Contribution of acidic extracellular microenvironment of cancer-colonized bone to bone pain

Abstract

Solid and hematologic cancers colonized bone produce a number of pathologies. One of the most common complications associated with bone-colonized cancer is bone pain. Cancer-associated bone pain (CABP) is a major cause of increased morbidity and mortality and diminishes the quality of life and affects survival in cancer patients. Current treatments do not satisfactorily control CABP and can elicit serious side effects. Thus, new therapeutic interventions are needed to manage CABP. However, the mechanisms responsible for CABP are poorly understood. The observation that specific osteoclast inhibitors can reduce CABP in patients indicates a critical role of osteoclasts in the pathophysiology of CABP. Osteoclasts create an acidic extracellular microenvironment by secretion of protons via plasma membrane vacuolar proton pumps during bone resorption. In addition, bone-colonized cancer cells also release protons and lactate via plasma membrane pH regulators to avoid intracellular acidification resulting from increased aerobic glycolysis known as Warburg effect, thus exacerbating the acidic microenvironment. Since acidosis is algogenic for primary afferent sensory neurons and bone is densely innervated by sensory neurons that express acid-sensing nociceptors, the acidic bone microenvironments can evoke CABP. Understanding of the cellular and molecular mechanism by which the acidic extracellular microenvironment is created in cancer-colonized bone and the expression and function of these acid-sensing nociceptors are regulated may facilitate the development of novel therapeutic approaches for management of CABP. In this review, the contribution of the acidic extracellular microenvironment created by bone-colonized cancer cells and bone-resorbing osteoclasts to excitation and sensitization of sensory nerves innervating bone and elicitation of CABP and potential therapeutic implications of blocking the development and recognition of acidic extracellular microenvironment will be described.

Transcriptional regulation of voltage-gated sodium channels contributes to GM-CSF induced pain

“…the most common form of primary bone cancer, in which pain is the most common symptom and is seen in 85% of patients (Yoneda, et al,2015). Osteochondroma is the most common benign bone tumor and the majority of osteochondromas form an asymptomatic hard immobile painless palpable mass (de Mooij, et al,2012).…”

Skeletal complications in cancer patients with bone metastases

“…The resulting osteoclasts can demineralize and destroy regions of bone rich with peripheral nerve innervation, causing bone pain . In addition, the bone destruction process leads to an acidic environment, further stimulating pain through pH sensing channels . Therefore, blocking the interactions between chemical mediators and their receptors on peripheral nociceptors, or preventing osteoclastogenesis altogether are both analgesic strategies used for cancer‐induced bone pain …”

“…14 In addition, the bone destruction process leads to an acidic environment, further stimulating pain through pH sensing channels. 15,16 Therefore, blocking the interactions between chemical mediators and their receptors on peripheral nociceptors, or preventing osteoclastogenesis altogether are both analgesic strategies used for cancerinduced bone pain. 12,17 Currently, pain associated with cancer is treated by following the three-step analgesic ladder approach developed by the World Health Organization.…”

“…54,55 An acidic environment within the bone marrow can also cause cancer-induced bone pain. 15 Osteoclasts secrete HCl by expressing high levels of the vacuolar electrogenic H + -ATPase. 56 The resulting acidic environment after osteoclastic bone resorption is thought to cause pain behaviors through TRPV1, 15 which is a well-known acid-sensing ion channel, 26,57,58 and also activated by capsaicin, an ingredient in hot peppers.…”

Nitric oxide and pH modulation in gynaecological cancer

“…). This phenomenon results in degradation of the extracellular matrix, promoting a prometastatic cellular behaviour . Thus, it is feasible that nitric oxide may play a role in metastasis and cancer cell migration, lowering the pHo in gynaecological cancers .…”