On metabolic reprogramming and tumor biology: A comprehensive survey of metabolism in breast cancer

Abstract

Altered metabolism in tumor cells has been a focus of cancer research for as long as a century but has remained controversial and vague due to an inhomogeneous overall picture. Accumulating genomic, metabolomic, and lastly panomic data as well as bioenergetics studies of the past few years enable a more comprehensive, systems-biologic approach promoting deeper insight into tumor biology and challenging hitherto existing models of cancer bioenergetics. Presenting a compendium on breast cancer-specific metabolome analyses performed thus far, we review and compile currently known aspects of breast cancer biology into a comprehensive network, elucidating previously dissonant issues of cancer metabolism. As such, some of the aspects critically discussed in this review include the dynamic interplay or metabolic coupling between cancer (stem) cells and cancer-associated fibroblasts, the intratumoral and intertumoral heterogeneity and plasticity of cancer cell metabolism, the existence of distinct metabolic tumor compartments in need of separate yet simultaneous therapeutic targeting, the reliance of cancer cells on oxidative metabolism and mitochondrial power, and the role of pro-inflammatory, pro-tumorigenic stromal conditioning. Comprising complex breast cancer signaling networks as well as combined metabolomic and genomic data, we address metabolic consequences of mutations in tumor suppressor genes and evaluate their contribution to breast cancer predisposition in a germline setting, reasoning for distinct personalized preventive and therapeutic measures. The review closes with a discussion on central root mechanisms of tumor cell metabolism and rate-limiting steps thereof, introducing essential strategies for therapeutic targeting.

Glycine and succinic acid are effective indicators of the suppression of epithelial-mesenchymal transition by fucoxanthinol in colorectal cancer stem-like cells

“…Positive aerobic glycolysis and subsequent metabolic reprogramming in cancer cells are collectively known as the Warburg effect (31). Various researchers have demonstrated the impact of the Warburg effect on the metabolite profiles of CSCs or CSC-like spheroids reconstructed from original breast, colorectal, hepatic and ovarian cancer PCs (32)(33)(34)(35)(36). Among the amino acids, aspartate, serine, glutamic acid and glutamine are assumed to be particularly good targets for cancer therapeutics in CSCs.…”

The reverse Warburg effect is likely to be an Achilles' heel of cancer that can be exploited for cancer therapy

“…Despite huge differences between the two metabolic phenotypes, they seem to be reconciled with each other due to the complex metabolic plasticity and regulation. Moreover, the metabolic diversity of cancer tissue reflects rapidly adaptation to the drastic changes in nutrient environment [ 98 ].…”

Does the 1H-NMR plasma metabolome reflect the host-tumor interactions in human breast cancer?

“…A second hypothesis to explain these observations could be that cancer cells and their microenvironment consume lactate leading to its levels drop with growing tumor mass. Several facts do not support such a speculation: cancer cells themselves produce and excrete large amounts of lactate in their stroma where this metabolite plays subtle and complex roles favoring tumor progression [ 21 , 22 ]; Kallinowski F. et al showed that in human breast cancer xenografts in nude rats, lactate is released from tumors [ 23 ]; Kennedy KM. et al found that, in vitro , lactate can be metabolized by some but not all types of BC cells [ 24 ].…”