could directly affect tumor growth through angiogenic mechanisms was explored.
Mice bearing ovarian cancer arising in the organ of origin (also known as orthotopic cancer model) were randomly assigned to social isolation through a novel physical restraining device or no isolation. This was done so as to not induce acute stress as a confounding variable. They were then randomly assigned to treatment intervention, which consisted of both β1 and β2 blockade. Efficacy was measured by number and extent of metastatic disease as well as tumor weight. Tumor biopsies were evaluated for the effects of angiogenesis, such as mean vessel counts and new vessel formation. The impact of stress blockade on these features was also studied.
Chronic stress, as induced through physical restraint, dramatically increased tissue catecholamine levels and accelerated the growth of tumors in this orthotopic model. Tumor burden and patterns of invasive disease was substantially greater and more adverse as well. Details from specific experiments on both cell lines and harvested tumor nodules isolated this effect to activation of the β-adrenergic pathway. Selective stimulation and blocking of β1 and β2 further isolated the genesis of this observation to the β-receptor, which was also found to be present in ovarian cancer cells. Inhibition of this pathway with propranolol (a non-specific β-blocker) administration led to inhibition of the stress-induced tumor growth. When tumors from stressed and treated animals were evaluated, it was clearly documented that tumor growth accompanied substantial activation of tumor angiogenesis (measured by tumor VEGF level, expression of bFGF, MMP2 and MMP9 and mean vessel density). These effects too were affected positively by β-stimulation and negatively by β2 blockade. Regulation of β1 activity had no effect on tumor growth or inhibition.
Behavioral stress as induced through restraint causes tumor growth in mice bearing orthotopic ovarian cancers. The mechanism of this observation appears to be through the β-adrenergic pathway where angiogenesis is induced. Blockade of this pathway could have therapeutic application in the management of ovarian cancer.
While this kind of paper is a bit of a departure from our usual focus, the scope of these finding are broad and have an important impact on discovery of new and novel mechanisms for ovarian cancer growth and metastases. The establishment of a reliable hybrid human-murine model of ovarian cancer allowed these investigators to carefully and convincingly dissect the specific mechanism for observed cancer growth, induced by behavioral stress. Among these manipulations were treatment and gene-silencing techniques geared specifically to the human cancer. Another was the documentation of the lack of angiogenic effects in cells that lacked the β-adrenergic receptor. The link between stress, β-adrenergic stimulation, angiogenesis, and tumor growth has heretofore not been previously outlined and the observation that β-blockade can prevent this inducement has substantial implications for new cancer therapy.
Another interesting correlate utilized in this study was non-invasive imaging during therapy experiments. It has become increasingly recognized that antivascular targeting, particularly those affecting the VEGF pathway, cause changes in the tumor microenvironment. Newly established vessels are poorly arranged and sparsely coated with supportive mesenchymal cells called pericytes. This causes the vasculature to be leaky and morphologically irregular. Tissue effects are characterized by edema and increased plasma to extracellular space fluid transfer, which, in the present case, was accelerated by stress. Dynamic contrast enhanced MRI or DCE-MRI was used to document this effect in control and stressed animals. Currently, the technology along with CT-PET imaging is undergoing validation as a reliable method of assessing target modulation in human cancer trials. Despite their promise, functional imaging is imperfect and new selective contrast agents are being evaluated. For instance, an important unanswered question of anti-VEGF targeting is whether tumor associated angiogenesis leads to a reduction in new vessels or just reduced perfusion. The situation is analogous to rubbing one's eyes and encumbering the filling of established microvessels ("pink eye").
While the authors' observations point to a pathway of tumorigenesis, it is important to note that not all stress is necessarily bad. We count on immediate catecholamine release and action for many survival mechanisms. Nor do these results provide insight into how pain or surgical stress can positively or negatively affect tumor growth. Nonetheless, the report points to an important pathway that appears to have a pharmacological solution and may be implicated in future studies of ovarian cancer treatment.