Oxygen and glucose consumption in gastrointestinal adenocarcinomas: Correlation with markers of hypoxia, acidity and anaerobic glycolysis

Abstract

This study gives an insight into tumor metabolic activity by investigating oxygen and glucose content, together with their metabolic products carbon dioxide and acids-pH, in the arterial and venous blood of a tumor. Nineteen patients with gastrointestinal adenocarcinomas undergoing surgery were studied. Biochemical analysis showed that in a large subgroup of tumors, oxygen consumption was reduced while that of glucose was increased in malignant, as compared to normal tissues; these features were more evident in tumors overexpressing lactate dehydrogenase ( During the past 15 years important developments in the biology of hypoxia brought forward a group of key transcription factors, namely the hypoxia inducible factors (HIFs) that, being upregulated by hypoxia, control the expression of a variety of genes related to glycolysis and angiogenesis.(2) Apart from hypoxia, however, the HIF pathway is also under oncogenic regulation. Activation of a single oncogene, Akt, is sufficient to stimulate aerobic glycolysis in tumors (3) while Akt is known to activate, under hypoxic conditions, HIF1α as well (4) and this in turn upregulates enzymes involved in anaerobic glycolysis and glucose intrusion. Moreover, the epidermal growth factor pathway stimulates the increased transcription of HIF mRNA. Among others, HIF controls important genes involved in glycolysis and pH regulation, such as: (i) the expression of lactate dehydrogenase A subunit and, hence, the LDH-5 cellular content that promotes the metabolic shift of pyruvate transformation to lactate for energy acquisition; (6) (ii) the expression of glucose transporters (GLUT) membrane pumps involved in glucose absorption, which is used as a fuel; (7) and (iii) the expression of carbonic anhydrase 9 (CA9) that, by regulating the hydration of carbon dioxide to carbonic acid, plays an important role in the acidification of a tumor environment. (8)

Hypoxia and Amino Acid Supplementation Synergistically Promote the Osteogenesis of Human Mesenchymal Stem Cells on Silk Protein Scaffolds

“…In addition, HIFs are believed to promote prolyl hydroxylase enzyme activity, which indirectly promotes collagen matrix synthesis. 44 However, the study suggested that the upregulation of HIF-1a alone is not sufficient to cause an overall significant increase in osteogenesis and metabolism in group 3 (low oxygen).…”

“…6A), which elevates the level of glycolytic enzymes, collagen matrix synthesis enzymes, and angiogenic factors to enhance osteogenesis. [29][30][31]43,44 Due to the increased glycolytic rate, there is an increase in the rate of glucose consumption (Fig. 6).…”

Regulation of tumor pH and the role of carbonic anhydrase 9

“…The current consensus is that, in most tumors, pH i lies between 7.0 and 7.4, similar to non-tumor cells, whereas pH e is typically between 6.9 and 7.0 [14], although values as low as 6.0 have been reported [15]. Indeed, some in vivo tumors can acidify venous blood in patients [16] because of their low pH e (Fig. 1).…”

Non-glucose metabolism in cancer cells—is it all in the fat?

“…Therefore, it is not correct to suggest that aerobic glycolysis is the exclusive ATP-generating system in cancer cells. In reality, in vivo tumors probably rely on both aerobic glycolysis and OXPHOS for their energy, the proportions of which are probably dependent on both the genetic background of the cancer cell (e.g., c-MYC oncogene expression and TP53 mutation), as well as its microenvironment [4], particularly intratumoral hypoxia, which induces hypoxia-inducible factor (HIF)-1α expression, an a priori transcription factor that in turn upregulates glycolytic enzyme gene expression [5].…”