Docosahexaenoic Acid: A Potential Modulator of Brain Tumors and Metastasis
Received Date: Oct 14, 2013 / Accepted Date: Oct 15, 2013 / Published Date: Oct 20, 2013
Although not specific to any particular region in the brain, primary tumors and/or metastases from other organs are life threatening and mortality is rapid. Treatment options for patients with primary brain tumors or metastases are limited and include (either alone or combined) whole-brain radiotherapy, cranial stereotactic radiosurgery, neurosurgery, and steroids [1,2]. However, the standard treatment for multiple brain lesions remains whole-brain radiation (WBRT) for symptom control. For cancer patients treated with WBRT, median survival is 3–6 months; in patients treated with steroids alone, 6–8 weeks; and for untreated patients with symptomatic brain metastasis, median survival is less than one month [3,4]. Furthermore, these treatments do not improve the quality of life and adversely affect cognitive functions. Clearly, patients who have brain tumors or are at risk of developing metastatic tumors need other treatment options.
The human brain contains nearly 60% fat, mostly in the cellular membranes. The lipid composition of the cellular membrane varies among cells of different organs and tissues. The lipid composition within cells also varies among plasma membranes, endoplasmic reticulum, mitochondrial membranes, and nuclear membranes. The biophysical properties of a membrane are regulated by the relative amounts and types of fatty acids present within the membrane’s phospholipid bilayer. Since the membranes are home to nearly 1/3 of all cellular proteins, including enzymes, transport proteins, ion channels, receptors, adhesion proteins, and components of cellular signaling pathways, the composition of these cellular membranes is extremely critical for cell responsiveness under normal and pathological situations. In the brain, neuronal membranes contain phospholipids that are predominantly rich in docosahexaenoic acid (DHA), the most unsaturated of the long-chain omega-3 fatty acids [5-7]. DHA, particularly abundant in cold-water fatty fish, has been excellently reviewed in recent articles for its role in brain development and intelligence [8-12]. Some authors have suggested that early humans who lived near water sources and ate seafood experienced a significant change in their brains, acquiring learning capabilities and intelligence that has revolutionized life on planet earth [13,14]. In contrast, Australopithecines did not have access to omega-3 fatty acids and, for 3 million years, got stuck at a brain capacity that was not much bigger than a chimpanzee’s.
The importance of DHA in learning, intelligence, Alzheimer disease, stroke, and traumatic brain injury has been highlighted in several excellent, recent studies [15-23]; however, its role in primary brain tumor development and metastasis from the cancers of other organs has not been so apparent. The importance of DHA in brain function was only realized in the late 1980s and early 1990s; Stein et al. as early as 1963, developed an interest in the fatty acid composition of brain tumors  and subsequently reported that transmissible glial tumors implanted in mice intracerebrally or subcutaneously contained 70-80% less DHA than normal brain tissues . This work demonstrated that tumors have specific lipid pattern, which is independent of tumor location. Similarly Martin et al. in 1996 reported that human gliomas contained almost 50% less DHA in both total lipid or phospholipid fractions than normal brain tissues . Another study also found significantly low levels of total omega-3 fatty acids and DHA in 19 patients with gliomas and meningiomas compared to control human brain tissues . The DHA in phospholipids was also found to be significantly reduced (by 60-70%) in human neuroblastoma cells compared to human and rat cerebellum tissue . We have also found low DHA levels in gliomas (unpublished data) in comparable ranges as reported by Martin et al. . Furthermore, a study published in 2003 on childhood cancer among Alaska Natives, who primarily eat food from marine sources rich in omega-3 fatty acids and DHA, reported almost 10 times less incidences of neuroblastomas compared to the US white population . These observations imply that a deficiency of omega-3 fatty acids, particularly DHA, may be linked to the development of brain tumors. Consistent with these findings, prophylactic treatment with DHA delayed neuroblastoma development and inhibited the growth of established tumors in a mouse xenograft model . These observations clearly suggest a profound role of DHA in regulating brain structure and metabolism that may offer a protection against developing primary brain tumors or metastasis from other cancerous sites to the brain. Furthermore, it is interesting to note that brain tumors are not only deficient in DHA content, but they also have elevated levels of proinflammatory AA [25,26,28]. DHA and AA have antagonistic effects. For example, metabolites of AA, such as PGE2 and epoxyeicosanoids, stimulate brain tumor growth , whereas the metabolites of DHA, such as hydroperoxy fatty acids,neuroprotectin and resolvins, are protective [32-34]. A deficiency of DHA in brain tumors suggests that a predominance of AA metabolism creates more permissive conditions for tumor survival and growth.
