7 Cancer Pathways Simply Explained
Cancer cells alter their metabolic requirements to ensure optimal nutrient use for their survival, evasion from host immune attack, and proliferation.
Cancer cells utilise different pathways to survive and proliferate. The glucose (glycolysis) pathway is NOT the only one.
Let's take a look:
Glycolysis pathway provides cancer cells with ATP to form nucleotides, amino acids (AAs) and lipids, and to maintain cancer cells redox homeostasis. Pyruvate is produced by glycolysis. Pyruvate is converted to lactate. Lactate favours cancer cells reproduction. THEREFORE, reduction of glycolysis in cancer cells will compromise their biosynthesis and alter their redox balance.
Cancer cells can produce ATP with oxidative phosphorylation pathway (OXPHOS). OXPHOS maintains intracellular redox balance to enable synthesis of AAs aspartate and asparagine as well as de novo synthesis of nucleotides. Metformin/Berberine are the most studied OXPHOS inhibitors in the clinical settings.
Tricarboxylic acid cycle (TCA) pathway: Multiple cancers harbour mutations or deletions in TCA cycle enzymes isocitrate dehydrogenase (IDH), fumarate hydratase (FH), succinate dehydrogenase (SDH) and succinyl-CoA ligase (SUCL). TCA removes epigenetic marks from the chromatin, affects epigenetics and promotes transformation and progression of tumorigenesis.
Glutaminolysis Pathway: Glutamine, a non-essential AA, is utilised by cancer cells for biomass synthesis and as a source of energy. To meet the increased metabolic needs of rapid proliferation, glutamine is supplied through blood at a concentration as high as 0.5 mM! For example, KRAS-mutated cancer cells are addicted to glutamine.
Amino Acids pathway (3)
a) L-asparaginase is effective because the enzyme asparagine synthase (ASNS, responsible for endogenous asparagine synthesis) is decreased in some cancer cells, making them dependent on exogenous asparagine for proliferation.
b) Methionine is an essential AA, still the dependence of cancer cell on methionine is particularly pronounced. Additionally, reducing methionine availability to cancer cells could stimulate immune response.
c) Proline is a non-essential amino acid. Nevertheless, proline synthesis enzymes are frequently unregulated in cancer. Proline synthesis supports cancer cell proliferation.
Fatty acid metabolism pathway: Fatty acid (FA) metabolism is important for proliferation and survival of cancer cells under conditions of glucose limitation. FAs could potentially also dampen the innate antitumor immune response, namely its most important effectors, the NK cells. In a lipid rich environment, NK cells tend to accumulate and store lipids to prevent lipid toxicity, but when this intracellular lipid accumulation becomes excessive, it can disrupt proper NK cell function.
Nucleotides pathway: In highly proliferating cells, purine and pyrimidine nucleotides are indispensable for nucleic acid synthesis. Tetrahydrofolate is essential in the production of purines and pyrimidines, and its deficiency results in lower DNA, RNA and protein synthesis. THEREFORE, antifolates are important to reduce purines and pyrimidines.
There is emerging evidence regarding the role of stromal components, creating an intricate metabolic network consisting of cancer cells, cancer-associated fibroblasts, endothelial cells, immune cells, and cancer stem cells. This metabolic rewiring and crosstalk with the tumour microenvironment play a key role in cell proliferation, metastasis, and the development of treatment resistance. Blocking or altering the 7 pathways is important to reduce proliferation and survival of tumour cells. However, such metabolic therapy is challenged by the diversity of cancers. A type of cancer might not need to follow all those pathways. Therapies must be individualised.
Li J, Eu JQ, Kong LR, Wang L, Lim YC, Goh BC, Wong ALA. Targeting Metabolism in Cancer Cells and the Tumour Microenvironment for Cancer Therapy. Molecules. 2020 Oct 20;25(20):4831. doi: 10.3390/molecules25204831. PMID: 33092283; PMCID: PMC7588013.
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