|Year : 2014 | Volume
| Issue : 6 | Page : 1270-1277
|Warburg's effect on solid tumors
Talal El Imad, Lara El Khoury, Abdallah Sassine Geara
Lebanese University, Beirut, Lebanon
Click here for correspondence address and email
|Date of Web Publication||10-Nov-2014|
| Abstract|| |
Lactic acidosis is the result of imbalance between the systemic formation of lactate and its hepatic metabolism. In cancer patients, lactic acidosis is mainly associated with hematologic malignancies (leukemia and lymphomas) and the mechanism is known as Warburg's effect. We report a 76-year-old male known to have hypertension and coronary artery disease, who presented with abdominal distension and lactic acidosis. His initial evaluation showed multiple liver masses that were biopsied and the patient was diagnosed with undifferentiated carcinoma of unknown primary, involving the liver. The patient had progression of lactic acidosis leading to his death on day-15. As the lactic acidosis was not in the setting of hypoxia or hemodynamic instability, we made the diagnosis of malignancy-associated type B lactic acidosis, also known as the Warburg's effect. Warburg's effect can occur in solid cancer if the tumor involves the liver. It has bad prognostic implications. The use of intravenous bicarbonate as a temporary measure is of controversial benefit, as it can potentially worsen the metabolic acidosis and its use should be limited to patients with very low pH. In cancer patients, the use of lactatebased intravenous fluids can be potentially harmful and can increase the risk of tumor metastasis, at least in animal malignancy models.
|How to cite this article:|
El Imad T, El Khoury L, Geara AS. Warburg's effect on solid tumors. Saudi J Kidney Dis Transpl 2014;25:1270-7
| Introduction|| |
In aerobic conditions, glucose metabolism includes the following steps: (a) Glycolysis leading to pyruvate, which is metabolized in (b) the Krebs cycle, and (c) the mitochondrial respiratory chain, with end-products of adenosine triphosphate (ATP), carbon dioxide (CO 2 ), and water (H 2 O).  In anaerobic conditions, glucose is metabolized by anaerobic glycolysis, leading to the formation of lactate. The malignant cell has an alteration of its metabolism known as the Warburg's effect or aerobic glycolysis (i.e., in aerobic conditions, the glucose metabolism in cancerous cells is shifted toward the formation of a lactate).  Clinically, patients present with severe lactic acidosis.
| Case Report|| |
A 76-year-old male patient, known to have hypertension, coronary artery disease, and diabetes mellitus type 2 presented for evaluation of weight loss and abdominal distension. The patient started to lose weight over the last two to three months; he was complaining of epigastric discomfort and over the last two weeks, he noticed abdominal distension. On initial evaluation, the patient was in acute renal failure (creatinine: 1.7 mg/dL; baseline: 1.1 mg/ dL), which improved back to baseline after one day of hydration. Since his admission, the patient had a high anion gap metabolic acidosis (lactic acidosis: blood lactate was 7.7 nM/L) [Table 1]. As the patient was complaining of abdominal distension, an ultrasound of the abdomen was performed in the Emergency Room, which showed hepatomegaly and multiple liver metastatic lesions; this result was confirmed by an abdominal computerized tomography (CT) scan and a positron emission tomography (PET) scan, and the lesions were biopsied on day-2 by Interventional Radiology [Figure 1] and [Figure 2]. The histology was compatible with moderately differentiated adenocarcinoma of unknown primary origin. On day-3, the lactic acidosis worsened and the patient became oliguric. Intravenous bicarbonate was started without improvement of the acidosis. As acute renal failure recurred on day-4, the patient was started on continuous renal replacement therapy (CRRT) for progressively worsening acidosis and fluid overload. After discussion with the family, and since the prognosis was very bad, it was determined by the oncologist that chemotherapy would be of limited benefit. CRRT was continued. The patient died on day-15 of hospitalization.
