Specific alterations of carbohydrate metabolism are associated with hepatocarcinogenesis in mitochondrially impaired mice

Thierbach, René; Florian, Simone; Wolfrum, Katharina; Voigt, Anja; Drewes, Gunnar; Blume, Urte; Bannasch, Peter; Ristow, Michael; Steinberg, Pablo

doi:10.1093/hmg/ddr499

Cited by 7 publications

(8 citation statements)

References 43 publications

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“…However, the peripheral abnormal structures were composed mainly of dying, frataxin-deficient hepatocytes whereas the inner liver structure in these mice contained proliferating frataxin-positive hepatocytes that contributed to liver regeneration, increased survival and an increase in body weight. The tumor-like lobules therefore appeared to be degenerating liver masses rather than composed by proliferating cancer cells, as previously suggested by Thierbach and colleagues (Thierbach et al, 2010; Thierbach et al, 2012; Thierbach et al, 2005). Together, our data demonstrate that an association between frataxin deficiency and tumorigenesis should be reconsidered.…”

Section: Introductionsupporting

confidence: 70%

“…Thus, although we cannot prove that FRDA has no association with cancer, particularly for rare forms of cancer, the clinical data presented here and published elsewhere (Tsou et al, 2011) do not support such an association. Furthermore, it is worth pointing out that, in particular, no liver cancer was detected in the natural history of the cohorts analyzed herein, despite reports of tumors in the liver conditional mouse model (Thierbach et al, 2010; Thierbach et al, 2012; Thierbach et al, 2005). …”

Section: Discussionmentioning

confidence: 73%

“…The idea that frataxin might be a tumor suppressor is essentially based on the evidence of tumor-like structure formation in a mouse model in which Fxn was specifically deleted in liver ( Alb-Cre-Fxn L3/L− mice) (Thierbach et al, 2010; Thierbach et al, 2012; Thierbach et al, 2005). To confirm whether frataxin depletion triggers tumorigenesis in mouse liver, we raised a new generation of liver-specific conditional mice.…”

Section: Resultsmentioning

confidence: 99%

“…While ageing, liver regeneration can eventually take over in some Alb-Cre-Fxn L3/L− mice, thus rescuing the phenotype resulting from early Fxn deletion and allowing mice to survive. Therefore, data obtained with Alb-Cre-Fxn L3/L− mice should be taken with care if old mice have been used to characterize the consequences of frataxin deficiency, such as in the recently reported reversion of carbohydrate metabolism impairment observed between 5-week-old and 17-month-old Alb-Cre-Fxn L3/L− mice (Thierbach et al, 2012). …”

Section: Discussionmentioning

confidence: 99%

“…Among the mouse models of FRDA, the conditional Fxn deletion in liver was reported to trigger tumorigenesis (Thierbach et al, 2010; Thierbach et al, 2012; Thierbach et al, 2005), suggesting that frataxin is a tumor suppressor protein and that FRDA might be associated with a predisposition to cancer. At the molecular level, tumorigenesis in frataxin-deficient cells was proposed to be the result of higher cellular sensitivity to oxidative stress and impaired capacity of the cellular DNA repair machinery (Thierbach et al, 2010; Thierbach et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Clinical data and characterization of the liver conditional mouse model exclude neoplasia as a non-neurological manifestation associated with Friedreich's ataxia

Martelli

Friedman

Reutenauer

et al. 2012

Disease Models &Amp; Mechanisms

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SUMMARYFriedreich’s ataxia (FRDA) is the most common hereditary ataxia in the caucasian population and is characterized by a mixed spinocerebellar and sensory ataxia, hypertrophic cardiomyopathy and increased incidence of diabetes. FRDA is caused by impaired expression of the FXN gene coding for the mitochondrial protein frataxin. During the past ten years, the development of mouse models of FRDA has allowed better understanding of the pathophysiology of the disease. Among the mouse models of FRDA, the liver conditional mouse model pointed to a tumor suppressor activity of frataxin leading to the hypothesis that individuals with FRDA might be predisposed to cancer. In the present work, we investigated the presence and the incidence of neoplasia in the largest FRDA patient cohorts from the USA, Australia and Europe. As no predisposition to cancer could be observed in both cohorts, we revisited the phenotype of the liver conditional mouse model. Our results show that frataxin-deficient livers developed early mitochondriopathy, iron-sulfur cluster deficits and intramitochondrial dense deposits, classical hallmarks observed in frataxin-deficient tissues and cells. With age, a minority of mice developed structures similar to the ones previously associated with tumor formation. However, these peripheral structures contained dying, frataxin-deficient hepatocytes, whereas the inner liver structure was composed of a pool of frataxin-positive cells, due to inefficient Cre-mediated recombination of the Fxn gene, that contributed to regeneration of a functional liver. Together, our data demonstrate that frataxin deficiency and tumorigenesis are not associated.

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Section: Introductionsupporting

confidence: 70%