|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
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|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.|
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|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|
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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.
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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]
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