Abstract
Calcium (Ca2+) is involved as a signalling mediator in a broad variety of physiological processes. Some of the fastest responses in human body like neuronal action potential firing, to the slowest gene transcriptional regulation processes are controlled by pathways involving calcium signalling. Under pathological conditions these mechanisms are also involved in tumoral cells reprogramming, resulting in the altered expression of genes associated with cell proliferation, metastatisation and homing to the secondary metastatic site. On the other hand, calcium exerts a central function in nociception, from cues sensing in distal neurons, to signal modulation and interpretation in the central nervous system leading, in pathological conditions, to hyperalgesia, allodynia and pain chronicization. It is well known the relationship between cancer and pain when tumoral metastatic cells settle in the bones, especially in late breast cancer stage, where they alter the bone micro-environment leading to bone lesions and resulting in pain refractory to the conventional analgesic therapies. The purpose of this review is to address the Ca2+ signalling mechanisms involved in cancer cell metastatisation as well as the function of the same signalling tools in pain regulation and transmission. Finally, the possible interactions between these two cells types cohabiting the same Ca2+ rich environment will be further explored attempting to highlight new possible therapeutical targets.
Highlights
A broad variety of cellular functions are tightly regulated by Ca2+ intracellular signals
Calcium is involved in functional and structural neuronal plasticity underlying peripheral and central sensitisation at all levels, while changes in the Ca2+ intracellular concentration are mediated by different channels including ligand-gated receptors, acidsensing ion channels triggered by extracellular protons, ATP-responsive receptors, transient receptor protein (TRP) channels and VOCCS, acting some times in different ways depending on the neuronal cell type and on their location on it, whether it is the cell body or one of the two axonal terminals of a primary sensory neuron (Figure 2) [14]
Calcium signalling exerts a pivotal role in many cellular mechanisms related to breast cancer disease like cancer progression, metastatisation, drug resistance and pain, especially after breast cancer cells homing to the bone
Summary
A broad variety of cellular functions are tightly regulated by Ca2+ intracellular signals. Other mechanisms taking place within minutes to hours, like gene transcription regulation and cell proliferation are slower but still of fundamental importance for cellular life, especially in the context of cancer evolution For this reason, calcium signalling lays behind many breast cancer tumoral mechanics [1]. Besides the mere fast signal transduction, slower calcium signalling mechanisms are involved in cues processing, especially at the level of the central nervous system, with a consequent role in pain sensitisation and chronicization In this complex context, breast cancer and bone pain seem to be connected with a narrow strand by calcium, pivotal player underlying a broad variety of signalling cascades going from the fast signal transmission in neurons to the slower migration and gene expression mechanisms in cancer cells [5]. The role of tumoral cells in CABP will be addressed, analysing the influence they have on the different cells involved in it, on bone microanatomy, on pain initiation and chronicization mechanisms
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