Role of endothelial nitric oxide synthase (eNOS) in chronic stress-promoted tumour growth.
Bottom Line: Accumulating evidence suggests that chronic stress can be a cofactor for the initiation and progression of cancer.Animals subjected to restraint stress showed increased levels adrenocorticotropic hormone, enlarged adrenal glands, reduced thymus weight and a 3.61-fold increase in tumour growth in respect to no-stressed animals.Because VEGF can induce eNOS increase, and nitric oxide is a relevant factor in angiogenesis, we assessed the levels of eNOS protein by Western blot analysis.
Affiliation: Animal Facility, National Institute of Tumours G. Pascale, Naples, Italy.Show MeSH
Related in: MedlinePlus
Mentions: In a murine model of ovarian carcinoma, β-adrenergic activation of the cAMP–PKA signalling pathway was identified as a major mechanism by which chronic stress can enhance tumour angiogenesis in vivo and thereby promote tumour growth . We therefore verified the role of stress and β-adrenergic signalling in tumour growth in our model. In C57BL/6 mice carrying melanoma (B16F10) implants, we measured peripheral blood levels of ACTH. We found a significant increase in such levels in animals subjected to chronic (restraint) stress, compared to unstressed animals in three independent experiments (Fig. 1A). To assess the effect of stress on sympatho–adrenal–medullary activity, we measured the size of both adrenal glands by using Vevo2100 high-resolution ultrasound imaging system. Adrenal glands of stressed mice were larger (2.68 ± 0.32 mm) than those of control animals (1.81 ± 0.15 mm; P < 0.05). Moreover, the weight of thymuses in stressed animals was significantly lower than in control animals (P= 0.04; Fig. 1B). Graphs depict results from three separate experiments. We also evaluated the atrophy of prevalently B lymphoid organs such as liver and spleen and did not find significant differences in stressed versus control animals, confirming that chronic stress preferentially affected T, and not B, compartment [21, 22]. Then, to assess the effects of chronic stress on tumour progression, we evaluated the growth of B16F10 tumour cell implants in syngenic C57BL/6 stressed mice. As shown in Figure 2, tumour growth in chronically stressed mice was increased by 3.6-fold respect to control group; increase was 35.5-fold reduced (P < 0.0001) in animals treated with the non-specific β-antagonist propranolol. Consistent with these observations, MRI showed increased tumour growth in stressed mice respect to the other groups (Fig. 3) [23,24]. Thus, chronic stress appeared to greatly enhance tumour growth; such effect involved β-adrenergic receptor signalling. Images are representative of three separate experiments.
Affiliation: Animal Facility, National Institute of Tumours G. Pascale, Naples, Italy.