|Figure 1: Abdominal computerized tomography scan showing multiple liver masses.|
Click here to view
|Figure 2: Positron emission tomography scan showing numerous, partially confluent foci of FDG-activity scattered throughout the hepatic segments, with the standardized uptake value up to 23.2|
Click here to view
Since the lactic acidosis was not in the setting of hypoxia or hemodynamic instability, we made the diagnosis of malignancy-associated type B lactic acidosis, also known as Warburg's effect.
| Discussion|| |
Lactic acidosis is the result of an imbalance between the systemic formation of lactate and its hepatic metabolism. As most of the hematological malignancies have a high cell turnover, lactic acidosis is described initially with leukemia and lymphomas.  It has become evident that Warburg can also occur in solid tumors, specifically when the malignancy is metastasized to the liver, limiting the metabolism of the lactate.  [Table 2] depicts all the previously described lactic acidosis associated with solid tumors. The most consistent feature is liver involvement. The tumor described includes both high-cell turn-over tumors (undifferentiated carcinoma) and well-differentiated tumors (prostate carcinoma or osteogenic sarcoma). Warburg's effect is a bad prognostic indicator and is fatal unless the underlying malignancy responds to chemotherapy. In some of these cases, intravenous bicarbonate and CRRT are utilized as temporary measures, with little success.
The proposed mechanisms of Warburg's effect include alteration of cellular metabolism mediated by several tumor suppressor genes and oncogenes (reviewed by Vander Heiden et al).  The authors of this review proposed three potential mechanisms to explain the advantage that tumor cells acquire by switching their metabolism to the "less efficient" lactic acid pathway: (a) As the primary objective of the tumor cell is to replicate, and as these cells are well-vascularized and have a continuous supply of glucose and nutrients, aerobic glycolysis will allow the formation of several macro-molecular precursors. These can be used in the replication of the cellular content to enable the cell to divide (utilization of glucose in the Krebs cycle and a mitochondrial respiratory chain may lead to CO 2 and water as end products, which are not useful as precursors for cell replication), (b) the formation of lactate leads to production of Nicotinamide adenine dinucleotide phosphate (NADPH) that redirects the glucose metabolism into the pentose phosphate shunt, leading to nucleotides and amino acid biosynthesis, and (c) during the initial steps of tumor genesis, cancerous cells grow in anaerobic conditions, cells with the 'best anaerobic machinery' are positively selected and are seen to maintain the same metabolism even in aerobic conditions after neo-vascularization of the tumor.
In addition to the prognostic value of lactic acidosis, Warburg's effect is being clinically utilized to develop a therapy for several tumors.  Tumor cells that utilize aerobic glycolysis for energy and replication express glucose transporter 1 (GLUT 1). Targeting this transporter can selectively kill tumor cells without toxicity to the normal tissue in renal cell carcinomas. 
Another clinical consequence of Warburg's effect is putting in question the safety of lactate solutions when used in patients with malignancies. A symbiotic relationship between tumor cells and its stoma could be the etiology of lactic acidosis: Malignant cells induce a modification of metabolism in the fibroblast of the supporting tumor stroma; these fibroblasts switch their metabolism to aerobic glycolysis leading to a formation of lactic acid, which is used as an 'easy fuel' by the malignant cells. ,, As lactate is the preferable energy source for malignant cells, using a lactate-based solution can potentiate growth of cancer cells. In mice injected with breast cancer cells, a lactate injection increased lung metastasis ten-fold. 
In conclusion, aerobic glycolysis or Warburg's effect is an alteration of both hematological and solid tumor metabolism and the acidosis becomes clinically evident in patients with liver liver metastasis. It has a bad prognostic implication. Blocking aerobic glycolysis pathways could cause an anti-cancerous activity. Using a lactate-based solution for patients with malignancy should be discouraged, as it can be used by malignant cells as "easy" fuel and could potentiate the risk of metastasis. 
