current page: Introduction

Introduction

Aggressive carcinomas ferment glucose to lactate even in the presence of oxygen. This particular metabolism, termed aerobic glycolysis, the glycolytic phenotype, or the “Warburg effect”, was discovered by Nobel laureate Otto Warburg in the 1920s. Since these times, controversial discussions about the relevance of the fermentation of glucose by tumours took place; however, a majority of cancer researchers considered the Warburg effect as a non-causative epiphenomenon. Recent researches demonstrated, that several common oncogenic events favour the expression of the glycolytic phenotype. Moreover, a suppression of the phenotypic features by either substrate limitation, pharmacological intervention, or genetic manipulation was found to mediate potent tumour-suppressive effects. Dr. J. F. Coy firstly recognised at his discoveries that the Transketolase-like 1 (TKTL1) enzyme in aggressive cancers delivers the missing link in the interpretation of the Warburg effect: TKTL1-activity is the basis for a rapid fermentation of glucose in aggressive carcinoma cells via the pentose phosphate pathway, which leads to matrix acidification, invasive growth, and ultimately metastasis. TKTL1 expression in certain non-cancerous tissues correlates with aerobic formation of lactate and rapid fermentation of glucose, which may be required for the prevention of advanced glycation end products and the suppression of reactive oxygen species. So far, three human Transketolase genes, TKT, TKTL1 and TKTL2, have been identified, and their relevance to tumour-specific aerobic glycolysis investigated. By now, many investigations have shown that with the discovery of the enzyme Transketolase-like 1 (TKTL1), one of the key enzymes of the non-oxidative part of the Pentose Phosphate Pathway , it is now possible to understand the biochemical principles of the Warburg effect. Several publications have TKTL1

This changed pathway for the generation of energy is accompanied by an elevated resistance to radical and apoptosis inducing therapies like radiation and chemotherapy. Furthermore, the elevated lactic acid produced by this energy metabolism protects the cancer cell from the attack of the body’s immune system and in addition leads to matrix degradation which results in enhanced invasiveness and metastasis. A growing number of studies have shown that elevated expression of TKTL1 is predictive for this changed energy metabolism of the cancer cell and is also a marker for poor survival of cancer patients.

Recent studies, done during a PhD Thesis at the DKFZ Heidelberg1 and the recent publications, show the validity and relevance of this new target.