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can vitamin b12 deficiency be a sign of cancer
Hartmann N., McMurtrey C., Sorensen M.L., Huber M.E., Kurapova R., Coleman F.T., Mizgerd J.P., Hildebrand W., Kronenberg M., Lewinsohn D.M., et al. The relevance of B1 in immunometabolism was illustrated in mice fed a B1-deficient diet that curtailed the maintenance of nave B cells but had little effect on differentiated IgA producing plasma cells [9]. New animal bioassays of It can be caused by a B12 deficiency (24). Vitamin B12 Deficiency: Symptoms, Causes & Treatment The hypoxia-inducible factor Hif-1 increases thiamine uptake in tumor cells under hypoxic conditions [19]. One-carbon metabolism-related micronutrients intake and risk for hepatocellular carcinoma: A prospective cohort study. Finally, a meta-analysis of prostate cancer risk found that both vitamin B9 and B12 were positively associated [136]. UP NEXT. [4] Without treatment, some of these problems may become permanent. Vanin-1-/- mice exhibit a glutathione-mediated tissue resistance to oxidative stress. Hypercobalaminemia (high serum vitamin B12 levels) is a frequent and underestimated anomaly. B vitamins and their corresponding vitamers are universally essential for all cellular life forms, from bacteria to humans. B Vitamins and Their Role in Immune Regulation and NAD-dependent enzymes are involved in base excision repair [50]. Jane, energy drinks contain so much vitamin B12 because of its energy reputation. PLP acts as a cosubstrate (phosphate donor) for glycogen phosphorylase. Lo-Bisgaard T., Espelund U., Frystyk J., Rasmussen T.R., Nexo E., Arendt J.F.H. Kim Y.I. These mice also attenuated chemically induced inflammation in models of colitis [77]. These activities have highlighted vitamin B6s potential role in genome stability and epigenetic regulation [126]. Indeed, B vitamin auxotrophs for vitamins B1, B2, B3, B5 and B9 represent ~2025% of bacterial communities, whereas B7 and B12 auxotrophy is more prevalent comprising 30 and >50% of the microbial community, respectively [3]. Spence J.T., Koudelka A.P. If youre diagnosed with too low B12 levels, your healthcare professional will recommend the most appropriate treatment. Is high vitamin B12 status a cause of lung cancer? Kim S.J., Zuchniak A., Sohn K.J., Lubinski J., Demsky R., Eisen A., Akbari M.R., Kim Y.I., Narod S.A., Kotsopoulos J. This article. Cancarini I., Krogh V., Agnoli C., Grioni S., Matullo G., Pala V., Pedraglio S., Contiero P., Riva C., Muti P., et al. Biosynthesis of riboflavin uses ribose-5-phosphate and GTP as substrates. A study of rats exposed to 1,2-dimethylhydrazine to induce intestinal damage observed that vitamin B6 supplementation reduced the expression of alkaline phosphatase, a marker of intestinal damage and reduced cell proliferation [87]. One-carbon metabolism refers to a complex network of biochemical pathways involving homocysteine, methionine and B vitamins (B2, B6, B9 and B12). The active form of thiamine is thiamine pyrophosphate (TPP). Animal studies allow a more direct assessment of individual B vitamers and in some cases give greater clarity of the beneficial and detrimental effects of B vitamin consumption. Pernicious anemia causes vitamin B12 deficiency and can lead to serious nervous system symptoms if untreated. Nicotinate, nicotinamide or N-ribosyl nicotinamide that is converted to nicotinic acid mononucleotide is subsequently used to form NAD in a two-step reaction. Testosterone and Estrogen Levels in Women. Learn more about the causes of vitamin B12 deficiency. The site is secure. Al-Harbi N.O., Imam F., Nadeem A., Al-Harbi M.M., Korashy H.M., Sayed-Ahmed M.M., Hafez M.M., Al-Shabanah O.A., Nagi M.N., Bahashwan S. Riboflavin attenuates lipopolysaccharide-induced lung injury in rats. Many adults and kids who have B12 deficiency report experiencing paresthesia, a burning or pins-and-needles sensation in certain areas of the body like the hands and feet. Folate deficiency has also been linked to reduced DC maturation and effector functions including: reduced IL-2, TNF-, IL-6 and IL1- in response to LPS stimulation. Additionally, certain medicines can interfere with B12 absorption including chloramphenicol, metformin, proton pump inhibitors and histamine. Makino E., Fukuyama T., Watanabe Y., Tajiki-Nishino R., Tajima H., Ohnuma-Koyama A., Takahashi N., Ohtsuka R., Okazaki Y. Subacute oral administration of folic acid elicits anti-inflammatory response in a mouse model