Metabolic plasticity of cancer cells.

BACKGROUND: A general characteristic of cancer metabolism is the skill to gain the essential nutrients from a relatively poor environment and use them effectively to maintain viability and create new bio-mass. The changes in intracellular and extracellular metabolites that accompany metabolic reprogramming associated with tumor growth subsequently affect gene expression, cell differentiation, and tumor microenvironment. During carcinogenesis, cancer cells face huge selection pressures that force them to constantly optimize dominant metabolic pathways and undergo major metabolic reorganizations. In general, greater flexibility of metabolic pathways increases the ability of tumor cells to satisfy their metabolic needs in a changing environment. PURPOSE: In this review, we discuss the metabolic properties of cancer cells and describe the tumor promoting effect of the transformed metabolism. We assume that changes in metabolism are significant enough to facilitate tumorigenesis and may provide interesting targets for cancer therapy.

Hepatocellular carcinoma - prognostic criteria of individualized treatment.

BACKGROUND: Though the sixth most frequent malignancy, hepatocellular carcinoma (HCC) is the third most common cause of death amongst solid tumours. Only surgery in the early stages may provide the cure; however, HCC still has a high recurrence rate. Non-surgical treatment lacks comparable efficacy. It was not sooner than in 2017 that the therapy galore started to extend. Thus prognostic factors driving the therapy have been gaining importance. MATERIAL AND METHODS: All relevant literature was checked for aetiology, epidemiology, dia-gnostic means, and individualised treatment of HCC. Cytochrome P-450 expression data from 22 patients operated in the University Hospital Brno in the period 2017-2020 were included. RESULTS: Screening the population at risk (presence of cirrhosis) with the transabdominal ultrasound lies at the centre of the dia-gnostic algorithm. Making the dia-gnosis does not require a bio-psy in most cases. Only a few parameters are thus known before the treatment - a size and number of lesions, and AFP level. These drive the indication to surgery. Relapses after surgery and response to palliative treatment depend on the expression of MET and AXL that directly affect anti-VEGF therapy. High AFP predicts a good response to regorafenib but early relapse after surgery. The pattern of P450 expression was found linked with tumour differentiation. The differentiation correlates with the size and number of lesions. We also found a link between the P450 expression and some mi-RNAs possibly detectable using liquid bio-psy techniques. CONCLUSION: The share of deaths from HCC overweighs its incidence. The risk population to screen is well-defined (cirrhosis). The BCLC staging system probably gives the best complication/efficacy results. This system does not require any bio-psy and does not comprise all predictive factors important in the expanding targeted molecular therapy. According to our results, small molecules to treat HCC should work better in poorly differentiated tumours. Surgery is more effective in those well-differentiated. It isnt easy to get all relevant information before therapy. Some factors need macrobio-psy (surgical). The pretreatment workup will probably require a mandatory bio-psy in BCLC B and C stages to get the information. This opens up a way for the liquid bio-psy that could use some specific mi RNAs.

Effect of prostate cancer cell line supernatant on functional polarization in macrophages.

OBJECTIVES: We aimed on effect of supernatant derived from prostate cancer cell line PC-3 on M1/M2 functional polarization in macrophages. BACKGROUND: Cytokines play an important role in carcinogenesis. Most of them are produced by macrophages. Macrophages are divided into groups M1 or M2. Classical phenotype macrophages M1 support pro-inflammatory effects and produce pro-inflammatory cytokines, such as interleukin 6 (IL-6), interleukin 12 (IL-12), tumor necrosis factor α (TNF-α). Macrophages exhibiting a phenotype M2 secrete anti-inflammatory cytokines, e. g. interleukin 10 (IL-10), transforming growth factor ß (TGF-ß). METHODS: Peripheral blood monocytes were cultivated for 7 days and during this time went through a differentiation into macrophages. Macrophages were stimulated for 24 hours by lipopolysaccharide (LPS) as a positive control and cultivated with supernatant for another 24 hours. RESULTS: Macrophages cultivated without LPS and without supernatant were used as negative control. Relative expression of IL-6, IL-10, IL-12 and TNF-α was measured by Quantitative real-time PCR. Expression of pro-inflammatory cytokines was lower in macrophages with supernatant compared to positive control. CONCLUSION: Expression of pro-inflammatory cytokines was lower in macrophages with supernatant (MΦ+sup) compared to positive control (MΦ+LPS). Effect of the supernatant on expression of IL-6, IL-10, IL-12 and TNF-α was not confirmed (Tab. 1, Fig. 5, Ref. 15).

Different doxorubicin formulations affect plasma 4-hydroxy-2-nonenal and gene expression of aldehyde dehydrogenase 3A1 and thioredoxin reductase 2 in rat.

Increased oxidative stress is indisputably an important mechanism of doxorubicin side effects, especially its cardiotoxicity. To prevent impairment of non-tumorous tissue and to improve the specificity in targeting the tumor tissue, new drug nanotransporters are developed. In many cases preclinical therapeutic advantage has been shown when compared with the administration of conventional drug solution. Three forms of doxorubicin--conventional (DOX), encapsulated in liposomes (lipoDOX) and in apoferritin (apoDOX) were applied to Wistar rats. After 24 h exposition, the plasma level of 4-hydroxy-2-nonenal (4-HNE) as a marker of lipoperoxidation and tissue gene expression of thioredoxin reductase 2 (TXNRD2) and aldehyde dehydrogenase 3A1 (ALDH3A1) as an important part of antioxidative system were determined. Only conventional DOX significantly increases the level of 4-HNE; encapsulated forms on the other hand show significant decrease in plasma levels of 4-HNE in comparison with DOX. They also cause significant decrease in gene expression of ALDH3A1 and TXNRD2 in liver as a main detoxification organ, and a mild influence on the expression of these enzymes in left heart ventricle as a potential target of toxicity. Thus, 4-HNE seems to be a good potential biomarker of oxidative stress induced by various forms of doxorubicin.

Mutation analysis of candidate genes SCN1B, KCND3 and ANK2 in patients with clinical diagnosis of long QT syndrome.

The long QT syndrome (LQTS) is a monogenic disorder characterized by prolongation of the QT interval on electrocardiogram and syncope or sudden death caused by polymorphic ventricular tachycardia (torsades de pointes). In general, mutations in cardiac ion channel genes (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2) have been identified as a cause for LQTS. About 50-60 % of LQTS patients have an identifiable LQTS causing mutation in one of mentioned genes. In a group of 12 LQTS patients with no identified mutations in these genes we have tested a hypothesis that other candidate genes could be involved in LQTS pathophysiology. SCN1B and KCND3 genes encode ion channel proteins, ANK2 gene encodes cytoskeletal protein interacting with ion channels. To screen coding regions of genes SCN1B, KCND3, and 10 exons of ANK2 following methods were used: PCR, SSCP, and DNA sequencing. Five polymorphisms were found in screened candidate genes, 2 polymorphisms in KCND3 and 3 in SCN1B. None of found polymorphisms has coding effect nor is located close to splice sites or has any similarity to known splicing enhancer motifs. Polymorphism G246T in SCN1B is a novel one. No mutation directly causing LQTS was found. Molecular mechanism of LQTS genesis in these patients remains unclear.