Brief report: The uricase mutation in humans increases our risk for cancer growth

Background Recent studies suggest that fructose, as well as its metabolite, uric acid, have been associated with increased risk for both cancer incidence and growth. Both substances are known to cause oxidative stress to mitochondria and to reduce adenosine triphosphate (ATP) production by blocking aconitase in the Krebs cycle. The uricase mutation that occurred in the Miocene has been reported to increase serum uric acid and to amplify the effects of fructose to stimulate fat accumulation. Here we tested whether the uricase mutation can also stimulate tumor growth. Methods Experiments were performed in mice in which uricase was inactivated by either knocking out the gene or by inhibiting uricase with oxonic acid. We also studied mice transgenic for uricase. These mice were injected with breast cancer cells and followed for 4 weeks. Results The inhibition or knockout of uricase was associated with a remarkable increase in tumor growth and metastases. In contrast, transgenic uricase mice showed reduced tumor growth. Conclusion A loss of uricase increases the risk for tumor growth. Prior studies have shown that the loss of the mutation facilitated the ability of fructose to increase fat which provided a survival advantage for our ancestors that came close to extinction from starvation in the mid Miocene. Today, however, excessive fructose intake is rampant and increasing our risk not only for obesity and metabolic syndrome, but also cancer. Obesity-associated cancer may be due, in part, to a mutation 15 million years ago that acted as a thrifty gene.

Influence of chronic neuropathic pain on VEGFA in tumors of mice with genetically determined inhibition of tumor growth.

e22103 Background: Chronic neuropathic pain (CNP) demonstrates the ability to stimulate tumor growth and neoangiogenesis. Our purpose was to study VEGFA levels in the growth of B16/F10 melanoma with CNP in mice with genetically determined inhibition of tumor growth. Methods: Females of С57ВL/6 mice (normal genome (uPA+), n = 26) and C57BL/6-Plautm1.1BugThisPlauGFDhu/GFDhu mice (urokinase gene knockout (uPA–), n = 16) received subcutaneous transplantation of B16/F10 melanoma 2 weeks after bilateral sciatic nerve ligation (CNP model). After 3 weeks of carcinogenesis in CNP, tumor volumes were measured and levels of VEGFA were studied in tumors by ELISA. Results: Tumor volumes in (uPA+) females with CNP in week 3 of carcinogenesis were similar to that in (uPA+) females without CNP and were on average 2.6 cm3 (2.5 and 2.8 cm3 respectively). Tumor volumes in (uPA–) females were 0.04 cm3, i.e. 70 times lower (p < 0.001) than in (uPA+) females without CNP. Tumor volumes in (uPA–) females with CNP were 144 times higher (p < 0.001) than in (uPA–) females without CNP and were 5.76 cm3. VEGFA levels in tumors of (uPA+) females with CNP were 11.1 times higher (p < 0.001) than in (uPA+) females without CNP. VEGFA in tumors of (uPA–) females with CNP was 5.2 times higher (p < 0.001) than in (uPA–) females without CNP. Conclusions: The CNP state showed higher VEGFA concentrations in tumor tissues of female mice with normal genome and uPA-deficient females (with genetically determined inhibition of tumor growth) which may cause a larger tumor volume in (uPA–) female mice.

Advances in neurometabolic therapy

Actovegin is a calf blood extract that contains more than 200 biologically active compounds. Experiments have shown that Actovegin reduces the neurotoxic effect of amyloid, neutralizes reactive oxygen species, and normalizes the endothelial function of small vessels. The drug has not been shown to stimulate tumor growth in the neuroblastoma model. Clinical experience with Actovegin suggests that the drug has an undoubted efficacy in treating moderate vascular cognitive impairment and chronic distal symmetric diabetic polyneuropathy and that it is used as additional therapy for primary degenerative and vascular dementia. The clinical efficacy of Actovegin in chronic obliterating diseases of the lowerlimb arteries is being actively studied now.