of allergic dermatitis. Progesterone Test. Liver Physiol. A meta-analysis of 27 studies involving nearly 50,000 cases and over 1.2 million individuals analyzing riboflavin and other B vitamins concluded that B2 might decrease the risk of breast cancer, although significance was borderline [44]. Kayashima T., Tanaka K., Okazaki Y., Matsubara K., Yanaka N., Kato N. Consumption of vitamin B6 reduces colonic damage and protein expression of HSP70 and HO-1, the anti-tumor targets, in rats exposed to 1,2-dimethylhydrazine. In addition to learning about your symptoms and giving you a physical exam, a healthcare professional can rule out a B12 deficiency by ordering various blood tests(2). The type I interferon signaling pathway was activated under folic acid insufficiency. These results suggest an alternative mechanism for these B vitamins absorption other than through SMVT. Hansen M.F., Jensen S., Fchtbauer E.M., Martensen P.M. High folic acid diet enhances tumour growth in PyMT-induced breast cancer. Progesterone Test. http://creativecommons.org/licenses/by/4.0/. A study of an Italian ORDET cohort including 391 breast cancer cases and B vitamin intake indicated that, overall, thiamine was protective and particularly protective in estrogen- and progesterone receptor-negative HER2-positive cases [23]. In the following sections, we describe a newly discovered source of B vitamins, as well as experimental and clinical findings that relate each B vitamin to its role in immune regulation and the related area of cancer. Methods A systematic search was performed in PubMed, Web of In rats treated with LPS to induce endotoxemia, high-dose niacin inhibited NF-B activation and inflammatory cytokine gene expression in lungs and tissue damage, thereby increasing survival. Vitamin B12 deficiency is determined as follows (2): Because the ability to absorb B12 from food declines with age, deficiency is more common in older adults. Severe asthma in children. This differential response is consistent with other data indicating that folic acid supplementation impacts cell migration and metastasis. 8600 Rockville Pike Dusitanond P., Eikelboom J.W., Hankey G.J., Thom J., Gilmore G., Loh K., Yi Q., Klijn C.J., Langton P., van Bockxmeer F.M., et al. TPP serves as a cofactor for steps regulating the pentose phosphate cycle, fate of pyruvate and the tricarboxylic acid cycle. Cheng W.W., Wang Z.K., Shangguan H.F., Zhu Q., Zhang H.Y. Here we review the expanding literature examining the relationship between B vitamins and the immune system and diverse cancers. The role of SIRT1 on DNA damage response and epigenetic alterations in cancer. Two common types of GERD medicines have been associated with B-12 deficiency to varying degrees: Kok D.E., OFlanagan C.H., Coleman M.F., Ashkavand Z., Hursting S.D., Krupenko S.A. Detailed understanding of methionine dependence of tumors is an area of active research to identify potential novel drug targets. vitamin B-12 deficiency WebMD Niacin signals through GPR109A, the same receptor as the short chain fatty acid (SCFA), butyrate. The methionine cycle requires methionine to generate cysteine, a key component of a third pathway referred to as trans-sulfuration, which generates glutathionea mediator of redox balance, inhibitor of ROS-induced oxidative stress and which generates SAM. NK cell activity was compromised in association with free unmetabolized folic acid illustrating the importance of achieving a proper balance between folate and B12 levels. Indeed, it is likely that MAIT cells primary function may be to protect the host from bacterial infection. Vitamin B12 deficiency can cause various symptoms, and you may wonder whether weight gain is among them. This article explains the benefits, downsides, and more of vitamin B12 liquid supplements. Pantothenate is then converted in a multistep reaction to CoA. Niacin increases adiponectin and decreases adipose tissue inflammation in high fat diet-fed mice. This step regenerates DHF for continued cycling. In a large meta-analysis of patients (757,185 subjects) for all cancers, elevated B12 was identified as a risk factor for cancer; this was particularly evident in liver, pancreatic and myeloid malignancies [135]. A study of B vitamins involved in one-carbon metabolism in the setting of esophageal cancer found that vitamin B2 and B12 were positively correlated with cancer risk, whereas vitamin B6 and B9 were inversely correlated [94]. one of the signs of anemia is Everyone