Abstract
Simple SummaryAlthough rare, malignant bone sarcomas have devastating clinical implications for the health and survival of young adults and children. To date, efforts to identify the molecular drivers and targets have focused on cancer cells or on the interplay between cancer cells and stromal cells in the tumour microenvironment. On the contrary, in the current literature, the role of the chemical-physical conditions of the tumour microenvironment that may be implicated in sarcoma aggressiveness and progression are poorly reported and discussed. Among these, extracellular acidosis is a well-recognized hallmark of bone sarcomas and promotes cancer growth and dissemination but data presented on this topic are fragmented. Hence, we intended to provide a general and comprehensive overview of the causes and implications of acidosis in bone sarcoma.In bone sarcomas, extracellular proton accumulation is an intrinsic driver of malignancy. Extracellular acidosis increases stemness, invasion, angiogenesis, metastasis, and resistance to therapy of cancer cells. It reprograms tumour-associated stroma into a protumour phenotype through the release of inflammatory cytokines. It affects bone homeostasis, as extracellular proton accumulation is perceived by acid-sensing ion channels located at the cell membrane of normal bone cells. In bone, acidosis results from the altered glycolytic metabolism of bone cancer cells and the resorption activity of tumour-induced osteoclasts that share the same ecosystem. Proton extrusion activity is mediated by extruders and transporters located at the cell membrane of normal and transformed cells, including vacuolar ATPase and carbonic anhydrase IX, or by the release of highly acidic lysosomes by exocytosis. To date, a number of investigations have focused on the effects of acidosis and its inhibition in bone sarcomas, including studies evaluating the use of photodynamic therapy. In this review, we will discuss the current status of all findings on extracellular acidosis in bone sarcomas, with a specific focus on the characteristics of the bone microenvironment and the acid-targeting therapeutic approaches that are currently being evaluated.
Highlights
It might be interesting to compare the ability of bone sarcomas to acidify the extracellular space with respect to other types of cancers that are able to expand in bone, such as bone metastases (BM); carcinoma cells metastasizing to the bone share with bone sarcoma cells different mechanisms of proton extrusion, including the expression of V1 B2 and V0 c V-ATPase subunits, CAIX, MCT1, and MCT4
This ‘vicious cycle’ between cancer cells and the bone microenvironment was first described in bone metastasis, but there is evidence supporting the notion that osteosarcoma cells, for example, mediate bone destruction by stimulating osteoclast differentiation and activity as bone metastasis [71,72]
The anarchic formation of new vessels that provide O2 and nutrients needed by actively proliferating cells is induced by tumour cells through the release of pro-angiogenic factors, such as vascular endothelial growth factor (VEGF) and interleukin 8 (IL-8) [98], or through the stabilisation of hypoxia-inducible factor-1 (HIF-1) that are promoted by extracellular acidosis [99,100]
Summary
Bone sarcomas comprise highly heterogeneous subtypes of mesenchymal tumours originating from the bone. The most common types of bone sarcoma are osteosarcoma, Ewing’s sarcoma, and chondrosarcoma. Osteosarcoma is the first primary cancer of bone Ewing’s sarcoma is the second most common primary malignant bone tumour. It occurs most frequently in children and adolescents, but adults can . The survival rate after 5 years for patients with localised primary tumour is. The survival rate of chondrosarcoma is 50–60% at 10 years according to the histological grade [4]. Current treatments for osteosarcoma and Ewing’s sarcoma combine surgery (preoperative or neoadjuvant), followed by chemotherapy (postoperative or neoadjuvant), and long-term polychemotherapy [5,6]. The employment of tyrosine kinase and cyclin-dependent kinase inhibitors, DNA repair or chemoresistance targeting, and immunotherapies are currently the most attractive [7]
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