Although controversial, Paget  introduced the “seed and soil” theory that tumor cells (seeds) could have a specific affinity for the microenvironment of certain organs (soil). Recent studies have supported this theory, showing that cancer metastasis depends not only on the ability of cancer cells to survive, proliferate, and promote vascularization, but also on the ability of the microenvironment surrounding the metastasis to regulate the area’s metastatic potential. The brain is relatively protected from metastasis because its microvascular endothelial cells provide an active permeability barrier and transport system known as the blood-brain barrier (BBB). The BBB involves the participation of astrocytes, pericytes, and endothelial cells and has characteristically complex tight junctions with very low permeability to solutes and hydrophilic molecules [36,37]. Although brain metastasis can be initiated without compromising the BBB, an impairment in the BBB has been reported in cancer patients who developed metastasis to the brain . DHA has been shown to play a role in maintaining the integrity of the BBB. These observations suggest that DHA deficiency creates a permissive environment for brain tumor growth and/or helps tumors metastasize to the brain from other primary sites, such as the breast, whereas improving the DHA concentration in the brain may protect the brain from tumor development as well as brain metastasis from other organs.
DHA is stably incorporated in brain phospholipids, as it has a halflife of 2.5 years. The brain consumes about 4.5 mg DHA/day. DHA is not synthesized in the brain. Rather, it is taken up as a preformed molecule from circulation. The human liver has a limited ability to elongate Linolenic Acid (LA), an omega-3 fatty acid present in plants nuts, to DHA at a slow rate, and this is enough to maintain DHA concentrations in the brain . This conversion rate can increase during certain conditions, particularly in women during pregnancy and lactation to meet fetal and newborn requirements . Vegetarians on a plant-based diet get enough LA to maintain their brain DHA despite having low serum DHA levels. Ironically, the DHA concentration in plasma is not a reliable marker for DHA levels in the brain—unless there is quite a large reduction in plasma DHA arising from long-term deficiency . However, a low n-3 PUFA concentration in plasma caused by nutritional deprivation can alter the concentration in the brain and its turnover, as well as altering brain function. Abnormal DHA concentrations in the brain have been linked to several human disorders [42-44]. The development and progression of cancer to brain metastasis occurs over a period of time, and it is likely that cancer patients with persistently reduced plasma DHA levels may have reduced brain DHA content. Conversely, a diet enriched by DHA, when DHA is accumulated slowly and over time, has been shown to delay or prevent neuroblastomas in mice .To our knowledge no published study has yet investigated the status of DHA in patients with brain cancer or with metastasis to the brain from other sites. Based on current findings, we hypothesize that a reduced DHA concentration in the brain provides a permissive environment for cancer cells to metastasize into brain tissues. Clearly, there is a need to investigate DHA’s role in metastasis, particularly in the brain. Correcting the DHA concentration may dampen brain AA metabolism and create less permissive conditions for metastases.
Maintaining the DHA concentration in the brain would provide a low-cost therapeutic approach with a potentially high reward and minimal risk to cancer patients. Several reports suggest that the increased prevalence of brain metastasis from Her-2+ breast cancer is due to improved systemic therapy for stage IV breast cancer with trastuzumab, an anti-Her-2-antibody [45-47] that is effective for primary tumors and systemic metastases but ineffective for brain metastases (Her-2 Paradigm). Elevating the DHA concentration in these patients may give them hope that complete elimination of systemic and metastatic tumors is achievable, allowing them to live cancer free for longer periods, or perhaps the rest of their lives. In conclusion, it is evident that DHA and its metabolites have a role in preventing brain tumors. Further investigation in this area will be very valuable in elucidating a mechanism through which DHA and its metabolism regulate important brain functions and prevent initiation and progression of primary and/or metastatic tumors in the brain.
- Lin NU, Winer EP (2007) Brain metastases: the HER2 paradigm. Clin Cancer Res 13: 1648-1655.
- Weil RJ, Palmieri DC, Bronder JL, Stark AM, Steeg PS (2005) Breast cancer metastasis to the central nervous system. Am J Pathol167: 913-920.
