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.
Highlights
Mitochondria are sub-cellular organelles that produce adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS)
New molecular mitochondrial markers might be of pivotal importance as histopathologic subtypes of cancer are associated with distinct clinical manifestations, but their diagnosis is often difficult because some tumor subtypes have overlapping microscopic characteristics
Ancillary methods are needed to optimize classification and we believe that distinct mitochondrial gene mutation-polymorphism profiles might serve as adequate pathologic markers [76]
Summary
It is hard to neglect the importance of mitochondria in cancer biology. Polymorphisms (and mutations) of mtDNA, even driven by random processes during malignant transformation, present an excellent possibility for early tumor detection by analyzing the bodily fluids from patients with tumors [74,75]. New molecular mitochondrial markers might be of pivotal importance as histopathologic subtypes of cancer are associated with distinct clinical manifestations, but their diagnosis is often difficult because some tumor subtypes have overlapping microscopic characteristics. The analysis based on mito-markers could significantly enhance the specificity of cancer detection and prediction of tumor behavior, as well as of patient outcome (see Figure 2) [77]. Mitochondrial polymorphisms may be candidates for cancer biomarkers, and deserve further investigation, perhaps through the use of experimental models including cybrids and analysis of large cohorts of patients. Carriers of some germ-line mtDNA polymorphism could be more susceptible to cancer development and selected as candidate population for intensive prevention and early detection programs [2,4,12,46]. Authors' contributions AMC, JSC, FC, WK - have made substantial contributions to the conception and design of the paper, AMC, AK, WK - have been involved in drafting the manuscript, JSC, AMC - have designed and drawn figures, AS, AK- revised and corrected the manuscript
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