Abstract: Mitochondria are subcellular organelles that produce adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS). As suggested over 70 years ago by Otto Warburg and recently confirmed with molecular techniques, alterations in respiratory activity and mitochondrial DNA (mtDNA) appear to be common features of malignant cells. Somatic mtDNA mutations have been reported in many types of cancer cells, but very few reports document the prevalence of inherited mitochondrial DNA polymorphisms in cancer patients compared to healthy control populations. Here we report the abundance of the 10398G polymorphism in a Polish breast cancer population and its frequency in controls. Amongst individuals with breast cancer the G single nucleotide polymorphism (SNP) is present in 23% of affected females compared to 3% of controls. This difference is highly statistically significant (P = 0.0008). It is therefore possible that the 10398G SNP constitutes an inherited predisposition factor for the development of breast cancer.
Abstract: Breast cancer is the most frequently diagnosed female cancer all over the world. Although the molecular genetics of this disease has been the focus of many projects for over 20 years, the number of prognostic markers used in clinics is still unsatisfactory. Mitochondrial DNA mutations have been reported in many breast cancer studies. To investigate the possible role of mitochondrial inherited polymorphisms in breast cancer development we analyzed the sequence of NADH-dehydrogenase genes in cancer samples and their corresponding normal tissues. We detected increased incidence of mtDNA polymorphisms, in particular very rare polymorphisms such as A4727G, G9947A, A10044G, A10283G, T11233C, and C11503T. Our report supports the notion that mtDNA polymorphisms establish a specific genetic background for breast cancer development and that mtDNA analysis may help in selection of cohorts that should undergo intensive screening and early detection programs.
Abstract: Mitochondria are sub-cellular organelles that produce adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS). As suggested over 70 years ago by Otto Warburg and recently confirmed with molecular techniques, alterations in respiratory activity and in mitochondrial DNA (mtDNA) appear to be common features of malignant cells. Somatic mtDNA mutations have been reported in many types of cancer cells, and some reports document the prevalence of inherited mitochondrial DNA polymorphisms in cancer patients. Nevertheless, a careful reanalysis of methodological criteria and methodology applied in those reports has shown that numerous papers can't be used as relevant sources of data for systematic review, meta-analysis, or finally for establishment of clinically applicable markers. In this review technical and conceptual errors commonly occurring in the literature are summarized. In the first place we discuss, why many of the published papers cannot be used as a valid and clinically useful sources of evidence in the biomedical and healthcare contexts. The reasons for introduction of noise in data and in consequence - bias for the interpretation of the role of mitochondrial DNA in the complex process of tumorigenesis are listed. In the second part of the text practical aspects of mtDNA research and requirements necessary to fulfill in order to use mtDNA analysis in clinics are shown. Stringent methodological criteria of a case-controlled experiment in molecular medicine are indicated. In the third part we suggest, what lessons can be learned for the future and propose guidelines for mtDNA analysis in oncology. Finally we conclude that, although several conceptual and methodological difficulties hinder the research on mitochondrial patho-physiology in cancer cells, this area of molecular medicine should be considered of high importance for future clinical practice.
Abstract: Mitochondria are cell organelles mostly known for their production of ATP through oxidative phosphorylation. As suggested over 70 years ago by O. Warburg and recently confirmed with molecular techniques, alterations in respiratory activity and mitochondrial DNA appear to be a common feature of malignant cells. Somatic mtDNA mutations have been reported in many types of cancer cells. MtDNA mutation pattern may enhance the specificity of cancer diagnostics, detection and prediction of tumor growth rate and patients' outcome. Therefore it may be used as a molecular cancer bio-marker. Nevertheless recently published papers list a large number of mitochondrial DNA mutations in many different cancer types, but their role in cell pathophysiology remains unsummarized. This review covers the consequences of mitochondrial genes mutations for human cell physiology and proliferation. We underline effects of mtDNA mutation-resulting amino acid changes in the respiratory chain proteins' structure, and propose changes in mitochondrial protein function. Mutations are critically evaluated and interpreted in the functional context and clinical utility of molecular mitochondrial research is summarized and new perspectives for 'mitochondrial oncology' suggested.
Abstract: Mitochondria have been implicated in cell transformation since Otto Warburg considered ârespiration damageâ to be a pivotal feature of cancer cells. Numerous somatic mitochondrial DNA (mtDNA) mutations have been found in various types of neoplasms, including breast cancer. Establishing the mtDNA mutation pattern in breast cancer cells may enhance the specificity of cancer diagnostics, detection and prediction of cancer growth rate and/or patients' outcomes; and therefore be used as a new molecular cancer bio-marker. The aim of this review is to summarize data on mtDNA mutation involvement in breast cancer and estimate effects of resulting amino acid changes on mitochondrial protein function. In this article published mtDNA mutation analyses are critically evaluated and interpreted in the functional context.
