Gallbladder cancer is diagnosed late and surgical resection is the only means to rescue. The survival rate is less than 5 years after surgical removal in advanced cases. During GBC progression the malignant cells secrete various enzymes, including LDH, both from cancerous as well as adjacent non-cancerous cells, resulting from inflammatory reactions. The total LDH or the specific LDH isoform/s, which are released in the blood stream draining from the gall bladder tissue, is likely to vary in concentration in the blood sera during different clinical stages or progression of GBC. Careful qualitative and quantitative analysis of this enzyme during different clinical conditions of gall bladder, including cholelithiasis, chronic cholecystitis and GBC, may be useful as an indicator of severity of the disease, and can also help in their prognostic management.
The molecular mechanisms, which play significant role in transforming normal gall bladder tissue into tumor, may be similar to other solid tumors as well. Thus, in GBC too, the tendency for conversion of pyruvate into lactate by LDH should be favored similarly as reported in endometrial cancer [24
]. In liver and skeletal muscle, LDH 4 and 5 were observed significantly expressed as compared to LDH 1, 2 and 3. The LDH isoenzymes (or its isoforms) are internally synthesized and are released to extracellular microenvironment en route to circulation through damaged cell membrane in the tissues or through inflamed cells [25
]. As the intensity of cellular stress increases in cholelithiasis, chronic cholecystitis or gall bladder carcinogenesis, the level of secretion of the cytoplasmic LDH isoenzymes may also go up. Due to poor oxygen availability the affected cells may generate at least the minimal required energy (ATP) to maintain cellular metabolism through anaerobic glycolysis (Warburg effect) [26
]. The rapidly proliferating populations of neoplastic cells depend largely upon the glycolytic mechanisms for deriving the energy with high requirement of LDH to generate NAD+ and ATP for glycolysis. The factors involved in influencing the quantity of tumor enzymes produced or released by tumour cells may be considered as the likely risk factors, increasing the cellular burden of tumors at a given time [15
]. Our findings provide strong support to this. But, the underlying factor inducing the release of these enzymes still remains to be fully elucidated.
While total LDH content may not be very specific to a particular tissue type, the differential expression pattern of its isoforms is more useful in determining the cellular metabolic status of the diseased tissue. In different types of cancers, increased expression of different LDH isoforms, for example, LDH 1(LDHB) in lung cancer [10
] and LDH 5 in colorectal, melanoma, breast cancer and endometrial cancers [11
], are found correlated with the progressive stages of malignancies. The present observation has shown significantly elevated expression of serum LDH 3 and 4 in GBC as compared to other isoforms. It appears interesting as these isoforms have earlier been shown specific to lung tissues (LDH 3) or liver (LDH 4) [8
]. In GBC, cholelithiasis or chronic cholecystitis, the increased expression of LDH 3 and 4 may be a consequence of the obstructions in the release of bile juice or disturbance in the cellular functions of inflamed tissue and are not specific to only lungs or liver as reported earlier [8
]. So far, no similar or related observation has yet been reported in the context of gall bladder diseases. The generally accepted major risk factors of gall bladder cancer include cholelithiasis and chronic cholecystitis. The epidemiological studies from our lab and others also suggest cholelithiasis as a major risk factor of gall bladder cancer [3
]. The presence of stone in cholelithiatic and inflammation in chronic cholecystitic gall bladder might potentially cause disturbance in the cellular glycolytic pathway. The relatively lower values of these isoforms in cholelithiasis or chronic cholecystitis (but significantly more than that of controls) as compared to GBC may be considered as an indication of more severe condition likely to come or a possible step towards gall bladder carcinogenesis. Thus, the significantly higher levels of LDH in gall bladder cancer and significantly lower level in cholelithiasis patients as compared to chronic cholecystitis and controls may have direct or indirect association with the advancement of pathogenesis or tumorgenesis. The conversion of pyruvate to lactate may likely be at lower rate in benign or cholelithiatic or chronic cholecystitic cells under the hypoxic environment, as compared to that in the advanced stages of gall bladder cancer. The increased cellular stress due to inflammatory reactions in chronic cholecystitic tissues is expected to raise the level of cellular LDH. We, therefore, suggest that the assessment of LDH 3 and 4 expression pattern alone or in association with other markers in the blood sera of gall bladder cancer, cholelithiasis and chronic cholecystitis may serve as diagnostic or prognostic marker in gall bladder cancer. The present observation is a pilot study and part of an ongoing study to search for an early diagnostic marker in GBC. Increasing the sample size of each clinical state may provide further support to the present observation. Interestingly, a recent study by Le et al. [7
] demonstrated that LDH A (LDH5) is needed for tumor progression, however, selective inhibition of metabolic activities of cancer cells, including expression of LDH 5, using small drugs like molecules, such as FX 11 [3-dydroxy-6-methyl-7(phenylmethyl)-4propylnaphthalene-1-carboxylic acid], may control the tumor growth. In this context, our observation is significant and provides first hand information for further research on the role of LDH-3 and 4 in gallbladder cancer pathogenesis.