Conflict of interest: None.
| References|| |
Chan FH, Carl D, Lyckholm LJ. Severe lactic acidosis in a patient with B-cell lymphoma: A case report and review of the literature. Case Rep Med 2009;2009:534561.
de Groot R, Sprenger RA, Imholz AL, Gerding MN. Type B lactic acidosis in solid malignancies. Neth J Med 2011;69:120-3.
Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science 2009;324:1029-33.
Pelicano H, Martin DS, Xu RH, Huang P. Glycolysis inhibition for anticancer treatment. Oncogene 2006;25:4633-46.
Chan DA, Sutphin PD, Nguyen P, et al. Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. Sci Transl Med 2011;3(94):94ra70.
Pavlides S, Whitaker-Menezes D, Castello-Cros R, et al. The reverse Warburg effect: Aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle 2009;8:3984-4001.
Migneco G, Whitaker-Menezes D, Chiavarina B, et al. Glycolytic cancer associated fibroblasts promote breast cancer tumor growth, without a measurable increase in angiogenesis: Evidence for stromal-epithelial metabolic coupling. Cell Cycle 2010;9:2412-22.
Bonuccelli G, Whitaker-Menezes D, Castello-Cros R, et al. The reverse Warburg effect: Glycolysis inhibitors prevent the tumor promoting effects of caveolin-1 deficient cancer associated fibroblasts. Cell Cycle 2010;9:1960-71.
Bonuccelli G, Tsirigos A, Whitaker-Menezes D, et al. Ketones and lactate "fuel" tumor growth and metastasis: Evidence that epithelial cancer cells use oxidative mitochondrial metabolism. Cell Cycle 2010;9:3506-14.
Evans TR, Stein RC, Ford HT, Gazet JC, Chamberlain GV, Coombes RC. Lactic acidosis. A presentation of metastatic breast cancer arising in pregnancy. Cancer 1992;69: 453-6.
Warner E. Type B lactic acidosis and metastatic breast cancer. Breast Cancer Res Treat 1992;24:75-9.
Varanasi UR, Carr B, Simpson DP. Lactic acidosis associated with metastatic breast carcinoma. Cancer Treat Rep 1980;64:1283-5.
Ellis RW. Breast cancer and lactic acidosis. An unusual metabolic complication. Minn Med 1985;68:441-42.
Brivet F, Fouqueray B, Rain B, Benattar C. Lactic acidosis in breast cancer. Intensive Care Med 1984;10:110-1.
Sculier JP, Nicaise C, Klastersky J. Lactic acidosis: A metabolic complication of extensive metastatic cancer. Eur J Cancer Clin Oncol 1983;19:597-601.
Manuel B, Suresh V, Saphwat E. Refractory metabolic acidosis in small cell cancer of the lung. South Med J 2006;99:782-3.
Rao KS, Mehta R, Ferlinz J. Unusual presentation of cancer-induced lactic acidosis. Postgrad Med J 1988;64:475.
Fujimura M, Shirasaki H, Kasahara K, Matsuda T. Small cell lung cancer accompanied by lactic acidosis and syndrome of inappropriate secretion of antidiuretic hormone. Lung Cancer 1998;22:251-4.
Sheriff DS. Lactic acidosis and small cell carcinoma of the lung. Postgrad Med J 1986; 62:297-8.
Rice K, Schwartz SH. Lactic acidosis with small cell carcinoma. Rapid response to chemotherapy. Am J Med 1985;79:501-3.
Colman LK, Baker TM. Lactic acidosis with extensive oat cell carcinoma of the lung--not necessarily a poor prognostic sign: Case report. Mil Med 1983;148:440.
Raju RN, Kardinal CG. Lactic acidosis in lung cancer. South Med J 1983;76:397-8.
Wesbey G. Lactic acidosis in oat cell carcinoma with extensive hepatic metastases. Arch Intern Med 1981;141:816-7.
Fraley DS, Adler S, Bruns FJ, Zett B. Stimulation of lactate production by administration of bicarbonate in a patient with a solid neoplasm and lactic acidosis. N Engl J Med 1980; 303:1100-2.
