cells are thought to take up this lactate forming a metabolic symbiosis. lactate and cancer the structure of lactic acid it is commonly accepted that cancer cells (both hypoxic and normoxic) produce large amounts of lactate in result of a large metabolic shift from oxidative phosphorylation to altered glycolysis. the high levels of released lactate contribute to immune escape for the tumor cells. activated t cells use glycolysis as an energy source and thus must regulate their own lactate levels. traditionally done by a secretion method, immune cells in a lactate rich environment cannot rid themselves of their own lactate due to the concentration gradient. it is thought that leukocytes may be asphyxiated by lactate while low extracellular phs may also reduce cytotoxic t-cell function. in endothelial cells it has also been shown that lactate stimulates vascular endothelial growth factor (vegf) production leading to enhanced cellular migration in result of lactate-induced angiogenesis recent work has also uncovered that lactate uptake by mct-1 in endothelial cells stimulates nf-κb activation and thus il-8 expression. release of lactate from tumor cells through mct-4 was sufficient to stimulate angiogenesis and tumor growth through an il-8-dependent mechanism. lactate has demonstrated the ability to increase hyaluronan production leading to elevated expression of cd44. hyaluronan is a glycosaminoglycan polymer critical for maintaining extracellular matrix integrity and modulating cell-cell interactions. hyaluronan is tethered to cell surfaces by cd44 which are anchored in caveolin-rich lipid rafts. cleavage and further degradation of hyaluronan is facilitated by hyal2 and hyal1, respectively. increased levels of hyaluronan surrounding carcinomas leads to the promotion of cellular growth and motility. a lactate-sensitive response element for genes in fibroblasts involved in hyaluronan metabolism has been identified. finally, it is also worth noting that lactate concentrations are positively correlated with radioresistance. 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. acidic microenvironment and metastasis it is thought that the low ph of hypoxic tumors in result of high levels of lactic acid can promote tumor cell invasion by destruction of adjacent non-cancerous tissue.> carbonic anhydrase 9 involved in maintaining a slightly alkaline intracellular ph does so by removing carbonate from the extracellular space consequently acidifying the cells surroundings. moreover, proton pumping from the hypoxic tumor cells further decreases the surrounding ph. on a completely different note, as briefly discussed above, the autocrine function of phosphoglucose isomerase also promotes cell motility and metastasis. metabolic symbiosis schematic highlighting the metabolic symbiosis formed between hypoxic and normoxic tumor cells with the hypoxic tumor cells consuming large amounts of glucose to maintain energy homeostasis, the tumor has found a way of using its resources most efficiently. the end glycolytic product of hypoxic tumors, lactate, is transported out of the hypoxic cell by monocarboxylate transporter 4 (mct4) which is a hypoxia-induced transporter. the free lactate in the extracellular space is then taken up by monocarboxylate transporter 1 (mct1) which is a non-hypoxia induced transporter found on the surface of aerobic cells. this transporter allows aerobic cancer cells to efficiently take up lactate, convert it back to pyruvate with the oxygen-dependent expression of lactate dehydrogenase b (ldh-b), and use it as an energy source. this frees these cells from requiring large quantities of glucose allowing the hypoxic cells to take up the majority of the available resources. tumor cells have also shown the remarkable ability to adapt to regional variation of oxygen availability. cancer cells demonstrate the ability to be hypoxic at one point in time and aerobic at the next. this shows cyclic variations in oxygenation implying dynamic regulation of the metabolic symbiosis between lactate-producing and lactate-consuming states. the pentose phosphate pathway in order to meet the demands of rapid tumor growth, the tumor must find ways to support the synthesis of a complete daughter cell while facing depleting nutrient supplies. they must coordinate production of precursors for macromolecular synthesis as well as maintain cellular bioenergetics without impairing cell growth, proliferation and viability. one way of doing this is by shuffling glycolytic intermediates such as glucose-6-phosphate into the pentose phosphate pathway to give ribose-5-phosphate and nadph. ribose-5-phosphate acts as an intermediate for the production of nucleotides thus providing a connection between glycolysis and nucleotide synthesis in hypoxic tumor cells. in cases where glycolysis remains highly active in normoxic conditions, nadph acts as a mediator of antioxidative reactions to protect cells from oxidative damage. cancer treatments and