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.

Enhancing cisplatin anticancer effectivity and migrastatic potential by modulation of molecular weight of oxidized dextran carrier.

The molecular weight (Mw) of dextran derivatives, such as regioselectively oxidized dicarboxydextran (DXA), is greatly influencing their faith in an organism, which could be possibly used to improve anticancer drug delivery. Here we present a modified method of sulfonation-induced chain scission allowing direct and accurate control over the Mw of DXA without increasing its polydispersity. Prepared DXA derivatives (Mw = 10-185 kDa) have been conjugated to cisplatin and the Mw of the carrier found to have a significant impact on cisplatin release rates, in vitro cytotoxicity, and migrastatic potential. Conjugates with the high-Mw DXA showed particularly increased anticancer efficacy. The best conjugate was four times more effective against malignant prostatic cell lines than free cisplatin and significantly inhibited the ovarian cancer cell migration. This was traced to the characteristics of spontaneously formed cisplatin-crosslinked DXA nanogels influenced by Mw of DXA and amount of loaded cisplatin.

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).

MicroRNAs in pathophysiology of acute myocardial infarction and cardiogenic shock.

AIM: Levels of circulating miRNA are considered to be potential biomarkers of acute myocardial infarction and disease progression. METHODS: In this study, the expression levels of circulating miRNA-1, miRNA-133 and miRNA-124a were investigated in a group of patients with acute myocardial infarction (STEMI) and cardiogenic shock (CS) compared to controls. RESULTS: During the hospitalization period, miRNA-133 showed a significant up-regulation in the serum of STEMI and CS patients compared to controls, while the expression of miRNA-1 was significantly different only in CS. The expression of miRNA-124 was significantly higher in STEMI and CS. Furthermore, miRNA-1 expression was related to the level of circulating glucose in patients with STEMI. We also found a negative correlation between miRNA-133 and MMP-9 levels. MiRNA-124 expression was significantly related to the level of soluble ST2; the marker correlated to cardiac damage. CONCLUSION: All selected miRNAs are potential markers of cardiac injury in cardiogenic shock, whereas miRNA-124a and -133 are markers of injury in STEMI. MiRNA-1 expression is related to circulating glucose in STEMI. None of miRNAs could be correlated to the extent of injury, progress of the disease, or prognosis of patient outcome. Therefore, the levels of circulating miRNA have no potential for becoming a biomarker of myocardial damage and as such would bring no further benefit compared to current markers (Tab. 4, Fig. 1, Ref. 47).

Transcription factor c-Myb inhibits breast cancer lung metastasis by suppression of tumor cell seeding.

Metastasis accounts for most of cancer-related deaths. Paracrine signaling between tumor cells and the stroma induces changes in the tumor microenvironment required for metastasis. Transcription factor c-Myb was associated with breast cancer (BC) progression but its role in metastasis remains unclear. Here we show that increased c-Myb expression in BC cells inhibits spontaneous lung metastasis through impaired tumor cell extravasation. On contrary, BC cells with increased lung metastatic capacity exhibited low c-Myb levels. We identified a specific inflammatory signature, including Ccl2 chemokine, that was expressed in lung metastatic cells but was suppressed in tumor cells with higher c-Myb levels. Tumor cell-derived Ccl2 expression facilitated lung metastasis and rescued trans-endothelial migration of c-Myb overexpressing cells. Clinical data show that the identified inflammatory signature, together with a MYB expression, predicts lung metastasis relapse in BC patients. These results demonstrate that the c-Myb-regulated transcriptional program in BCs results in a blunted inflammatory response and consequently suppresses lung metastasis.

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.

Prostate cancer, miRNAs, metallothioneins and resistance to cytostatic drugs.

MicroRNAs (miRNAs) translationally repressing their target messenger RNAs due to their gene-regulatory functions play an important but not unexpected role in a tumour development. More surprising are the findings that levels of various miRNAs are well correlated with presence of specific tumours and formation of metastases. Moreover, these small regulatory molecules play a role in the resistance of cancer cells to commonly used anti-cancer drugs, such as cisplatin, anthracyclines, and taxanes. In that respect, miRNAs become very attractive target for potential therapeutic interventions. Improvements in the sensitivity of miRNAs detection techniques led to discovery of circulating miRNAs which became very attractive non-invasive biomarker of cancer with a substantial predictive value. In this review, the authors focus on i) oncogenic and anti-tumour acting miRNAs, ii) function of miRNAs in tumour progression, iii) possible role of miRNAs in resistance to anticancer drugs, and iv) diagnostic potential of miRNAs for identification of cancer from circulating miRNAs with special emphasis on prostate cancer. Moreover, relationship between miRNAs and expression of metallothionein is discussed as a possible explanation of resistance against platinum based drugs.

Evaluation of alpha-methylacyl-CoA racemase, metallothionein and prostate specific antigen as prostate cancer prognostic markers.

