Molecular oncology focus - is carcinogenesis a 'mitochondriopathy'?

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.

Figure 1

The three - horn dilemma in molecular mitochondrial marker oncology research. The figure represents the interdependence of factors that should be considered in mitochondrial oncology experiments design.

Figure 2

Possible usage of mitochondrial bio-markers in cancer screening, diagnostics and prognosis. The co-dependence of mitochondrial failure (orange) and cancer development (red); mitochondrial disruption is accompanied by cell transformation and cancer development (red/orange-blue dashed area). At each stage of tumor growth, mitochondrial markers (purple, pink, yellow) may be used, and provide new tools of clinical utility, hence uniting molecular biology (green) and clinical diagnostics (blue) in 'mitochondrial oncology' (blue-green dashed area).