PHYSICAL FACTORS AND THEIR ROLE IN ONCOLOGY

The analysis of the effect of various physical therapy methods on tumor growth in the historical aspect and comparison with our own scientific results were carried out. The role of physical therapy methods such as galvanization (electrophoresis), light therapy (ultraviolet irradiation, lasers of different light wave spectra), alternating currents (UHF, microwave, inductothermia), mechanical vibrations (ultrasound, vibration), magnetic field, pulse currents (DDT, SMT), high voltage currents (darsonvalization), and thermal factors (mud and heat treatment) in stimulation of tumor growth was studied. The results of our own studies confirm the statement that the physiotherapeutic factors used do not stimulate tumor growth, and can have a beneficial influence on the improvement of the quality of life of cancer patients. Thus, there is a growing evidence that physiotherapy is a safe and effective adjunct to cancer treatment.

Cyst Fluid From Cystic, Malignant Brain Tumors: A Reservoir of Nutrients, Including Growth Factor-Like Nutrients, for Tumor Cells

BACKGROUND: Brain tumors may have cysts, whose content of nutrients could influence tumor cell microenvironment and growth. OBJECTIVE: To measure nutrients in cyst fluid from glioblastoma multiforme (GBM) and metastatic brain tumors. METHODS: Quantification of nutrients in cyst fluid from 12 to 18 GBMs and 4 to 10 metastatic brain tumors. RESULTS: GBM cysts contained glucose at 2.2 mmol/L (median value; range &lt;0.8-3.5) and glutamine at 1.04 mmol/L (0.17-4.2). Lactate was 7.1 mmol/L (2.4-12.5) and correlated inversely with glucose level (r = –0.77; P &lt; .001). Amino acids, including glutamate, varied greatly, but median values were similar to previously published serum values. Ammonia was 75 μmol/L (11-241). B vitamins were present at previously published serum values, and riboflavin, nicotinamide, pyridoxal 5΄-phosphate, and cobalamin were higher in cyst fluid than in cerebrospinal fluid. Inorganic phosphate was 1.25 mmol/L (0.34-3.44), which was &gt;3 times higher than in ventricular cerebrospinal fluid: 0.35 mmol/L (0.22-0.66; P &lt; .001). Tricarboxylic acid cycle intermediates were in the low micromolar range, except for citrate, which was 240 μmol/L (140-590). In cystic metastatic malignant melanomas and lung tumors values were similar to those in GBMs. CONCLUSION: Tumor cysts may be a nutrient reservoir for brain tumors, securing tumor energy metabolism and synthesis of cell constituents. Serum is one likely source of cyst fluid nutrients. Nutrient levels in tumor cyst fluid are highly variable, which could differentially stimulate tumor growth. Cyst fluid glutamate, lactate, and phosphate may act as tumor growth factors; these compounds have previously been shown to stimulate tumor growth at concentrations found in tumor cyst fluid.

Antitumor Macrophage Response to Bacillus pumilus Ribonuclease (Binase)

Extracellular bacterial ribonucleases such as binase from Bacillus pumilus possess cytotoxic activity against tumor cells with a potential for clinical application. Moreover, they may induce activation of tumor-derived macrophages either into the M1-phenotype with well-documented functions in the regulation of the antitumor immune response or into M2-macrophages that may stimulate tumor growth, metastasis, and angiogenesis. In this study, binase or endogenous RNase1 (but not RNA or short oligonucleotides) stimulated the expression of activated NF-κB p65 subunit in macrophages. Since no changes in MyD88 and TRIF adaptor protein expression were observed, toll-like receptors may not be involved in RNase-related NF-κB pathway activation. In addition, short exposure (0.5 hr) to binase induced the release of cytokines such as IL-6, МСР-1, or TNF-α (but not IL-4 and IL-10), indicative for the polarization into antitumor M1-macrophages. Thus, we revealed increased expression of activated NF-κB p65 subunit in macrophages upon stimulation by binase and RNase1, but not RNA or short oligonucleotides.