In recent years there has been a growing interest among cancer biologists in cancer metabolism. This Review summarizes past and recent advances in our understanding of the reprogramming of glucose metabolism in cancer cells, which is mediated by oncogenic drivers and by the undifferentiated character of cancer cells. The reprogrammed glucose metabolism in cancer cells is required to fulfil anabolic demands. This Review discusses the possibility of exploiting the reprogrammed glucose metabolism for therapeutic approaches that selectively target cancer cells.

Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy?

Epigenetic alternations concern heritable yet reversible changes in histone or DNA modifications that regulate gene activity beyond the underlying sequence. Epigenetic dysregulation is often linked to human disease, notably cancer. With the development of various drugs targeting epigenetic regulators, epigenetic-targeted therapy has been applied in the treatment of hematological malignancies and has exhibited viable therapeutic potential for solid tumors in preclinical and clinical trials. In this review, we summarize the aberrant functions of enzymes in DNA methylation, histone acetylation and histone methylation during tumor progression and highlight the development of inhibitors of or drugs targeted at epigenetic enzymes.

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Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials.

Cadmium is a heavy metal of considerable toxicity with destructive impact on most organ systems. It is widely distributed in humans, the chief sources of contamination being cigarette smoke, welding, and contaminated food and beverages. Toxic impacts are discussed and appear to be proportional to body burden of cadmium. Detoxification of cadmium with EDTA and other chelators is possible and has been shown to be therapeutically beneficial in humans and animals when done using established protocols.

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Cadmium Toxicity and Treatment

Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia

Advanced cholangiocarcinoma continues to harbor a difficult prognosis and therapeutic options have been limited. During the course of a clinical trial of whole genomic sequencing seeking druggable targets, we examined six patients with advanced cholangiocarcinoma. Integrated genome-wide and whole transcriptome sequence analyses were performed on tumors from six patients with advanced, sporadic intrahepatic cholangiocarcinoma (SIC) to identify potential therapeutically actionable events. Among the somatic events captured in our analysis, we uncovered two novel therapeutically relevant genomic contexts that when acted upon, resulted in preliminary evidence of anti-tumor activity. Genome-wide structural analysis of sequence data revealed recurrent translocation events involving the FGFR2 locus in three of six assessed patients. These observations and supporting evidence triggered the use of FGFR inhibitors in these patients. In one example, preliminary anti-tumor activity of pazopanib (in vitro FGFR2 IC50≈350 nM) was noted in a patient with an FGFR2-TACC3 fusion. After progression on pazopanib, the same patient also had stable disease on ponatinib, a pan-FGFR inhibitor (in vitro, FGFR2 IC50≈8 nM). In an independent non-FGFR2 translocation patient, exome and transcriptome analysis revealed an allele specific somatic nonsense mutation (E384X) in ERRFI1, a direct negative regulator of EGFR activation. Rapid and robust disease regression was noted in this ERRFI1 inactivated tumor when treated with erlotinib, an EGFR kinase inhibitor. FGFR2 fusions and ERRFI mutations may represent novel targets in sporadic intrahepatic cholangiocarcinoma and trials should be characterized in larger cohorts of patients with these aberrations.

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Integrated Genomic Characterization Reveals Novel, Therapeutically Relevant Drug Targets in FGFR and EGFR Pathways in Sporadic Intrahepatic Cholangiocarcinoma

Although cancer metabolism has received considerable attention over the past decade, our knowledge on its specifics is still fragmentary. Altered cellular metabolism is one of the most important hallmarks of cancer. Cancer cells exhibit aberrant glucose metabolism characterized by aerobic glycolysis, a phenomenon known as Warburg effect. Accelerated glucose uptake and glycolysis are main characteristics of cancer cells that allow them for intensive growth and proliferation. Accumulating evidence suggests that O-GlcNAc transferase (OGT), an enzyme responsible for modification of proteins with N-acetylglucosamine, may act as a nutrient sensor that links hexosamine biosynthesis pathway to oncogenic signaling and regulation of factors involved in glucose and lipid metabolism. Recent studies suggest that metabolic reprogramming in cancer is connected to changes at the epigenetic level. O-GlcNAcylation seems to play an important role in the regulation of the epigenome in response to cellular metabolic status. Through histone modifications and assembly of gene transcription complexes, OGT can impact on expression of genes important for cellular metabolism. This paper reviews recent findings related to O-GlcNAc-dependent regulation of signaling pathways, transcription factors, enzymes and epigenetic changes involved in metabolic reprogramming of cancer.

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O-GlcNAcylation and Metabolic Reprograming in Cancer

O-GlcNAcylation is an abundant, dynamic, and inducible posttranslational modification in which single β-N-acetylglucosamine residues are attached by O-glycosidic linkage to serine or treonine residues. It is suggested that abnormally regulated O-GlcNAcylation may contribute to the pathology of cancer. Cycling of O-GlcNAc residues on intracellular proteins is controlled by two enzymes, O-GlcNAc transferease (OGT), which catalyses the addition of O-GlcNAc residues and nucleocytoplasmic β-N-acetylglucosaminidase (O-GlcNAcase; encoded by MGEA5 gene), an enzyme involved in the removal of O-GlcNAc. In this study, relationship between the mRNA expressions of genes coding O-GlcNAc cycling enzymes in breast ductal carcinomas and clinicopathological parameters were analyzed. The results showed that poorly differentiated tumors (grade II and III) had significantly higher OGT expression than grade I tumors. Contrary, MGEA5 transcript levels were significantly lower in grade II and III in comparison with grade I tumors. The Spearman rank correlation showed the expressions of OGT and MGEA5 in breast cancer was negatively correlated (r = −0.430, P = 0.0002). Lymph node metastasis status was significantly associated with decreased MGEA5 mRNA expression. This result suggests that elevation in O-GlcNAc modification of proteins may be implicated in breast tumor progression and metastasis.