Current diagnostic techniques are inefficient in distinguishing latent and low-risk forms of prostate cancer from high-risk forms. The present study is focused on determination of putative tumor markers of aggressive high-grade forms of prostate cancer. Potential markers were determined in blood sera of 133 patients (82 cases and 51 controls) and in cell lines (Gleason score 9-derived 22Rv1 and normal tissue derived PNT1A) on mRNA and protein levels. Alpha-methylacyl-CoA racemase (AMACR), metallothionein classes 1A and 2A (MT1A and MT2A) were determined and compared to prostate specific antigen (PSA) levels. On mRNA level, significantly increased expression of MT2A (2.4-fold), PSA (2.6-fold) and AMACR (8.4-fold) and insignificantly (1.9-fold) elevated MT1A in 22Rv1 compared to non-tumor PNT1A were determined. On protein level, significant enhancement of free PSA and total PSA in tumor cell line was evident. AMACR protein was 1.5-fold elevated in tumor line (below the level of significance). Contrary to mRNA, significantly (p = 0.01) reduced level of MT protein in tumor lines was determined. In the case of serum level, significantly enhanced MT level (4.5-fold) in patients' sera was found. No significant changes were observed in the case of AMACR. These findings indicate possible alternative role of MT to PSA prostate cancer marker. In addition, level of AMACR is distinctly higher in the Gleason score 9 in serum of patients and MT shows a descending trend in relation to Gleason score.

Insight to physiology and pathology of zinc(II) ions and their actions in breast and prostate carcinoma.

Zinc(II) ions contribute to a number of biological processes e.g. DNA synthesis, gene expression, enzymatic catalysis, neurotransmission, and apoptosis. Zinc(II) dysregulation, deficiency and over-supply are connected with various diseases, particularly cancer. 98 % of human body zinc(II) is localized in the intracellular compartment, where zinc(II) is bound with low affinity to metallothionein (MT). Zinc transporters ZIP and ZnT maintain transmembrane transport from/to cells or organelles. Imbalance of their regulation is described in cancers, particularly prostate (down-regulated zinc transporters ZIP1, 2, 3 and ZnT-2) and breast, notably its high-risk variant (up-regulated ZIP6, 7, 10). As a result, intracellular and even blood plasma zinc(II) levels are altered. MT protects cells against oxidative stress, because it cooperates with reduced glutathione (GSH). Recent studies indicate elevated serum level of MT in a number of malignancies, among others in breast, and prostate. MT together with zinc(II) affect apoptosis and proliferation, thus together with its antioxidative effects it may affect cancer. To date, only little is known about the influence of zinc(II) and MT on cancer, while these compounds may play an important role in pathogenesis. This review concludes current data regarding the impact of zinc(II) on the pathogenesis of breast and prostate cancers with potential outlines of new, targeted therapy and prevention. Moreover, blood plasma zinc(II) and MT levels and dietary zinc(II) intake are discussed in relation to breast and prostate cancer risk.

[Molecular mechanisms of zinc in prostate cancer]. / Zinek--molekulární mechanizmy u karcinomu prostaty.

In many developed countries, prostate cancer is the most common male tumour disease. The high incidence and mortality requires early diagnosis, differentiation of aggressive, highly malignant forms from clinically silent forms and understanding of the pathogenesis with its typical metabolic aberrancies (if any) in order to develop new targeted therapies. Prostate cells (including prostate cancer cells) are unique in their relation to zinc ions. Prostate tissue can accumulate these ions in up to tenfold higher concentration than other body cells. These ions influence many cellular processes incl. proliferation, differentiation and apoptosis. Prostate cancer cells lack ability to accumulate zinc. Therefore, zinc ions may be expected to play an important role in the disease pathogenesis, in its propagation and metastatic potential of tumour cells. Intracellular zinc levels are regulated by zinc-binding proteins, especially metallothioneins, and zinc transporters. Zinc level regulation dysfunction has been identified in prostate cancer cells and may thus play an important role in the prostate cancer pathogenesis. Moreover, due to its overproduction by prostate tissue, metallothionein serum levels are elevated and can be used as an important tumour marker.

Clinical importance of matrix metalloproteinases.

This review gives a brief summary on clinical applications of MMPs and their determination. Primarily, the activity of MMPs in cancer formation, development and metastasis is discussed. Further, survey on methods including fluorimetric methods, zymographies, Western-blotting, immunocapture assay, enzyme-linked immunosorbent assay, immunocytochemistry and immunohistochemistry, phage display, multiple-enzyme/multiple-reagent system, activity profiling, chronopotentiometric stripping analysis and imaging methods for detection and determination of MMPs follows (Fig. 3, Ref. 100).

Matrix metalloproteinases.

Matrix metalloproteinases (MMPs), also known as matrixins, belong to a group of zinc-dependent proteins, which are thought to play a central role in the breakdown of extracellular matrix. Collagen, elastin, gelatin and casein are major components cleaved by MMPs. The breakdown of these components is essential for many physiological processes such as embryonic development, morphogenesis, reproduction, and tissue resorption and remodelling. MMPs also participate in pathological processes such as arthritis, cancer, cardiovascular and neurological diseases. This review summarizes current knowledge regarding these proteins, their participation in physiological and pathophysiological roles, their involvement in activation and inhibition, and their interactions with other metal-binding proteins including metallothioneins.