Cause and effect of microenvironmental acidosis on bone metastases

Abstract

Skeletal involvement is a frequent and troublesome complication in advanced cancers. In the process of tumor cells homing to the skeleton to form bone metastases (BM), different mechanisms allow tumor cells to interact with cells of the bone microenvironment and seed in the bone tissue. Among these, tumor acidosis has been directly associated with tumor invasion and aggressiveness in several types of cancer although it has been less explored in the context of BM. In bone, the association of local acidosis and cancer invasiveness is even more important for tumor expansion since the extracellular matrix is formed by both organic and hard inorganic matrices and bone cells are used to sense protons and adapt or react to a low pH to maintain tissue homeostasis. In the BM microenvironment, increased concentration of protons may derive not only from glycolytic tumor cells but also from tumor-induced osteoclasts, the bone-resorbing cells, and may influence the progression or symptoms of BM in many different ways, by directly enhancing cancer cell motility and aggressiveness, or by modulating the functions of bone cells versus a pro-tumorigenic phenotype, or by inducing bone pain. In this review, we will describe and discuss the cause of acidosis in BM, its role in BM microenvironment, and which are the final effectors that may be targeted to treat metastatic patients.

Acid Microenvironment in Bone Sarcomas

“…The V-ATPase consists of an ATP-hydrolytic domain (V 1 ) and a proton-translocation domain (V 0 ) [49]. Its energyconsuming activity requires the close association of all the components of the complex, which is provided by the C-loop [50]. Studies on V-ATPase expression and activity in bone sarcomas are mainly related to the analysis of preclinical models and, less frequently, of tissue samples.…”

“…In this context, 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) (see ref. [50]); carcinoma cells metastasizing to the bone share with bone sarcoma cells different mechanisms of proton extrusion, including the expression of V 1 B 2 and V 0 c V-ATPase subunits, CAIX, MCT1, and MCT4. As an example, we have recently found mRNA expression of CAIX in breast and renal carcinoma cell lines, with a significant increase under reduced oxygen conditions with respect to normoxia [50,56].…”

“…[50]); carcinoma cells metastasizing to the bone share with bone sarcoma cells different mechanisms of proton extrusion, including the expression of V 1 B 2 and V 0 c V-ATPase subunits, CAIX, MCT1, and MCT4. As an example, we have recently found mRNA expression of CAIX in breast and renal carcinoma cell lines, with a significant increase under reduced oxygen conditions with respect to normoxia [50,56]. Additionally, different isoforms of V-ATPase, including the V 1 C 1 [57] and the V 1 B 2 and V 1 G 1 subunits [58], are expressed by breast carcinoma cells with a specific tropism for bone.…”

New Advances in the Study of Bone Tumors: A Lesson From the 3D Environment

“…Collagen-based hydrogels rely also on pH and plays a crucial role in cancer progression and is the most common protein of mammalian ECM. However, the pH-dependency makes collagen-based hydrogels unsuitable for the study of the effects of tumor acidosis, a feature that is crucial for the development of bone cancer (Cortini et al, 2017; Avnet et al, 2019), or of cancer-induced bone pain (Yoneda et al, 2015; Di Pompo et al, 2017).…”

Acid-Induced Inflammatory Cytokines in Osteoblasts: A Guided Path to Osteolysis in Bone Metastasis

“…Furthermore, acidosis upregulates the activity of cathepsin K (required for organic matrix degradation), tartrate-resistant acid phosphatase (TRACP), and TNF receptor-associated factor 6 (TRAF6) (Shibutani and Heersche, 1993;Arnett, 2010;Yuan et al, 2016). Thus, in the context of BM, low extracellular pH may be an essential requirement for the initiation of the osteolytic process [for a more detailed update on the current state-of-the-art on acid-related effects in BM, see our recent review (Avnet et al, 2019b)]. Vice versa, osteogenesis (OB differentiation, mineralization, and bone formation) is affected by a low extracellular pH (Brandao-Burch et al, 2005;Massa et al, 2017).…”