Abstract: Endometrial carcinoma is the most commonly diagnosed gynaecological cancer in developed countries. Although the molecular genetics of this disease has been in the focus of many research laboratories for the last 20 years, relevant prognostic and diagnostic markers are still missing. At the same time mitochondrial DNA mutations have been reported in many types of cancer during the last two decades. It is therefore very likely that the mitochondrial genotype is one of the cancer susceptibility factors. To investigate the presence of mtDNA somatic mutations and distribution of inherited polymorphisms in endometrial adenocarcinoma patients we analyzed the D-loop sequence of cancer samples and their corresponding normal tissues and moreover performed mitochondrial haplogroup analysis. We detected 2 somatic mutation and increased incidence of mtDNA polymorphisms, in particular 16223C (80% patients, p = 0.005), 16126C (23%, p = 0.025) and 207A (19%, p = 0.027). Subsequent statistical analysis revealed that endometrial carcinoma population haplogroup distribution differs from the Polish population and that haplogroup H (with its defining polymorphism - C7028T) is strongly underrepresented (p = 0.003), therefore might be a cancer-protective factor. Our report supports the notion that mtDNA polymorphisms establish a specific genetic background for endometrial adenocarcinoma development and that mtDNA analysis may result in the development of new molecular tool for cancer detection.
Abstract: Mitochondria have been implicated in cell transformation since Otto Warburg considered 'respiration damage' to be a pivotal feature of cancer cells. Numerous somatic mitochondrial DNA (mtDNA) mutations have been found in various types of neoplasms, including breast cancer. Establishing the mtDNA mutation pattern in breast cancer cells may enhance the specificity of cancer diagnostics, detection and prediction of cancer growth rate and/or patients' outcomes; and therefore be used as a new molecular cancer bio-marker. The aim of this review is to summarize data on mtDNA mutation involvement in breast cancer and estimate effects of resulting amino acid changes on mitochondrial protein function. In this article published mtDNA mutation analyses are critically evaluated and interpreted in the functional context.
Abstract: The problem of diagnosis in the field of head and neck region is still valid. Specific diagnosis and precise estimation of the tumor's size with the use of CT and MRI imaging is generally unsatisfactory. The Positron Emission Tomography (PET) supports this process with additional information about the tumor's metabolism. Numerous publications show that PET-CT has a great influence on the evaluation of the size of the tumor, presence of lymph node metastases, choice of treatment and the prognosis of the recurrence. Cancer cells represent a specific metabolic state. These cells intake large quantities of glucose and utilize it in the process of glycolysis. The oxidative phosphorylation is not efficient in the transformed cells and defects in mitochondrial functions are at the heart of malignant cell transformation. Disruption of the oxidative phosphorylation chain has been described in the neoplasms. As a consequence, in cancer the glycolysis is active even in the normoxic environment. This metabolic shift in cell transformation has been described in early XX century and so called Warburg's hypothesis profoundly influenced the present perception of cancer metabolism, positioning what is termed aerobic glycolysis in the mainstream of clinical oncology. Today we know that neoplastic cells differ at the proteomic level. A subset of different proteins such as hexokinase II or HIF are upregulated. These abnormalities might be used as the neoplastic markers.
Abstract: ABSTRACT. Mitochondrial DNA has been described as veritable Pandoraâs box of pathogenic mutations associated with a wide variety of clinical syndromes including cancer. Nevertheless careful reanalysis of methodological and methodical criteria used in experiments shows that numerous papers could not be used as relevant source of clinically applicative data. It has been shown that much noise has been introduced to the interpretation of the role of mitochondrial DNA in the complex tumorigenesis process and that numerous experiments do not fulfill logical methodological criteria of case-control molecular medical experiment, as originate from technical and conceptual errors that reduce the finding of mitochondrial DNA mutations in tumors to the level of technical and methodological artifacts. Under such circumstances it remains unclear how many of the disease-associated mutations have been determined adequately and the guidelines for reanalysis of previous experiments and design of new trials are needed. This article represents and justify methodological criteria to be used in mitochondrial medicine. Proposed guidelines describe the choice of the sample and patient selection process including patient number, geographical origin and ethnicity; clinicopathological data collection with special care for additional medical factors influencing mitochondrial DNA research as mitochondria influencing diseases. Also the importance of tissue and cell extraction and normal tissue and reference sequence selection are characterized. Finally we describe three â horn dilemma and the significance of avoiding scientific silos in mitochondrial DNA research, including hypothesis formulation and verification.