- Boogerd W, Vos VW, Hart AA, Baris G (1993) Brain metastases in breast cancer; natural history, prognostic factors and outcome. J Neurooncol15:165-174.
- Sneed PK, Larson DA, Wara WM (1996) Radiotherapy for cerebral metastases. Neurosurg Clin N Am 7: 505-515.
- Giusto NM, Salvador GA, Castagnet PI, Pasquare SJ, Ilincheta de Boschero MG (2002) Age-associated changes in central nervous system glycerolipid composition and metabolism. Neurochem Res27: 1513-1523.
- Innis S (2005) Essential fatty acid metabolism during early develoment. In Biology of metabolism in growing animals. Volume 3 Edited by Burrin D Amsterdam: Elsevier Science 235-274.
- Uauy R, Dangour AD (2006) Nutrition in brain development and aging: role of essential fatty acids. Nutr Rev64: S24-33.
- Cohen JT, Bellinger DC, Connor WE, Shaywitz BA (2005) A quantitative analysis of prenatal intake of n-3 polyunsaturated fatty acids and cognitive development. Am J Prev Med29: 366-374.
- Crawford MA, Broadhurst CL, Guest M, Nagar A, Wang Y, et al. (2013) A quantum theory for the irreplaceable role of docosahexaenoic acid in neural cell signalling throughout evolution. Prostaglandins Leukot Essent Fatty Acids88: 5-13.
- Katzen-Luchenta J (2007) The declaration of nutrition, health, and intelligence for the child-to-be. Nutr Health19: 85-102.
- Koo WW (2003) Efficacy and safety of docosahexaenoic acid and arachidonic acid addition to infant formulas: can one buy better vision and intelligence? J Am Coll Nutr22: 101-107.
- Suzuki H, Morikawa Y, Takahashi H (2001) Effect of DHA oil supplementation on intelligence and visual acuity in the elderly. World Rev Nutr Diet 88: 68-71.
- Cunnane S, Stewart K (2010) Human brain evolution. The influence of freshwater and marine food resources. Hoboken: John Wiley & Sons.
- Tobias P (1997) Evolution of brain size, morphological restructuring and longevity in early hominids. In Principles of neural aging. Edited by Su D, Hori A, Walter G. Amsterdam: Elsevier; 1997: 153-174.
- Belayev L, Khoutorova L, Atkins KD, Eady TN, Hong S, et al. (2011) Docosahexaenoic Acid Therapy of Experimental Ischemic Stroke. Transl Stroke Res2: 33-41.
- Connor WE, Connor SL (2007) The importance of fish and docosahexaenoic acid in Alzheimer disease. Am J Clin Nutr 85: 929-930.
- Dacks P, Shineman D, Fillit H (2013) Current evidence for the clinical use of long-chain polyunsaturated n-3 fatty acids to prevent age-related cognitive decline and Alzheimer's disease. J Nutr Health Aging17: 240-251.
- Eady TN, Belayev L, Khoutorova L, Atkins KD, Zhang C, et al. (2012) Docosahexaenoic acid signaling modulates cell survival in experimental ischemic stroke penumbra and initiates long-term repair in young and aged rats. PLoS One7: e46151.
- Farias SE, Heidenreich KA, Wohlauer MV, Murphy RC, Moore EE (2011) Lipid mediators in cerebral spinal fluid of traumatic brain injured patients. J Trauma71: 1211-1218.
- Hong SH, Larissa Khoutorova, Daniela Anzola, Qiang Wu, Bokkyoo Jun, et al. (2013) Protection against blood-brain barrier disruption in focal cerebral ischemia by docosahexanoic acid. Stroke44: A94.
- Mills JD, Hadley K, Bailes JE (2011) Dietary supplementation with the omega-3 fatty acid docosahexaenoic acid in traumatic brain injury. Neurosurgery68: 474-481.
- Roberts L, Bailes J, Dedhia H, Zikos A, Singh A, et al. (2008) Surviving a mine explosion. J Am Coll Surg207: 276-283.
- Stonehouse W, Conlon CA, Podd J, Hill SR, Minihane AM, et al. (2013) DHA supplementation improved both memory and reaction time in healthy young adults: a randomized controlled trial. Am J Clin Nutr97: 1134-1143.
- Stein AA, Opalka E, Schlip AO (1963) Fatty-Acid Analysis of Meningiomas by Gas-Phase Chromatography. J Neurosurg 20: 435-438.
