Different Mechanisms of Regulation of the Warburg Effect in Lymphoblastoid and Burkitt Lymphoma Cells

Mushtaq, Muhammad; Darekar, Suhas; Klein, George; Kashuba, Elena

doi:10.1371/journal.pone.0136142

Cited by 23 publications

(26 citation statements)

References 24 publications

(32 reference statements)

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“…amply been reported that genetic and/or pharmacological inhibition of MCT1 and/or 4 in tumour cell lines and mice xenograft models of glioma [38], breast [39], colorectal [40], cervical [41] and lung [42] cancer leads to reduced lactate export, cell proliferation, migration and invasion, and increased responses to radiation and cell death. With respect to lymphomas, MCT4 has been found to be overexpressed in Burkitt's lymphomas and in lymphoblastoid cell lines [43]. Gan et al found that expression of MCT1 was significantly elevated in c-MYC amplified lymphomas, correlating with a poor prognosis and an unfavourable survival.…”

Section: Discussionmentioning

confidence: 99%

Clinical significance of metabolism-related biomarkers in non-Hodgkin lymphoma – MCT1 as potential target in diffuse large B cell lymphoma

et al. 2019

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Purpose Increased glycolytic activity with accumulation of extracellular lactate is regarded as a hallmark of cancer. In lymphomas, FDG-PET has undeniable diagnostic and prognostic value, corroborating that these tumours are avid for glucose. However, the role of glycolytic metabolism-related molecules in lymphoma is not well known. Here, we aimed to evaluate the clinical and prognostic significance of a panel of glycolytic metabolism-related molecules in primary non-Hodgkin lymphomas (NHL) and to test in vitro the putative therapeutic impact of lactate transport inhibition. Methods We assessed, by immunohistochemistry, the expression of the metabolism-related molecules MCT1, MCT2, MCT4, CD147, GLUT1, LDHA and CAIX in both tumour and stroma compartments of tissue sections obtained from 104 NHL patients. In addition, the lymphoma-derived cell lines OZ and DOHH-2 were used to evaluate the effect of AZD3965 on their viability and on apoptosis induction, as well as on extracellular lactate accumulation. Results We found that expression of MCT1 in the NHL tumour compartment was significantly associated with a poor clinicopathological profile. We also found that MCT4 and CAIX were present in the stromal compartment and correlated with an aggressive phenotype, while MCT1 was absent in this compartment. In addition, we found that AZD3965-mediated disruption of MCT1 activity led to inhibited NHL cell viability and extracellular lactate accumulation, while increasing apoptotic cell death.Conclusions Our results indicate that elevated glycolytic activity is associated with NHL aggressiveness, pointing at metabolic cooperation, mediated by MCT1 and MCT4, between tumour cells and their surrounding stroma. MCT1 may serve as a target to treat NHL (diffuse large B cell lymphoma) patients with high MCT1/low MCT4 expressing tumours. Further (pre-)clinical studies are required to allow the design of novel therapeutic strategies aimed at e.g. reprogramming the tumour microenvironment.

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Section: Discussionmentioning

confidence: 99%

Clinical significance of metabolism-related biomarkers in non-Hodgkin lymphoma – MCT1 as potential target in diffuse large B cell lymphoma

et al. 2019

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“…During the rapid proliferation associated with antigenic stimulation, lymphocytes are known to utilize aerobic glycolysis, which results in the generation of large amounts of extracellular lactate, a phenomenon known as the Warburg effect . This phenomenon was originally described in neoplastic cells and occurs in a variety of cancers, including lymphoma . Thus, it is possible that some dogs had an abundance of actively proliferating lymphocytes within the CSF and lactate concentrations in these individuals served as a proliferative marker.…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal fluid lactate in dogs with inflammatory central nervous system disorders