Abstract: Hsp60, a mitochondrial chaperonin highly conserved during evolution, has been found elevated in the cytosol of cancer cells, both in vivo and in vitro, but its role in determining apoptosis during oxidative stress (OS) has not yet been fully elucidated. The aim of the present work was to study the effects of OS on Hsp60 levels and its interactions with procaspase- 3 (p-C3) and p53 in tumor cells. NCI-H292 (mucoepidermoid carcinoma) cells were exposed to various concentrations of hydrogen peroxide (H2O2) for 24 hours. Cell viability was determined by Trypan blue and MTT assays. DNA damage was assessed by the Comet assay, and apoptosis was measured by the AnnexinV cytofluorimetric test. Exposure to increasing concentrations of H2O2 resulted in a reduction of cell viability, DNA damage, and early apoptotic phenomena. Hsp60, p-C3, p53, and p21 were assessed by Western blotting and immunocytochemistry before and after OS. Hsp60 and p-C3 were present before and after OS induction. Immunoprecipitation experiments showed an Hsp60/p-C3 complex before OS that persisted after it, while an Hsp60/p53 complex was not detected in either condition. The presence of wild type (wt) p53 was confirmed by RT-PCR, and p21 detection suggested p53 activation after OS. We postulate that, although OS may induce early apoptosis in NCI-H292 cells, Hsp60 exerts an anti-apoptotic effect in these cells and, by extension, it may do so in other cancer cells.
Abstract: Badania ostatnich lat wskazujÄ na wystÄpowanie w wielu typach nowotworów zwiÄkszonej czÄstoÅci mutacji w mitochondrialnym DNA, jednak ich znaczenie dla struktury i funkcji systemu fosforylacji oksydacyjnej nie zostaÅo dotychczas podsumowane. W niniejszej pracy omówiono mutacje genów mitochondrialnych kodujÄcych biaÅka w raku prostaty, przeÅyku oraz w nabÅoniaku rdzeniastym. Ze wzglÄdu na fakt, że wszystkie kodowane przez genom mitochondriów polipeptydy sÄ podjednostkami kompleksów systemu fosforylacji oksydacyjnej, szczególnÄ uwagÄ zwrócono na wpÅyw mutacji tego genomu na metabolizm tlenowy komórki.
Abstract: In human mitochondria, the characterization of multiple functional and structural interactions of mitochondrial chaperones is needed for the understanding of the cellular protein biogenesis as well as of the process of carcinogenesis. In light of current available data, we propose that mitochondrial Hsp70, Hsp60/10, DnaJ-like proteins, GrpE-like proteins, Clp/Hsp100, and Hsp90 families should be analyzed as a part of multi-chaperones-interactors network, and that single protein-protein interaction analysis does not constitute sufficient explanatory framework of carcinogenic potential of mitochondrial chaperones. We also believe that new chaperones and cell-cycle regulatory interactors are to be defined in the near future, but many technical and methodological efforts are needed before any generalization of the data will be possible and a reliable map of multi-chaperones-interactors network will be constructed.
Abstract: Data reported until today suggested a pivotal role of nuclear DNA mutations in the process of carcinogenesis. Recently more and more authors claim that disruption of mitochondrial DNA should not be excluded from this analysis. mtDNA have been reported in many cancers of head and neck region. Mitochondrial D-loop has been proven to be mutation hot - spot with majority of mutations in the positions 303 to 315 of poly-C tract. Data show that 37% of patients with premalignant lesions and 62% with carcinoma in situ are positive for mtDNA mutations. Moreover mutations in genes encoding ND2, ND5, COIII, CYTB, and ATP6 were observed in 17% of patients. Mutations in mitochondrial rRNA genes occured in similar number of cases. Neoplastic cells undifferentiation and disease progression is accompanied by multiplication of mtDNA number and increased mtDNA content. mtDNA content corellates with the stage of the disease. mtDNA mutations faciliate cell proliferation and inhibit apoptosis by increasing the production of ractive oxygen species (ROS). Cells harbouring mutated mtDNA have increased proliferation rate, as increased ROS concentration may act as an endogenous growth factor.
