Abstract
Although numerous therapeutic strategies have attempted to target aerobic glycolysis to inhibit tumor progression, these approaches have not resulted in effective clinical outcomes. Murine squamous cell carcinoma (SCC) can be initiated by hair follicle stem cells (HFSCs). HFSCs utilize aerobic glycolysis, and the activity of lactate dehydrogenase (Ldh) is essential for HFSC activation. We sought to determine whether Ldh activity in SCC is critical for tumorigenesis or simply a marker of the cell type of origin. Genetic abrogation or induction of Ldh activity in HFSC-mediated tumorigenesis shows no effect on tumorigenesis as measured by number, time to formation, proliferation, volume, epithelial to mesenchymal transition, gene expression, or immune response. Ldha-null tumors show dramatically reduced levels of glycolytic metabolites by metabolomics, and significantly reduced glucose uptake by FDG-PET live animal imaging. These results suggest that squamous cancer cells of origin do not require increased glycolytic activity to generate cancers.
Highlights
While there is a mountain of data suggesting that lactate dehydrogenase activity is important for cancer cell growth in in vitro and ex vivo models[11,12,13,14], the relevance of lactate production to tumor initiation and progression in vivo has not been well explored
To investigate the relevance of lactate production to cutaneous squamous cell carcinoma, we used a previously demonstrated murine model of SCC driven by gain of oncogenic Ras coupled with loss of p53 activity in HFSCs15
Based on decades of research showing that most tumors display increased lactate production, our null hypothesis was that deletion of Ldha would block tumor formation from hair follicle stem cells (HFSCs)
Summary
While there is a mountain of data suggesting that lactate dehydrogenase activity is important for cancer cell growth in in vitro and ex vivo models[11,12,13,14], the relevance of lactate production to tumor initiation and progression in vivo has not been well explored. One study that used a model of lung carcinoma driven by oncogenic Ras coupled with deletion of Ldha showed a regression of tumors, suggesting a requirement of Ldh activity for maintenance of tumor cells[11]. Ldh activity was abrogated in the entire tissue in that model, which left uncertain the role of glycolytic activity in cancer cells of origin. HFSCs, which have been shown to be cancer cells of origin for squamous cell carcinoma[15,16], exhibit a high level of glycolytic activity during homeostatic conditions[17].
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