needs vitamin B-12, and most people get enough through their diet. The speculation of a role for thiamine in cancer stems from its role in mediating enzyme activities that are relevant to tumor cells increased proliferation and accompanying energy demands. WebHealth Checklist for Women Over 40. Additional animal studies show that nicotinamide suppressed chemically induced lung tumors, liver tumors, non-lymphocytic leukemia and kidney tumors [70]. Powers H.J. . Estrogen Test. These results have been recapitulated in humans [56]. UP NEXT. The inhibition of cell proliferation in these models was assumed or verified as being correlated with elevated PLP. The effects of vitamin B(6) compounds on cell proliferation and melanogenesis in B16F10 melanoma cells. WebCauses Diagnosis Treatment Complications Vitamin B12 or folate deficiency anaemia occurs when a lack of either of these vitamins affects the body's ability to produce fully functioning red blood cells. Shortness of breath, fatigue, cold hands and feet. Su G., Sun G., Liu H., Shu L., Zhang J., Guo L., Huang C., Xu J. Niacin suppresses progression of atherosclerosis by inhibiting vascular inflammation and apoptosis of vascular smooth muscle cells. Focus on ascorbic acid. The mechanism proposed for this effect was due to increased expression of apoptotic genes and decreases in antiapoptotic factors [40]. Li S.S., Tan H.Z., Xu Y.W., Wu Z.Y., Wu J.Y., Zhao X.K., Wang L.D., Long L., Li E.M., Xu L.Y., et al. Fania L., Mazzanti C., Campione E., Candi E., Abeni D., Dellambra E. Role of nicotinamide in genomic stability and skin cancer chemoprevention. Breast Biopsy. Vitamin B12 is a nutrient you need for good health. Several studies have demonstrated the bioactivity of B6 and its vitamers in cancer models in vitro as inhibitors of cell proliferation, enhancement of chemotherapy cytotoxicity and alterations in gene expression. Therapeutic role of niacin in the prevention and regression of hepatic steatosis in rat model of nonalcoholic fatty liver disease. SAM is demethylated during the methyltransferase reactions to form S-adenosylhomocysteine (SAH) which is then hydrolysed by S-adenosylhomocysteine hydrolase (AHCY) to form Hcy. Gupta T.K., Vishnuvajjala B.R., Witiak D.T., Gerald M.C. The variation in B vitamin demands represents a complex relationship between the absorption, stability and number of enzymes requiring these cofactors. Humans are unable to synthesize most B vitamins and are therefore dependent on their diet for these essential micronutrients. Using apoE-null mice provided a diet rich in methionine but depleted in vitamins B6, B9 and B12, increased cardiovascular signatures were found to develop in said mice, including elevated expression of the receptor for advanced glycation products, VCAM-1 and MMP-9 in the vasculature; provision of the B vitamins alleviated these effects [130]. Vitamin B12 deficiency Structure, mechanism and catalytic duality of thiamine-dependent enzymes. After the treatment, 84% of the participants reported significant improvements in symptoms, like poor focus, memory decline, and forgetfulness (21). Gebhard K.J., Gridley D.S., Stickney D.R., Shulz T.D. Protective role of benfotiamine, a fat-soluble vitamin B1 analogue, in lipopolysaccharide-induced cytotoxic signals in murine macrophages. Summary. Berruyer C., Pouyet L., Millet V., Martin F.M., LeGoffic A., Canonici A., Garcia S., Bagnis C., Naquet P., Galland F. Vanin-1 licenses inflammatory mediator production by gut epithelial cells and controls colitis by antagonizing peroxisome proliferator-activated receptor gamma activity. In humans, several FAD-dependent enzymes, such as glutathione reductase, that facilitate the redox cycle of glutathione point to riboflavins role as a regulator of oxidative stress. Galluzzi L., Marsili S., Vitale I., Senovilla L., Michels J., Garcia P., Vacchelli E., Chatelut E., Castedo M., Kroemer G. Vitamin B6 metabolism influences the intracellular accumulation of cisplatin. A deficiency in vitamin B12 can lead to various symptoms, including:. Elevated serum vitamin B(12) levels in association with tumor markers as the prognostic factors predictive for poor survival in patients with hepatocellular carcinoma. Vitamin B-12 deficiency is considered to develop years after gastrectomy because of large hepatic storage. By Harvard Health Publishing Staff What harm can having too little of vitamin B 12 do? However, most gastric cancer develops after long-standing atrophic