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Gene expression of O-GlcNAc cycling enzymes in human breast cancers

Increased glucose uptake mediated by glucose transporters and reliance on glycolysis are common features of malignant cells. Hypoxia-inducible factor-1α supports the adaptation of hypoxic cells by inducing genes related to glucose metabolism. The contribution of glucose transporter (GLUT) and hypoxia-inducible factor-1α (HIF-1α) activity to tumor behavior and their prognostic value in head and neck cancers remains unclear. The aim of this study was to examine the predictive value of GLUT1, GLUT3, and HIF-1α messenger RNA (mRNA)/protein expression as markers of tumor aggressiveness and prognosis in laryngeal cancer. The level of hypoxia/metabolic marker genes was determined in 106 squamous cell laryngeal cancer (SCC) and 73 noncancerous matched mucosa (NCM) controls using quantitative real-time PCR. The related protein levels were analyzed by Western blot. Positive expression of SLC2A1, SLC2A3, and HIF-1α genes was noted in 83.9, 82.1, and 71.7 % of SCC specimens and in 34.4, 59.4, and 62.5 % of laryngeal cancer samples. Higher levels of mRNA/protein for GLUT1 and HIF-1α were noted in SCC compared to NCM (p < 0.05). SLC2A1 was found to have a positive relationship with grade, tumor front grading (TFG) score, and depth and mode of invasion (p < 0.05). SLC2A3 was related to grade and invasion type (p < 0.05). There were also relationships of HIF-1α with pTNM, TFG scale, invasion depth and mode, tumor recurrences, and overall survival (p < 0.05). In addition, more advanced tumors were found to be more likely to demonstrate positive expression of these proteins. In conclusion, the hypoxia/metabolic markers studied could be used as molecular markers of tumor invasiveness in laryngeal cancer.

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Gene and protein expression of glucose transporter 1 and glucose transporter 3 in human laryngeal cancer—the relationship with regulatory hypoxia-inducible factor-1α expression, tumor invasiveness, and patient prognosis

Aims The aim of this study was to investigate the cadmium (Cd), nickel (Ni) and aluminium (Al) concentrations in female breast cancer and normal tissue. Materials and methods The concentration of metals in 16 non-cancerous breast tissues and 67 breast cancer samples was measured by flame atomic absorption spectrometry. Results In the case of normal breast tissue the concentrations were 0.61 ± 0.24 μg Cd/g dry tissue, 1.84 ± 0.67 μg Ni/g dry tissue, and 3.63 ± 1.00 μg Al/g dry tissue, whereas in breast cancer concentrations of metals were 0.76 ± 0.38 μg/g dry tissue, 2.26 ± 0.79 μg/g dry tissue, and 4.40 ± 1.82 μg/g dry tissue, respectively. The concentration of Cd and Al in normal breast tissue was significantly lower than in breast cancer. In the case of Ni concentration, we did not observe statistically significant differences between normal and cancerous tissue. There were no significant differences in concentration of studied metals, in breast cancer, in the context of age, menopausal status, and cancer histological grading. Conclusion The data obtained show higher concentration of cadmium and aluminium and support a possible relationship between those metals and breast cancer.

https://www.termedia.pl/Journal/-55/pdf-18079-10?filename=Concentration of cadmium.pdf

Concentration of cadmium, nickel and aluminium in female breast cancer

Purpose: Although the androgen receptor (AR) has been found to be expressed in female breast tumours, its role in breast cancer remains unclear. In addition to the oestrogen receptor (OR) and progesterone receptor (PR), AR functional status may be important in the control of female breast cancer growth. Methods: In order to define AR in breast cancer, 67 primary breast tumours and 8 normal breast samples as control tissue were analysed for AR expression at the mRNA and protein levels using RT-PCR and Western blotting, respectively. The association of AR expression with tumour size and axillary lymph node status was investigated. Expression of AR mRNA was compared with that of OR and PR. Results: AR expression was identified in 66% (44/67) and 51% (34/67) of the cancers studied by RT-PCR and Western blotting, respectively. The number of positive samples and the level of AR mRNA were significantly higher among the cancer samples than among normal samples. No expression of AR protein was detected in normal breast tissue. A significant correlation between AR gene expression and its protein level in nuclei of carcinoma samples was demonstrated. The expression level of both AR gene and AR protein in nuclei was found to be positively correlated with tumour invasiveness. Of the breast carcinoma specimens, 44.8% (30/67) were OR-, PR- and AR-positive, while 14.9% (10/67) were steroid receptor-negative. However, 18% (12/67) of the primary breast tumours negative for OR and PR were positive for AR. Conclusions: The high incidence of AR expression in female breast tumours suggests a potential role of AR in breast cancer, in addition to OR and PR.

Magdalena Bryś

Papers

O-GlcNAcylation and Metabolic Reprograming in Cancer

Gene expression of O-GlcNAc cycling enzymes in human breast cancers

Gene and protein expression of glucose transporter 1 and glucose transporter 3 in human laryngeal cancer—the relationship with regulatory hypoxia-inducible factor-1α expression, tumor invasiveness, and patient prognosis

Concentration of cadmium, nickel and aluminium in female breast cancer

Androgen receptor status in female breast cancer: RT-PCR and Western blot studies.