- Stein AA, Opalka E, Rosenblum I (1965) Fatty Acid Analysis of Two Experimental Transmissible Glial Tumors by Gas-Liquid Chromatography. Cancer Res 25: 201-205.
- Martin DD, Robbins ME, Spector AA, Wen BC, Hussey DH (1996) The fatty acid composition of human gliomas differs from that found in nonmalignant brain tissue. Lipids31: 1283-1288.
- Kokoglu E, Tuter Y, Yazici Z, Sandikci KS, Sonmez H, et al. (1998) Profiles of the fatty acids in the plasma membrane of human brain tumors. Cancer Biochem Biophys16: 301-312.
- Reynolds LM, Dalton CF, Reynolds GP (2001) Phospholipid fatty acids and neurotoxicity in human neuroblastoma SH-SY5Y cells. Neurosci Lett 309: 193-196.
- Lanier AP, Holck P, Ehrsam Day G, Key C (2003) Childhood cancer among Alaska Natives. Pediatrics112: e396.
- Gleissman H, Segerstrom L, Hamberg M, Ponthan F, Lindskog M, et al. (2011) Omega-3 fatty acid supplementation delays the progression of neuroblastoma in vivo. Int J Cancer128: 1703-1711.
- Panigrahy D, Edin ML, Lee CR, Huang S, Bielenberg DR, et al. (2012) Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice. J Clin Invest122: 178-191.
- Gleissman H, Yang R, Martinod K, Lindskog M, Serhan CN, et al. (2010) Docosahexaenoic acid metabolome in neural tumors: identification of cytotoxic intermediates. FASEB J 24: 906-915.
- Serhan CN, Chiang N, Van Dyke TE (2008) Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol8: 349-361.
- Zhang G, Panigrahy D, Mahakian LM, Yang J, Liu JY, et al. (2013) Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis. Proc Natl Acad Sci USA110:6530-6535.
- Paget S (1989) The distribution of secondary growths in cancer of the breast 1889. Cancer Metastasis Rev 8: 98-101.
- Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci7: 41-53.
- Dejana E (2004) Endothelial cell-cell junctions: happy together. Nat Rev Mol Cell Biol5: 261-270.
- Cheng X, Hung MC (2007) Breast cancer brain metastases. Cancer Metastasis Rev 26: 635-643.
- Rapoport SI, Chang MC, Spector AA (2001) Delivery and turnover of plasma-derived essential PUFAs in mammalian brain. J Lipid Res42: 678-685.
- Burdge GC, Wootton SA (2002) Conversion of alpha-linolenic acid to eicosapentaenoic, docosapentaenoic and docosahexaenoic acids in young women. Br J Nutr88: 411-420.
- Rapoport SI, Ramadan E, Basselin M (2011) Docosahexaenoic acid (DHA) incorporation into the brain from plasma, as an in vivo biomarker of brain DHA metabolism and neurotransmission. Prostaglandins Other Lipid Mediat 96: 109-113.
- Conquer JA, Tierney MC, Zecevic J, Bettger WJ, Fisher RH (2000) Fatty acid analysis of blood plasma of patients with Alzheimer's disease, other types of dementia, and cognitive impairment. Lipids35: 1305-1312.
- Hibbeln JR (1998) Fish consumption and major depression. Lancet351: 1213.
- Quinn JF, Raman R, Thomas RG, Yurko-Mauro K, Nelson EB, et al. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA304: 1903-1911.
- Bendell JC, Domchek SM, Burstein HJ, Harris L, Younger J, et al. (2003) Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer97: 2972-2977.
- Burstein HJ, Lieberman G, Slamon DJ, Winer EP, Klein P (2005) Isolated central nervous system metastases in patients with HER2-overexpressing advanced breast cancer treated with first-line trastuzumab-based therapy. Ann Oncol16:1772-1777.
- Clayton AJ, Danson S, Jolly S, Ryder WD, Burt PA, et al. (2004) Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer. Br J Cancer91: 639-643.
Citation: Siddiqui RA, Harvey K, Bammerlin E, Ikhlaque N (2013) Docosahexaenoic Acid: A Potential Modulator of Brain Tumors and Metastasis. J Biomol Res Ther 2:e119. Doi: 10.4172/2167-7956.1000e119
Copyright: © 2013 Siddiqui RA et al., This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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