gastritis with vitamin B-12 Low B12 symptoms can vary from physical to psychological. Buck M.D., Sowell R.T., Kaech S.M., Pearce E.L. Metabolic instruction of immunity. Honein M.A., Paulozzi L.J., Mathews T.J., Erickson J.D., Wong L.Y. Molecular and cellular effects of vitamin B12 in brain, myocardium and liver through its role as co-factor of methionine synthase. A 2013 study published in the Journal of the National Cancer Institute concluded that elevated B12 levels were associated with [5]: Subsequent cancer diagnoses, primarily in the first year of follow-up. In a similar study using nasopharyngeal epidermoid carcinoma cell growth in folate-deficient medium, hypermethylation of H-cadherin promoter sequences were observed, which corresponded to reduced expression [111]. Analysis of pantothenate in the absence of pantetheinase activities, while challenging, may shed light on the more subtle roles of pantetheine in human health. Hysteroscopy. Riboflavin inhibits the lipopolysaccharide (LPS)-induced ROS that leads to activation of NF-kB, thereby downregulating TNF- and NO in a variety of experimental models [31]. Vitamin B-12 deficiency is considered Cancer. Comin-Anduix B., Boren J., Martinez S., Moro C., Centelles J.J., Trebukhina R., Petushok N., Lee W.N., Boros L.G., Cascante M. The effect of thiamine supplementation on tumour proliferation. Federal government websites often end in .gov or .mil. This activity did not affect CD4+ T cells [105]. Vitamin B12 (B12) or cobalamin is essential for cell division [].Although its assay is mainly intended to detect deficiencies, incidental findings of PDK is over-expressed in tumor cells and phosphorylation of PDH drives aerobic glycolysis to complement TCA cycle energy generation. vitamin B-12 deficiency Cysteamine breaks disulfide bonds that inactivate proteins and directly inhibits -glutamylcysteine synthase, the rate-limiting step in glutathione synthesis [76]. Carcinomas have been reported to over-express folate receptor . These issues can affect both adults and children (2, 20). See additional information. Vitamin B-12 deficiency is Pain and inflammation of the mouth and tongue, 9. One-carbon metabolism balances the flux of one-carbon units toward either the folate cycle that generates nucleotides for DNA and RNA synthesis and energy metabolism or alternatively, toward the methionine cycle for methionine generation where it serves as precursor of SAM, which is required for the methylation of DNA, RNA, histones and proteins impacting gene expression (reviewed in [128]). Taken together, these results suggest that thiamine may promote or inhibit tumorigenesis depending on the cancer type analyzed or the effective dose or amount of intracellular TPP. Jones P.T., Anderson R. Oxidative inhibition of polymorphonuclear leukocyte motility mediated by the peroxidase/H. Cognitive impairment in older adults. Niacin attenuates lung inflammation and improves survival during sepsis by downregulating the nuclear factor-kappaB pathway. Symptoms of vitamin B12 deficiency can include tingling or numbness in the extremities, brain fog and mouth sores. Mice deficient in vanin-1 are resistant to apoptotic oxidative tissue injury caused by -irradiation or paraquot [76]. Dietary folate, methionine, riboflavin, and vitamin B-6 and risk of sporadic colorectal cancer. Authors This single example suggests that a more detailed and sophisticated analysis of B vitamins will be of high potential importance. High prevalence of vitamin B-12 deficiency before and early after Therefore, the impact of B5 must be gathered through its known metabolism that has thus far highlighted cysteamines pro-inflammatory properties. Cancer Male and female infertility Answer: Their signs and symptoms can all be mimicked by a vitamin B12 deficiency. the contents by NLM or the National Institutes of Health. Paul L., Selhub J. Interaction between excess folate and low vitamin B12 status. Learn more on vitamin B12 deficiency treatment. In high-fat diet-fed mice, niacin increased adiponectin (hormone regulating fatty acid catabolism) gene and protein expression and decreased MCP-1, IL-1 and the frequency of activated M1 macrophage [52]. B12 deficiency leads to the trapping and accumulation of methyltetrahydrofolate disrupting the normal cycling of cofactors [127]. Biotin deficiency stems primarily from genetic changes in biotinidase which is required for cleavage from BCCP and recycling, resulting in alopecia, delays in development, seizures, aciduria