Lactate in Sarcoma Microenvironment: Much More than just a Waste Product

Abstract

Sarcomas are rare and heterogeneous malignant tumors relatively resistant to radio- and chemotherapy. Sarcoma progression is deeply dependent on environmental conditions that sustain both cancer growth and invasive abilities. Sarcoma microenvironment is composed of different stromal cell types and extracellular proteins. In this context, cancer cells may cooperate or compete with stromal cells for metabolic nutrients to sustain their survival and to adapt to environmental changes. The strict interplay between stromal and sarcoma cells deeply affects the extracellular metabolic milieu, thus altering the behavior of both cancer cells and other non-tumor cells, including immune cells. Cancer cells are typically dependent on glucose fermentation for growth and lactate is one of the most heavily increased metabolites in the tumor bulk. Currently, lactate is no longer considered a waste product of the Warburg metabolism, but novel signaling molecules able to regulate the behavior of tumor cells, tumor-stroma interactions and the immune response. In this review, we illustrate the role of lactate in the strong acidity microenvironment of sarcoma. Really, in the biological context of sarcoma, where novel targeted therapies are needed to improve patient outcomes in combination with current therapies or as an alternative treatment, lactate targeting could be a promising approach to future clinical trials.

Chondrosarcoma-from Molecular Pathology to Novel Therapies

“…In addition, an increased level of lactate dehydrogenase-A (LDH-A) was observed in CHS [ 59 ], which contributes to its treatment resistance [ 21 ]. In CHS, high expression of amphiregulin was also found, a ligand for epidermal growth factor receptor (EGFR), and correlates with histological grading in CHS [ 44 ].…”

Lactate induced up‐regulation of KLHDC8A (Kelch domain‐containing 8A) contributes to the proliferation, migration and apoptosis of human glioma cells

“…With the increase of exogenous lactate concentration, the expression of KLHDC8A was gradually increased (Figure 7A). In the tumour microenvironment, lactate accumulation was a result of increased glycolysis 29 . We want to know whether glycolysis was correlated with KLHDC8A expression levels.…”

“…In the tumour microenvironment, lactate accumulation was a result of increased glycolysis. 29 We want to know whether glycolysis was correlated with KLHDC8A expression levels. As expected, the glioma cells stimulated with gradient concentrations of glucose (0-4.5 mg/mL) showed a significant increase in the expression of KLHDC8A ( Figure 7B).…”

Immunotherapy in soft tissue and bone sarcoma: unraveling the barriers to effectiveness

“…Various studies have reported that they may sustain tumor progression by inhibiting T cell proliferation and activation, suppressing the cytotoxic activity of NKs, redirecting macrophages towards the immunosuppressive M2 phenotype and promoting regulatory T cell differentiation. In addition, MSCs inhibit B cell proliferation and antibody production 151 .…”