Energy metabolism in bone tumors: fuel selection and adaptation

Glucose and lactate

Similar to many tumor cells and as mentioned previously, bone metastases used glucose and glycolysis to progress [ , , ]. Indeed, glycolytic enzyme such as phosphoglycerate kinase 1 (PGK1) secreted by PCa cells can regulate bone formation at the metastatic site by increasing osteoblastic activity, osteomimicry, and decreasing osteoclastic function [ ]. Moreover, glucose is used for ATP generation through lactate production and via the pentose phosphate pathway (PPP) for nucleotide synthesis that is essential for cell proliferation. Accordingly, comparison of 28 paired primary metastatic breast cancers (BCas) revealed differential expression patterns of PPP proteins and the expression of the 6-phosphogluconolactonase (6PGL) in bone metastases was associated with shorter overall survival [ ]. Similarly, MDA-MB-231 cancer cells are described to release a large amount of lactate [ ]. In fact, Warburg et al. observed increased venous lactate levels in tumor-bearing limbs of rats compared to controls [ ]. It has been reported that the release of lactate at the bone site by glycolytic BCa cells is mediated by the monocarboxylate transporter 4 (MCT4), and that this protein is more expressed in metastases to bone compared to other sites like brain, lung, or liver [ , ]. Interestingly, MCT4 and MCT1 overexpression is also observed in OS and is linked to poor prognosis, tumor growth, metastatic process, and chemotherapy response [ , ]. Moreover, in the context of the bone, increase in acidosis due to lactate released by tumor cells may strongly stimulate bone metastases progression, by increasing not only tumor cells aggressiveness, but also by modulating bone cell functions and inducing cancer-related bone pain, showing a major impact that may have the energetic metabolism of metastatic cells on the global bone physiology [ , ] ( Fig. 26.2 ). More precisely, low pH can directly contribute to the mineralized matrix destruction since a large majority of the matrix is alkaline mineral (hydroxyapatite). Moreover, lactate uptake by osteoclasts has been described through MCT1, a transporter highly expressed by the bone resorbing cells, stimulating osteoclasts resorption activity and deciphering the lactate as a metabolic fuel for the oxidative metabolism of osteoclasts [ ]. Osteoblasts can also perceive tumor metabolic acidosis that inhibits most of their bone formation functions by altering alkaline phosphatase and extracellular matrix proteins expression, inhibiting mineral deposition [ ]. On the other side, low pH induces pro-osteoclastogenic factors, i.e., receptor activator of nuclear factor kappa-B ligand (RANKL), TNF-α, parathyroid hormone-related protein (PTH/PTHrP) receptors, IL-6, IL-8, and the chemokine (C–C motif) ligand 5 (CCL5) overexpression in osteoblasts, conducting the bone forming cells toward a protumoral phenotype by activating osteoclasts resorption and leading to more bone destruction [ ]. With the addition of osteoclasts and osteoblasts, mesenchymal stem cells (MSCs) may be sensitive to low pH. Indeed acidosis can induce MSC stemness maintenance and stimulate TGF-β, IL-8 secretion [ , ]. MSC under low pH conditions may also contribute to tumor cells aggressiveness, tumor immune escape, and bone resorption in OS. Coculture with MSC incubated with short-term acidosis can stimulate OS cells clonogenicity and invasiveness through NF-kB signaling (RelA, RelB) and downregulated cytokines secretion (CSF2/GM-CSF, CSF3/G-CSF, CCL5, CXCL5, CXCL1, IL-6, and IL-8) in MSC [ ]. Finally, extracellular lactate has been shown to affect myeloid lineages, by decreasing monocytes motility (contrasted with the stimulation of tumor cells migration), by reprogramming macrophages into a tumor-supporting M2 phenotype, and by inhibiting differentiation of monocytes into dendritic cells [ ]. Similarly, high lactate levels alter lymphoid lineage, by inhibiting CD8+ T cells function through depleting extracellular glucose stores (T cell anergy), impairing IFNγ-producing T cells and NK cells, and NK generation contributing to the phenomenon of tumor immune escape [ ]. Beside its participation into the bone metastases vicious circle, the lactate contribution to cancer-related bone pain is also strongly documented [ ]. The low pH induced by extracellular lactate can stimulate acid-sensing receptors highly expressed by sensoring neurons (nociceptors) that innervate the bone marrow and the periosteum including transient receptor potential vanilloid 1 (TRPV1), acid-sensing ion channels (ASIC1-3), and metabotropic proton-sensing G-protein-coupled receptors (GPCRs), thereby creating the formation of neuromas at the origin of the oncologic pain observed in many patients with bone metastases [ ]. Interestingly, TRPV1, ASIC, and GPCRs are also expressed in osteoclasts and osteoblasts [ ]. Moreover, the GPCR OGR1, a dual membrane receptor for both protons (extracellular pH) and lysolipids, expression level can be stimulated by RANKL treatment in osteoclasts and can mediate RANKL expression in osteoblasts in response to lactate acidosis [ , ]. Finally, low pH in the bone marrow microenvironment stimulate the release of nociceptive and inflammatory mediators by bone cells such as the nerve growth factor (NGF), the brain-derived neurotrophic factor (BDNF) causing axonal chemoattraction, and IL-6, IL-8, and IL-1 promoting tumor-associated hyperalgesia [ , ].