and others neurological conditions. This can help ensure that any potential cancer could be detected and treated promptly. Jul 3, 2023 Contributor: Misora Ao,Masaaki Awane,Yoshito Asao,Sadahiko Kita,Takashi Miyawaki,Kiyoshi Tanaka Gastrectomy causes vitamin B-12 deficiency since vitamin B-12 requires gastric acid and intrinsic factor for its absorption. The methionine and folate cycle pathways involving PLP-, FAD- and B12-dependent enzymes. Surjana D., Halliday G.M., Damian D.L. The conversion of homocysteine to methionine is carried out by methionine synthase which transfers a methyl group from 5-methyl THF in the presence of cobalamin. Vitamin B12 deficiency mimicking acute leukemia Many tumors become methionine-dependent, unable to proliferate in the absence of exogenous methionine even when its precursor homocysteine is available. Vitamin B12 deficiency symptoms as unusual sign can show up Alkaline phosphatase (tissue-nonspecific isoenzyme) is a phosphoethanolamine and pyridoxal-5-phosphate ectophosphatase: Normal and hypophosphatasia fibroblast study. Gibson G.E., Ksiezak-Reding H., Sheu K.F., Mykytyn V., Blass J.P. High Plasma Vitamin B12 and Cancer in Human Studies: A Sometimes Niacin treatment increased glutathione levels and decreased malondialdehyde levels (a marker of oxidative stress) [60]. These changes were coupled to reduced CD4+ T cell differentiation with reduced Th1 and Treg cell populations [107]. A number of studies indicate that riboflavin reduces mortality in LPS-induced septic shock by reducing a number of inflammatory cytokines, such as IL-1, IL-1, IL-6, IFN- and NO, in mice [37]. Licensee MDPI, Basel, Switzerland. In a high fat diet (HFD) model of liver steatosis, niacin decreased liver fat content and oxidative products in rats. These findings point to cysteamine as the source of oxidative stress (ROS) generated during inflammation in vanin-1-deficient mice rather than pantothenate. Monocyte-derived DCs cultured in biotin-deficient medium produced elevated inflammatory cytokines in response to an LPS challenge [99]. Verdrengh M., Tarkowski A. Riboflavin in innate and acquired immune responses. They may even offer. Other changes included the Wnt/APC pathway and genes involved in cell adhesion, migration and invasion [114]. Importantly one-carbon metabolism generates S-adenosylmethionine (SAM) which is a universal methyl donor for methylation of DNA and RNA and histones, thereby regulating transcription and translation. Deficiency of B12 can lead to a wide variety of hematologic, neurologic, and psychiatric disorders and may increase the risk of cardiovascular diseases. Kunisawa J., Sugiura Y., Wake T., Nagatake T., Suzuki H., Nagasawa R., Shikata S., Honda K., Hashimoto E., Suzuki Y., et al. Revuelta J.L., Buey R.M., Ledesma-Amaro R., Vandamme E.J. Evidence of B vitamins role in immune cell regulation has accumulated in recent years and may help to clarify the disparate findings of numerous studies attempting to link B vitamins to cancer development. In addition, certain medical conditions and medications can cause vitamin B12 deficiency (30). Bacterial biosynthesis of pantothenic acid is initiated with aspartic acid that is converted to -alanine, which is then linked to pantoate and subsequently converted to pantothenate. Intestinal deletion of SMVT results in stunted growth, spontaneous and severe inflammation, increased gut permeability and early death. Nicotinamide is anti-inflammatory and downregulates NF-B via SIRT1 deacetylation [67]. Reduced dietary intake of vitamin B6 has been documented as a risk factor for developing cancer [85,91]. 10 Citations 8 Altmetric Metrics Abstract Elevated plasma vitamin B12 has been associated with solid cancers, based on a single B12 measurement. MAIT cell ligands include riboflavin-derived molecules that are presented by MR1, a non-polymorphic major histocompatibility complex class I-like molecule [34]. 