Aim: comparative analysis of plasmin, plasminogen (PG), urokinase PG activator (uPA) and its receptor (uPAR) in tissues of malignant tumors and intact skin of С57ВЬ/6 mice of both genders in В16/F10 melanoma reproduced in chronic neurogenic pain (CNP). Methods: The study was performed on 130 mice and В16/ F10 melanoma cell line. Levels of uPA-antigen (uPA-AG) and uPA-activity (uPA-act), uPAR, PG, PAP (plasmin-a2-antiplasmin complex) were determined by ELISA. Statistics: the Statistica 10 program. Results. CNP-induced depletion of the content and activity of uPA was maintained in the skin and tumors after melanoma transplantation. Elevation of uPAR in females under the influence of CNP after the transplantation normalized at the terminal stage only; decreased levels of uPAR in males were maintained during the whole experiment. Elevation of PAP in females with CNP was maintained in the skin and tumors after the transplantation, and in males it was less marked. CNP affected the time of development of transplantable В16/F10 melanoma in female and male С57ВL/6 mice, changed gender differences typical of the standard tumor transplantation, decreased the period prior to the development of metastases, increased their number and extended localization. Conclusions. The study confirmed involvement of plasmin and uPAR in the formation of В16/F10 melanoma in CNP with changing gender priorities in development and spread of the process.
Glioblastoma multiforme (GBM) is the most common and invasive poorly differentiated brain tumor with nearly 100 % rate of recurrence and unfavorable prognosis. The aim of the present review is to analyze recent studies and experimental results (Scopus, Web of Science, PubMed) concerning somatic mutations in glioblastoma, aberrant regulation of gene expression of signal pathways including EGFR, TGFß, etc. and markers for GBM progression. Particularly the molecular subtypes of glioblastoma and NGS results are considered in this review.
Biogenic amines (BA) are known to be involved in the malignant growth, and their levels change in the CNS when exposed to pain; however, the combined effect of chronic pain and cancer on the BA dynamics in the brain has not been studied. The aim of the study was to evaluate characteristics of BA balance in the brain cortex during melanoma growth with chronic neurogenic pain (CNP). Material and methods. The study included 64 male C57Bl/6 mice weighing 22-24 g. В16/F10 melanoma was transplanted under the skin of the back to animals of the main group 2 weeks after the sciatic nerve ligation. Mice with melanoma without pain were the comparison group. Levels of BA: adrenaline, noradrenaline, dopamine (DA), serotonin (5-HT), histamine, and 5-HIAA were determined by ELISA. Results. Changes in adrenaline levels were registered in the brain of mice with CNP. The growth of melanoma in males was accompanied by elevated brain levels of adrenaline and noradrenaline and decreased dopamine and serotonin. Similarities in the direction of shifts in the neurotransmitter profile were observed in melanoma development with and without CNP. Conclusions. The influence of CNP on the neurotransmitter balance in the CNS was probably one of the factors that influenced the course of transplanted B16/F10 melanoma in males of the main group.
Since chronic neurogenic pain has been reported to affect biological characteristics of B16/F10 melanoma, the purpose of the study was to analyze concentrations of components of the NO-system in mice during the growth of transplantable B16/F10 melanoma combined with chronic neurogenic pain. Methods. The study included 64 female mice. Melanoma was transplanted under the skin of the back to animals of the main group 2 weeks after the bilateral sciatic nerve ligation. Levels of NOS-3, NOS-2, endothelin-1, L-arginine, citrulline, total nitrite and ADMA were determined by ELISA in the intact skin and in tumor tissues. Results. The study showed that the dynamics of the studied parameters differed in tumor growth alone and in combination with chronic pain. Stably increased levels of NO-synthases in the tumor and stably increased ADMA levels with their decrease by week 3 of the growth were registered in the tumor growth with pain. Conclusions. Chronic pain probably contributes to the development of immunological tolerance to tumor antigens in the skin. Conditions are formed that facilitate the survival of tumor cells and contribute to the further development of melanoma. The dynamics of the NO-system activity can stimulate neoangiogenesis and enhance tumor invasion. Changes in the ADMA inhibitor levels in the tumor growth combined with chronic pain may indicate the control of NO levels through the metabolic regulation of NO-synthase activity, thus providing increased melanoma invasiveness.
Tumor vascularisation is an important aspect of melanoma growth. The system of urokinase and its receptor (uPA/uPAR system) plays an important role in tumor metastasis which makes it an attractive therapeutic target. Our purpose was to study the dynamics of angiogenic growth factors in male and female uPA gene-knockout mice (C57BL/6-PlautmI.IBug-This Plau6FDhu/GFDhu strain) during the growth of experimental B16/F10 melanoma developing in animals with chronic neurogenic pain (CNP). Material and methods. Group 1 included С57BL/6 mice of both genders, n=75; group 2 - C57BL/6-Plautm1.1Bug-This PlauGFDhu/GFDhu mice (uPA gene knockout), n=46. Levels of VEGF-A, VEGF-C, sVEGF-R1, and sVEGF-R3 were determined by ELISA (CUSABIO BIOTECH Co.,Ltd., China). Results. uPA gene-knockout mice of both genders with melanoma and CNP showed survival similar to animals with a normal genome; however, the period to tumor onset was longer in such animals (by 2.6 times on average), and the volume of primary tumors was on average 2.2 times higher. The concentration of angiogenesis factors in skin and tumor samples was lower in male and female uPA gene-knockout mice with experimental B16/F10 melanoma and CNP, compared to animals without the knockout. Conclusions. uPA gene knockout inhibits VEGF in males, unlike females, and chronic neurogenic pain stimulates the formation of this factor in knockout animals of both genders which confirms triggering of urokinase-independent pathway of angiogenesis activation under the influence of CNP.
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