tumor hypoxia radiotherapy the presence or absence of oxygen has a strong influence on ionizing radiation to cause cell death of tumour and normal cells. this is called the oxygen effect. under hypoxic conditions it has been shown that cells obtain radioresistance through hif-1 mediated mechanisms. to overcome this problem, radiation oncologists have developed powerful tools and approaches such as simultaneous integrated boost intensity-modulated radiation therapy (sib-imrt), which enables a booster dose of radiation to be delivered to small target fractions in a malignant tumor, hypoxia-selective cytotoxins/drugs, and hif-1 inhibitors. moreover, it is possible to treat a hypoxic tumor by means of ion beam therapy, in particular with 12c. as ions' damage is direct, oer (oxygen enhancement ratio) is 1, so the effect of oxygen it is not important. an important approach of hypoxia-related treatment interventions is a procedure called dose painting, in which a higher radiation dose is targeted to hypoxic subvolumes of tumor. however, one of the major challenges is a lack of clinically applicable method to detect tumor hypoxia. 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. pet imaging is the preferred method in clinical use, and the most investigated pet radiotracers for imaging of tumor hypoxia are 18f-fmiso, 18f-ef5, 18f-faza and 18f-hx4. the feasibility of hypoxia pet based dose painting is already being evaluated in a few interventional clinical trials. other treatment options bioreductive prodrugs play a significant part in dealing with these kinds of cells: they can kill the oxygen-deficient tumor cells selectively as hypoxia-activated prodrugs. example drugs include tirapazamine and evofosfamide. the study of tumors in such conditions was pioneered by dr l. h. gray. targeting tumor hypoxia to overcome metastasis an association between tumor hypoxia and metastatic progression has been shown through numerous publications. drug development several approaches have been taken to address tumor hypoxia. some companies tried to develop drugs that are activated in hypoxic environments (novacea, inc. proacta, inc, and threshold pharmaceuticals, inc), while others are currently seeking to reduce tumor hypoxia (diffusion pharmaceuticals, inc. and nuvox pharma, llc). several companies have tried to develop drugs that are activated in hypoxic environments. these drug candidates target levels of hypoxia that are common in tumors but are rare in normal tissues. the hypoxic zones of tumors generally evade traditional chemotherapeutic agents and ultimately contribute to relapse. in the literature, hypoxia has been demonstrated to be associated with a worse prognosis, making it a determinant of cancer progression and therapeutic response several review articles summarize the current status of hypoxic cytotoxins (hypoxia activated prodrugs). companies that have tried drugs that are activated in hypoxic environments included novacea, inc. proacta, and threshold pharmaceuticals. novacea inc discontinued development of its hypoxia activated drug. proacta's drug pr610 failed a phase i clinical trial due to toxicity. threshold pharmaceuticals discontinued the hypoxia activated prodrug, th-302, after phase iii trials failed to show statistically significant overall survival. niacinamide, the active form of vitamin b3, acts as a chemo- and radio-sensitizing agent by enhancing tumor blood flow, thereby reducing tumor hypoxia. niacinamide also inhibits poly(adp-ribose) polymerases (parp-1), enzymes involved in the rejoining of dna strand breaks induced by radiation or chemotherapy. as of august 2016, no clinical trials appear to be in progress for this indication. another approach to the treatment of tumor hypoxia is the use of an oxygen diffusion-enhancing compound to reoxygenate the hypoxic zones of tumors. the developer of oxygen diffusion-enhancing compounds, diffusion pharmaceuticals, tested its lead compound, trans sodium crocetinate (tsc), in a phase ii clinical trial in 59 patients newly diagnosed with glioblastoma multiforme. 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. the main endpoint of the trial was survival at two years, not overall survival. another drug in development that is designed to reduce tumor hypoxia is nuvox pharma's nvx-108. nvx-108 is a formulation of the perfluorocarbon, dodecafluoropentane (ddfpe). nvx-108 is injected intravenously, flows through the lungs and picks up oxygen, then flows through the arteries and releases oxygen in the presence of hypoxic tissue. a phase ib/ii clinical trial is in progress for newly diagnosed glioblastoma multiforme. early results have shown reversal of tumor hypoxia, and the trial continues to progress. another approach to target hypoxia is to use nanoparticles coated or loaded with specific targeting moieties. 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. however, more preclinical research should be conducted using hypoxia modeling in vitro and in vivo.