4. Schramm M., Wiegmann K., Schramm S., Gluschko A., Herb M., Utermohlen O., Kronke M. Riboflavin (vitamin B2 ) deficiency impairs NADPH oxidase 2 (Nox2) priming and defense against Listeria monocytogenes. More recently, another source of B vitamins has been identified which is derived from portions of the 1013 bacterial cells inhabiting the gastrointestinal tract. Gene expression changes in the intestine were pronounced in aged rats fed a folate-deficient diet including reduced expression of urokinase, p53, insulin-like growth factor binding protein-3 and the vav-1 oncogene [113]. Vitamin D Deficiency Lin C.Y., Kuo C.S., Lu C.L., Wu M.Y., Huang R.F. This consideration highlights an important unanswered question for all B vitamins that should strive to distinguish protective effects in healthy individuals distinctly from their role in cancer patients, where B vitamins may be therapeutic or contribute to oncogenesis. Indeed, S. pneumoniae ribD knockout strains were unable to activate MAIT cells. Some studies have reported an inverse correlation between PLP and different cancers [85]. Treatment of B12 deficiency typically includes oral supplements or injections. Definition Vitamin B12 deficiency is a common condition that can manifest with neurologic, psychiatric, and hematologic disorders. While biotin is available in many foods that are part of a standard diet, it is usually presented as a protein-bound form of biotin that is not readily available to cell metabolism. These include pancreatic, gastric adenocarcinoma, prostate, oral/pharyngeal, lung and colon cancers. Effects of folic acid withdrawal on transcriptomic profiles in murine triple-negative breast cancer cell lines. Bourquin F., Capitani G., Grtter M.G. The folate cycle is segregated in the cytoplasm and the reactions occurring in the mitochondria. Marginal dietary thiamin deficiency induces the formation of colonic aberrant crypt foci (ACF) in rats. Wang T.P., Hsu S.H., Feng H.C., Huang R.F. Chen X., Ahamada H., Zhang T., Bai Z., Wang C. Association of intake folate and related gene polymorphisms with breast cancer. Folate/Vitamin B12 supplementation combats oxidative stress-associated carcinogenesis in a rat model of colon cancer. WebMD Sabui S., Kapadia R., Ghosal A., Schneider M., Lambrecht N.W.G., Said H.M. Biotin and pantothenic acid oversupplementation to conditional SLC5A6 KO mice prevents the development of intestinal mucosal abnormalities and growth defects. Riboflavin concentrations in the blood of patients with esophageal squamous cell carcinoma is reduced compared to healthy subjects [46]. Dietary riboflavin deficiency promotes N-nitrosomethylbenzylamine-induced esophageal tumorigenesis in rats by inducing chronic inflammation. Riboflavin is then converted in a single-step to the active cofactors, FMN and FAD generated by riboflavin kinase and FAD synthase, respectively, that act as electron carriers for a number of critical redox reactions. Obesity, long considered a condition of metabolic imbalance, is now viewed as an inflammatory disease. This reduction was associated with reduced glycolysis and activation of the pyruvate dehydrogenase (PDH) complex [18]. Vitamin B-12 - Mayo Clinic Shortness of breath, fatigue, cold hands and feet. Debra Rose Wilson, Ph.D., MSN, R.N., IBCLC, AHN-BC, CHT, Vitamin B12 Deficiency and Weight Gain What to Know, Liquid Vitamin B12: Dosage, Benefits, and More, Vitamin B12 and Folic Acid Not Miracle Brain-Boosters, 8 Best Personalized Vitamin Subscription Services of 2023, According to Dietitians, have a medical condition that can deplete B12 levels, take a B12-depleting medication, like metformin or proton pump inhibitors. B12 deficiency - Cancer Therapy Advisor Cysteamine administration to vanin-1 mice restores the inflammation observed to levels comparable to wild-type mice [76,80]. Finally, high oral doses of folic acid reduced the inflammatory response of mice with allergic dermatitis through inhibition of T cell cytokine secretion [109]. Handfoot syndrome (HFS) is a dermatological reaction to toxicities generated by some cancer chemotherapies. Folate, colorectal carcinogenesis, and DNA methylation: Lessons from animal studies. Moderate folate depletion modulates the expression of selected genes involved in cell cycle, intracellular signaling and folate uptake in human colonic epithelial cell lines. Folate deficiency in primary human lymphocytes reduced cell proliferation and resulted in increased DNA strand breaks, apoptosis and cell cycle arrest [106]. Alternatively, human studies in the future may require more comprehensive molecular analyses of B vitamins and their corresponding vitamers to be coupled with a high-resolution analysis of a variety of immune functions and tumor subtypes that may allow stronger and more convincing associations to be uncovered. Alves-Fernandes D.K., Jasiulionis M.G. Terzis A.J., Fiskerstrand T., Refsum H., Ueland P.M., Arnold H., Bjerkvig R. Proliferation, migration and invasion of human glioma cells exposed to antifolate drugs.