Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2009) 20 S22.1

ECE2009 Symposia Tumorigenesis in pheochromocytoma/paraganliomas (4 abstracts)

The Warburg effect in pheochromocytoma: a link between genetic disorders and cell metabolism

Judith Favier


INSERM U772, Paris, France.


Tumorigenesis and intermediary metabolism have a long common history. Eighty years ago, the biochemist Otto Warburg pioneered a large field of researches devoted to the metabolism of tumour cells. He reported a spectacular shift from a normal aerobic metabolism to a highly glycolytic metabolism, associated with a low respiration rate, despite aerobic conditions. After being forgotten for decades, a renewed interest in the Warburg effect has resulted from the report that, mitochondrial enzyme involved in the tricarboxylic acid cycle, also known as the Krebs Cycle, can act as tumor suppressor genes in hereditary tumor syndrome.

Three of the four subunits of succinate dehydrogenase, or mitochondrial complex II, namely, SDHB, SDHC, and SDHD, have been involved in the tumorigenesis resulting in paragangliomas and pheochromocytomas. Primary mutations in the fumarase hydratase (FH)-encoding gene unexpectedly result in uterine fibroids, skin leiomyomata, and papillary renal cell cancer. These inactivation seem to have a common pathway with the Von Hippel Lindau (VHL) tumor suppressor gene inactivation, as they all lead to the abnormal activation of hypoxia-inducible factors (HIF) in normoxic conditions, a phenomenon know as pseudo-hypoxia.

We used the heterogeneous genetic determinism of pheochromocytomas as a tool to decipher the molecular basis for the Warburg effect and its link with pseudohypoxia in tumors. We studied oxidative phosphorylation (OXPHOS), angiogenesis and glycolysis in pheochromocytomas induced by germ-line mutations in VHL (Von Hippel Lindau disease type 2A, 2B and 2C) and compared them to those associated with mutations in RET, NF1 and SDH genes. SDH, VHL-2A and VHL-2B tumors, but not RET, NF1 and VHL-2C pheochromocytomas, have been suggested to be related to a pseudo-hypoxic drive. Our findings suggest an unexpected association between pseudohypoxia and loss of p53, which leads to a distinctive Warburg effect, specifically in VHL-2A- and -2B-related pheochromocytomas. This study illustrates how the molecular consequences of genetic disorders can strongly modulate metabolic functions in tumor tissues.

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