Lactate: mirror and motor of tumor malignancy.

A number of studies have shown that malignant transformation is associated with an increase in glycolytic flux and in anaerobic and aerobic cellular lactate excretion. Using quantitative bioluminescence imaging in various primary carcinomas in patients (uterine cervix, head and neck, colorectal region) at first diagnosis of the disease, we showed that lactate concentrations in tumors in vivo can be relatively low or extremely high (up to 40 micromol/g) in different individual tumors or within the same lesion. In all tumor entities investigated, high concentrations of lactate were correlated with a high incidence of distant metastasis already in an early stage of the disease. Low lactate tumors (<median of approximately 8 micromol/g) were associated with both a longer overall and disease-free survival compared with high lactate lesions (>8 micromol/g). Lactate dehydrogenase was found to be upregulated in most of these tumors compared with surrounding normal tissue. Numerous recent reports support these data by showing various biological activities of lactate that can enhance the malignant behavior of cancer cells. These mechanisms include the activation of hyaluronan synthesis by tumor-associated fibroblasts, upregulation of vascular endothelial growth factor and of hypoxia-inducible factor 1alpha, and direct enhancement of cellular motility that generates favorable conditions for metastatic spread. Thus, lactate accumulation not only mirrors but also actively enhances the degree of tumor malignancy. We propose that determination of lactate in primary tumors may serve as a basis of a novel metabolic classification, which can lead to an improvement of prognosis and therapy in clinical oncology.