Neurotrophins in the brain of C57BL/6-Plautm1.1BugThisPlauGFDhu/GFDhu mice with B16/F10 melanoma growing with comorbid pathology.

Abstract

e21557 Background: 10% of cancer patients have comorbidities accompanied by chronic pain. Neurotrophins and fibrinolytic system are involved in carcinogenesis and pain pathogenesis. The purpose of the study was to measure levels of neurotrophins in white matter of the brain of urokinase-deficient (uPA–) mice with B16/F10 melanoma growing in presence of chronic neuropathic pain (CNP). Methods: The study included female mice С57ВL/6 (normal genome uPA+, n = 40) and C57BL/6-Plautm1.1BugThisPlauGFDhu/GFDhu (urokinase gene-knockout uPA–, n = 28) with B16/F10 melanoma (M) implanted subcutaneously 2 weeks after bilateral sciatic nerve ligation (CNP model). Intact mice (I) were controls. Levels of brain-derived neurotrophic factor BDNF, nerve growth factor NGF-β and neurotrophins 3 and 4 (NT3, NT4) were measured by ELISA in white matter of the brain after 3 weeks of tumor growth in presence of CNP. Results: Tumor volume in (uPA–) females by week 3 of carcinogenesis was 0.04 cm3, which was 70 times smaller than in (uPA+) females. Tumor volume in (uPA–) females with CNP was 5.76 cm3, which was 144 times larger than in (uPA–) females without CNP, and in (uPA+) females – 2.5 cm3. The brain of I (uPA–) showed higher levels of NT3 (by 1.3 times, p < 0.05), NT4 (by 2.6 times) and NGF-β (by 1.9 times, p < 0.05) and lower BDNF (by 1.7 times, p < 0.05), compared to I (uPA+). Both strains of mice with M or CNP demonstrated decreased levels of NGF-β, more pronounced in animals with a combination of these factors. (uPA–) females with CNP+M showed a decrease of NT3 and BDNF by 2 times, with NGF-β 2.2 times higher than in (uPA+) mice. Conclusions: The study revealed underlying differences in levels of neurotrophins in the brain of (uPA–) females which could contribute to the creation of conditions for the inhibition of tumor growth. Changes in the levels of NGF-β in mice with melanoma or CNP were nonspecific. Changes in the BDNF, NT3 and NGF-β balance in the brain of (uPA–) mice may be part of the mechanism of greater stimulation of melanoma growth under the influence of CNP.