Mariani

Nye

Tokarz

et al. 2019

Veterinary Internal Medicne

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Background: Cerebrospinal fluid (CSF) lactate is frequently used as a biomarker in humans with inflammatory central nervous system (CNS) disorders including bacterial meningitis and autoimmune disorders such as multiple sclerosis. Hypothesis: Cerebrospinal fluid lactate concentrations are increased in a subset of dogs with inflammatory CNS disorders. Animals: One hundred two client-owned dogs diagnosed with inflammatory CNS disease. Methods: Case series. Cases were identified both prospectively at the time of diagnosis and retrospectively by review of a CSF biorepository. Cerebrospinal fluid lactate was analyzed with a commercially available, handheld lactate monitor. Subcategories of inflammatory disease were created for comparison (eg, steroid-responsive meningitis arteritis, meningoencephalitis of unknown etiology).Results: Cerebrospinal fluid lactate concentrations were above reference range in 47% of dogs (median, 2.5 mmol/L; range, 1.0-11.7 mmol/L). There was no significant difference in lactate concentrations between disease subcategories (P = .48). Significant but weak correlations were noted between CSF lactate concentration and nucleated cell count (r = .33, P < .001), absolute large mononuclear cell count (r = .44, P < .001), absolute small mononuclear cell count (r = .39, P < .001), absolute neutrophil cell count (r = .24, P = .01), and protein (r = .44, P < .001). No correlation was found between CSF lactate concentration and CSF red blood cell count (P = .58). There was no significant association of CSF lactate concentration with survival (P = .27).Conclusions and Clinical Importance: Cerebrospinal fluid lactate concentrations could serve as a rapid biomarker of inflammatory CNS disease in dogs.

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“…The same is true for lymphomas. [106][107][108][109][110][111] Development of multiple myeloma is also supported by essentially the same cell logistics, [112][113][114][115][116][117] and this seems to apply to sarcomas too. [118][119][120][121][122][123] The shared group of functional properties at issue here is in fact a subset of the currently recognized hallmarks of cancer.…”

Section: Related Specific Regulationmentioning

confidence: 97%

<p>Plausibility of trophoblastic-like regulation of cancer tissue</p>

Piechowski¹

2019

CMAR

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Background: Thus far, a well-established logical pattern of malignancy does not exist. The current approach to cancer properties is primarily descriptive with usually, for each of them, extensive analyses of the underlying associated biomolecular mechanisms. However, this remains a catalog and it would be valuable to determine the organizational chart that could account for their implementation, hierarchical links and input into tumor regulation. Hypothesis: Striking phenotypic similarities exist between trophoblast (invasive and expanding early placenta) and cancer regarding cell functions, logistics of development, means of protection and capacity to hold sway over the host organism. The concept of cancer cell trophoblastic-like transdifferentiation appears to be a rational proposal in an attempt to explain this analogy and provide a consistent insight into how cancer cells are functioning. Should this concept be validated, it could pave the way to promising research and therapeutic perspectives given that the trophoblastic properties are vital for the tumor while they are permanently epigenetically turned off in normal cells. Specifically targeting expression of the trophoblastic master genes could thereby be envisaged to jeopardize the tumor and its metastases without, in principle, inducing adverse side effects in the healthy tissues. Conclusion: A wide set of functional features of cancer tissue regulation, including some apparently paradoxical facts, was reviewed. Cancer cell misuse of physiological trophoblastic functions can clearly account for them, which identifies trophoblastic-like transdifferentiation as a likely key component of malignancy and makes it a potential relevant anticancer target.

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Different Mechanisms of Regulation of the Warburg Effect in Lymphoblastoid and Burkitt Lymphoma Cells

Cited by 23 publications

References 24 publications

Clinical significance of metabolism-related biomarkers in non-Hodgkin lymphoma – MCT1 as potential target in diffuse large B cell lymphoma

Clinical significance of metabolism-related biomarkers in non-Hodgkin lymphoma – MCT1 as potential target in diffuse large B cell lymphoma

Cerebrospinal fluid lactate in dogs with inflammatory central nervous system disorders

<p>Plausibility of trophoblastic-like regulation of cancer tissue</p>

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