Abstract
Metabolism is essential for life, and its alteration is implicated in multiple human diseases. The transformation from a normal to a cancerous cell requires metabolic changes to fuel the high metabolic demands of cancer cells, including but not limited to cell proliferation and cell migration. In recent years, there have been a number of new discoveries connecting known aberrations in oncogenic and tumour suppressor pathways with metabolic alterations required to sustain cell proliferation and migration. However, an understanding of the selective advantage of these metabolic alterations is still lacking. Here, we review the literature on mathematical models of metabolism, with an emphasis on their contribution to the identification of the selective advantage of metabolic phenotypes that seem otherwise wasteful or accidental. We will show how the molecular hallmarks of cancer can be related to cell proliferation and tissue remodelling, the two major physiological requirements for the development of a multicellular structure. We will cover different areas such as genome-wide gene expression analysis, flux balance models, kinetic models, reaction diffusion models and models of the tumour microenvironment. We will also highlight current challenges and how their resolution will help to achieve a better understanding of cancer metabolism and the metabolic vulnerabilities of cancers.
Highlights
The hallmarks of cancer [1] highlight major processes and mechanisms required for cancer development
Pathway expression analysis is probably the best means to understand the heterogeneity of metabolism across cancers and to create hypotheses about major cancer metabolism subtypes
Flux balance models are a flexible framework to investigate the selective advantage of different metabolic pathways depending on the environmental conditions and the metabolic objective
Summary
The hallmarks of cancer [1] highlight major processes and mechanisms required for cancer development. The discussions above about metabolic signatures associated with tissue of origin, cell proliferation and tissue remodelling are examples of pathway analysis applications to investigate the differential utilization of metabolic pathways across cancer subtypes. Genome-scale flux balance models The metabolic pathway analyses described above are based on pathway annotations and gene expression alone. A mathematical model of energy metabolism based on flux balance, the minimization of nutrient utilization together with the macromolecular capacity constraint, is sufficient to explain the Warburg effect [41]. Flux balance models can be further constrained to take into account metabolic enzyme expression patterns that are specific to a given tissue or that are the consequence of molecular alterations present in cancer cells. The key factors are the enzyme turnover rate, the enzyme concentration, a substrate saturation term and a thermodynamics term associated with the enzyme properties at
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