Spechler SJ, Esposito AL, Koff RS, Hong WK. Lactic acidosis in oat cell carcinoma with extensive hepatic metastases. Arch Intern Med 1978;138:1663-4.
Cheng JC, Esparza SD, Knez VM, Sakamoto KM, Moore TB. Severe lactic acidosis in a 14-year-old female with metastatic undifferentiated carcinoma of unknown primary. J Pediatr Hematol Oncol 2004;26:780-2.
Chau WK, Yang CF, Chou YH, Ho CH. Aggressive undifferentiated carcinoma of unknown primary site complicated by lactic acidosis after bleeding: A case report. Jpn J Clin Oncol 2002;32:210-4.
Munoz J, Stoltenberg M. Severe lactic acidosis in a patient with metastatic prostate cancer. J Cancer Res Ther 2011;7:201-2.
Colombo GM, Del Vecchio LR, Sacco T, Cicchinelli M. Fatal lactic acidosis due to widespread diffusion of melanoma. Minerva Med 2006;97:295.
Wall BM, Mansour N, Cooke CR. Acute fulminant lactic acidosis complicating metastatic cholangiocarcinoma. Am J Med Sci 2000;319: 126-9.
Muntz HG, Brown E. Lactic acidosis and hypoglycemia: A metabolic complication of advanced gynecologic malignancy. Int J Gynecol Cancer 1992;2:163-7.
Fields AL, Wolman SL, Halperin ML. Chronic lactic acidosis in a patient with cancer: Therapy and metabolic consequences. Cancer 1981;47:2026-9.
Stacpoole PW, Lichtenstein MJ, Polk JR, Greco FA. Lactic acidosis associated with metastatic osteogenic sarcoma. South Med J 1981;74:868-70.
Kachel RG. Metastatic reticulum cell sarcoma and lactic acidosis. Cancer 1975;36:2056-9.
Dr. Abdallah Sassine Geara
Nephrology Department, West Virginia University, 527 medical Park drive, Bridgeport, WV, 26330
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]
[Table 1], [Table 2]
|This article has been cited by|
||A chronic low-dose magnesium L-lactate administration has a beneficial effect on the myocardium and the skeletal muscles
| ||Marlène Magalhaes Pinto, Hervé Dubouchaud, Chrystèle Jouve, Jean-Paul Rigaudière, Véronique Patrac, Damien Bouvier, Isabelle Hininger-Favier, Stéphane Walrand, Luc Demaison |
| ||Journal of Physiology and Biochemistry. 2021; |
|[Pubmed] | [DOI]|
||Metabolic Variations between Low-Grade and High-Grade Gliomas—Profiling by 1H NMR Spectroscopy
| ||Jayalakshmi Jothi, Vanisree Arambakkam Janardhanam, Rama Krishnaswamy |
| ||Journal of Proteome Research. 2020; 19(6): 2483 |
|[Pubmed] | [DOI]|
||A case of malignant hyperlactaemic acidosis appearing upon treatment with the mono-carboxylase transporter 1 inhibitor AZD3965
| ||Rosie McNeillis, Alastair Greystoke, Jon Walton, Chris Bacon, Hector Keun, Alexandros Siskos, George Petrides, Nicola Leech, Fiona Jenkinson, Ann Bowron, Sarah Halford, Ruth Plummer |
| ||British Journal of Cancer. 2020; 122(8): 1141 |
|[Pubmed] | [DOI]|
||Type B lactic acidosis: a rare oncological emergency
| ||Qiuying Selina Liu, Farzana Harji, Anna Jones, Amy C Tarnower |
| ||BMJ Case Reports. 2020; 13(3): e233068 |
|[Pubmed] | [DOI]|
| Article Access Statistics|
| Viewed||3084 |
| Printed||44 |
| Emailed||0 |
| PDF Downloaded||509 |
| Comments ||[Add] |
| Cited by others ||4 |