Tumor hypoxia
In order to support continuous growth and proliferation in challenging hypoxic environments, cancer cells are found to alter their metabolism.
[1][2] A particular change in metabolism, historically known as the Warburg effect[3] results in high rates of glycolysis in both normoxic and hypoxic cancer cells.
Expression of genes responsible for glycolytic enzymes and glucose transporters are enhanced by numerous oncogenes including RAS, SRC, and MYC.
Hypoxia inducible factor-1α (HIF-1α) is a key oxygen-regulated transcriptional activator, playing a fundamental role in the adaptation of tumor cells to hypoxia by upregulating the transcription of target genes related to multiple biological processes, including cell survival, proliferation, angiogenesis and anti-apoptosis.
With the role of transporting sugars from the extracellular to the intracellular environment, GLUT1, along with other members of the GLUT family, can be rate-controlling for cellular glycolytic metabolism.
Extracellularly, PGI is known as an autocrine motility factor (AMF) eliciting mitogenic, motogenic, differentiation functions as well as tumor progression and metastasis.
[13] Activation of PGI through proposed HIF-1 induced mechanisms results in increased conversion of glucose 6-phosphate to fructose 6-phosphate and also contributes to cell motility and invasion during cancer metastasis.
Allosteric regulation of glycolysis by fructose-2,6-bisphosphate allows cancer cells to maintain a glycolytic balance to match their bioenergetic and biosynthetic demands.
Both protein and mRNA levels were shown to increase 2-3-fold in research exposing fetal rat lung fibroblasts to hypoxic conditions.
Maximum up regulation was shown following 16 hours thus supporting its role in contributing to an increased glycolytic flux for adaption of cells to hypoxia.
Although the exact roles of post-translational modifications have not been completely elucidated, patterns are shown between certain cancer cell types suggesting they may have important influence on function, localization and immunogenicity.
[19] Aside from its role in promoting glycolytic flux and anaerobic energy production, it has been shown to induce a specific humoral and cellular immune response.
On all levels, hypoxia-induced over-expression of enolase 1 may possess important roles in hypoxic tumors including the most straightforward increase in anaerobic respiration.
In cancer cells pyruvate kinase M2 has been shown to interact directly with HIF-1α enhancing HIF-1 binding and p300 recruitment to hypoxia response elements.
[20] Pyruvate kinase M2 is often considered the main regulator of cancer metabolism with roles in various parallel, feed-forward, positive and negative feedback mechanisms.
Pyruvate kinase M2 has metabolic activity regulated by post-translational modifications including acetylation, oxidation, phosphorylation, hydroxylation and sumoylation.
[21] In hypoxic conditions found in a solid tumor, pyruvate kinase M2 plays a large role in promoting anaerobic energy production.
Under anaerobic conditions, such as those found in hypoxic tumors, the TCA cycle provides little ATP yield due to the lack of electron transport chain function.
They also assist in acidifying the extracellular environment and maintaining a slightly alkaline intracellular compartments contributing to tumor cell survival.
Many anti-cancer therapies, including ionizing radiation and many chemotherapeutics, rely on the overproduction of reactive oxygen species to cause genomic instability.
Lactate, as an antioxidant, may act to scrub down the levels of reactive oxygen species thus enhancing resistance to radiation and chemotherapy.
On a completely different note, as briefly discussed above, the autocrine function of phosphoglucose isomerase also promotes cell motility and metastasis.
[32] This shows cyclic variations in oxygenation implying dynamic regulation of the metabolic symbiosis between lactate-producing and lactate-consuming states.
They must coordinate production of precursors for macromolecular synthesis as well as maintain cellular bioenergetics without impairing cell growth, proliferation and viability.
In cases where glycolysis remains highly active in normoxic conditions, NADPH acts as a mediator of antioxidative reactions to protect cells from oxidative damage.
[38] Accordingly, the evaluation of non-invasive hypoxia detection methods, such as positron emission tomography (PET) and magnetic resonance imaging (MRI), has been a subject of intense research for several years.
[50] Threshold Pharmaceuticals discontinued the hypoxia activated prodrug, TH-302, after Phase III trials failed to show statistically significant overall survival.
Niacinamide also inhibits poly(ADP-ribose) polymerases (PARP-1), enzymes involved in the rejoining of DNA strand breaks induced by radiation or chemotherapy.
[54] The results of the Phase II showed that 36% of the full-dose TSC patients were alive at 2 years, compared with historical survival values ranging from 27% to 30% for the standard of care.
Although hyaluronic acid CD44 pathway to target cancer and cancer metastasis has been investigated before; Almoustafa et al. demonstrated that targeting CD44 receptors with Hyaluronic acid coated nanoparticles reduced drug resistance to doxorubicin compared to free drug and to non-targeted nanoparticles.