Abstract: AIMS: CD1a is a molecule belonging to the highly conserved group of CD1 proteins. Its expression in dendritic cells is related to the presentation of tumour-derived glycolipid antigens to T cells and, consequently, the development of a successful antitumour response. The aim was to investigate the presence of CD1a+ cells in both primary tumours and lymph nodes (LN) of a series of 35 invasive ductal carcinomas by both immunohistochemistry and reverse transcription-polymerase chain reaction. METHODS AND RESULTS: CD1a antigen was more expressed in N0 than N1 breast cancer (P < 0.0001) in both primary lesions and LN metastases and correlated positively and significantly with oestrogen (ER) (P = 0.0025) and progesterone (P = 0.0226) receptor (PR) status, as well as CD4+ and CD8+ T-lymphocyte infiltration. CONCLUSIONS: This is the first report to show a link between CD1a+ mononuclear cells in breast cancer and in paired LN metastases. The positive and significant correlations between the number of CD1a+ cells and positivity of the primary tumour for ER and PR suggest a possible role for CD1a as a prognostic marker for breast cancer, raising the possibility that hormone receptor-positive breast cancer patients may have a better prognosis in the presence of greater dendritic cell infiltration.
Abstract: Recently published papers report a large number of mitochondrial DNA mutations in many different cancer types, but their significance for electron transport chain proteins remains unknown. This review covers structural mutations of mitochondrial genes, choosing prostate cancer, esophageal cancer and epithelioma as research models. As all mitochondrial genes encode subunits of the electron transport chain, the review focuses on the consequences of structural mutations on cell metabolism.
Abstract: Endometrial carcinoma is among the most frequently diagnosed gynecological malignancies in highly developed countries. Research has been conducted for 20 years to define the molecular pathology of this disease and much is already known, but adequate prognostic, diagnostic, and monitoring markers are still missing. Recently, mitochondrial research opened a new perspective. The participation of abnormalities of those organelles and mutations of the mitochondrial genome has been defined in some types of cancer and is still under investigation. MtDNA mutations are also found in endometrial adenocarcinoma, although their impact on cell physiology has not been determined so far. Some processes involving mitochondria are widely known and described in numerous papers. These include electron transport and apoptosis, but others await further research. A forward genetics approach has been used in a wide spectrum of projects in which cancer tissue samples were collected from subjects with defined diagnoses and metabolic abnormalities and mtDNA mutations were checked. Thanks to this approach, characteristic patterns of mitochondrial disruption have been assigned to specific types of cancer. This review focuses on the molecular characteristics of endometrial adenocarcinoma with special focus on mitochondrial abnormalities. Research on cancer molecular pathology in endometrial adenocarcinoma may lead to the development of specific screening and/or diagnostic markers.
Abstract: The molecular chaperones Hsp60 and Hsp10 are, according to recent reports, involved in cancer development and progression. We, for instance, have found that their expression varies with distinctive patterns in different malignancies: they are overexpressed in colorectal, exocervical and prostate carcinogenesis, and colorectal cancer progression, but they are downregulated during bronchial carcinogenesis. There is also evidence showing that Hsp60 and Hsp10 can be used as therapeutic agents, for example in rheumatoid arthritis. In view of these findings we want now to call attention to the potential of Hsp60 and Hsp10 in cancer therapy.
Abstract: Mitochondria are subcellular organelles, whose well-known function is to produce ATP through the oxidative phosphorylation system. Alterations in respiratory activity and mitochondrial DNA (mtDNA) appear to be a general feature of malignant cells. The presence of mtDNA mutations has been reported in various cancer cells, and the abundance of mtDNA damage is consistent with the intrinsic susceptibility to constitutive oxidative stress. Research about the functional aspects of mtDNA mutations in cancer development and therapeutic response is likely to be fruitful and to have significant clinical and prognostic impact. Although many studies to date have been focused on the identification and characterization of altered mtDNA, it is not clear if these accumulated mutations are the cause or the consequence of the carcinogenic process. This article provides a brief summary of our current understanding of mitochondrial pathobiology in cancer development.
Abstract: Mitochondria are cell organelles involved in processes of cell life and death, and therefore also in tumoral transformation. Indeed, mitochondria dysfunction is a prominent feature of cancer cells. Mitochondrial proteins and DNA have also been previously studied as markers of tumorigenesis. Heat shock proteins (HSPs) are ubiquitous evolutionary conserved proteins. HSPs enhance their expression in stressed cells and they are involved in gene expression regulation, DNA replication, signal transduction, differentiation, apoptosis, cellular senescence or immortalization. This review reflects recent views on the role of some mitochondrial molecular chaperones as prohibitin, mortalin and HSP60/HSP10 complex and their modifications leading to cell transformation and cancer development. These molecules could represent modern molecular biomarkers for oncological management.
Abstract: To date, little is known either about the physical interactions of heat shock protein 10 (Hsp10) with other proteins within the cell or its involvement in signal transduction pathways. Hsp10 has been considered mainly as a partner of Hsp60 in the Hsp60/10 protein folding machine. Only recently, Hsp10 was reported to interact with proteins involved in deoxyribonucleic acid checkpoint inactivation, termination of M-phase, messenger ribonucleic acid export, import of nuclear proteins, nucleocytoplasmic transport, and pheromone signaling pathways. At the same time, Hsp10 expression can be up-regulated in cancer cells, because it accumulates as the cell transformation progresses. Recent data suggest that Hsp10 may be not only a component of the folding machine but also an active player of the cell signaling network, influencing cell cycle, nucleocytoplasmic transport, and metabolism, with putative roles in the lack of cell differentiation and in the inhibition of apoptosis. In this review, we revise the involvement of Hsp10 in signal transduction pathways and its possible role in cancer etiology.
Abstract: This review addresses the significance of the expression of proliferating cell nuclear antigen (PCNA), p53 and some heat shock proteins (Hsps) in prostate carcinoma (PC). In fact, PCNA and p53 are two widely discussed tools in PC diagnosis, mainly because of the controversy regarding the significance of their expression during prostate cancer development and progression. At the same time, only few studies have shown the potential role of Hsps in carcinogenesis and their overexpression in pre-neoplastic and neoplastic lesions of the prostate. We briefly describe the physiological roles of Hsps in normal cells, and the significance of their immunohistochemical detection in PC as well as in pre-cancerous lesions of the prostate. We will also discuss the possible functional interactions of these molecules in both dysplastic and neoplastic cells.
Abstract: Many models of tumour formation have been put forth so far. In general they involve mutations in at least three elements within the cell: oncogenes, tumour suppressors and regulators of telomere replication. Recently numerous mutations in mitochondria have been found in many tumours, whereas they were absent in normal tissues from the same individual. The presence of mutations, of course, does not prove that they play a causative role in development of neoplastic lesions and progression; however, the key role played by mitochondria in both apoptosis and generation of DNA-damaging reactive oxygen species might indicate that the observed mutations contribute to tumour development. Recent experiments with nude mice have proven that mtDNA mutations are indeed responsible for tumour growth and exacerbated ROS production. This review describes mtDNA mutations in main types of human neoplasia.
Abstract: The Saccharomyces cerevisiae SUV3 gene encodes the helicase component of the mitochondrial degradosome (mtEXO), the principal 3'-to-5' exoribonuclease of yeast mitochondria responsible for RNA turnover and surveillance. Inactivation of SUV3 (suv3Delta) causes multiple defects related to overaccumulation of aberrant transcripts and precursors, leading to a disruption of mitochondrial gene expression and loss of respiratory function. We isolated spontaneous suppressors that partially restore mitochondrial function in suv3Delta strains devoid of mitochondrial introns and found that they correspond to partial loss-of-function mutations in genes encoding the two subunits of the mitochondrial RNA polymerase (Rpo41p and Mtf1p) that severely reduce the transcription rate in mitochondria. These results show that reducing the transcription rate rescues defects in RNA turnover and demonstrates directly the vital importance of maintaining the balance between RNA synthesis and degradation.
Abstract: Supernumerary, old or damaged cells of multicellular organisms are eliminated by apoptosis - programmed cell death. Apoptosis is accompanied by series of characteristic morphological and biochemical events. The cell activates a cascade of cysteine proteases, caspases, that digest target proteins. Nucleases are also activated, which together leads to irreversible cell damage within few hours. Mitochondria are the cell compartment that integrates signals from different apoptotic pathways activated by ischemia, heat shock or growth hormones depletion. Mitochondria play the primary role in coordination and amplification of cell autodegradation signals. They regulate apoptosis by sequestration of pro- and antiapoptotic proteins. Perturbation of activation or execution of apoptosis is characteristic feature of cancer cells.
Abstract: Mitochondria are subcellular organelles with the most well-known and best-characterized function of adenosine triphosphate (ATP) production through oxidative phosphorylation (OXPHOS). Mitochondria play an important role in apoptosis, a fundamental biological process by which cells die in a programmed manner and are the strategic point in the cell death cascade. Alterations in respiratory activity and mitochondrial DNA (mtDNA) abnormalities appear to be a general feature of malignant cells. The presence of mtDNA mutations has been reported in most types of cancer. However, the functional consequences and clinical relevance of these mutations are not clear.
