Neuroblastoma, a type of solid malignant tumour diagnosed during infancy represents around 10% of all paediatric cancers, marking it as the second most common paediatric cancer. It is identified as a highly heterogeneous tumour that varies from persistent progression to a spontaneous progression. Development of neuroblast masses occur mostly in abdomen (65%), chest (20%), neck (5%) or pelvis (5%) and is classified to four major stages as L1 (very low), L2 (low), M (intermediate) and MS (risk) group of patients. Intracellular calcium ([Ca2+]i), the secondary messenger, plays a vital role in regulating cellular processes and hence maintaining the cellular calcium homeostasis is critical. Levels of [Ca2+]i in cancer cells is eminent as it modulates the proliferative or apoptotic pathway of the cell, bestowing the effect of anti-cancer drugs on [Ca2+]i. Here we focus on the effect of [Ca2+]i in the development and treatment of neuroblastoma. In resting cells, the concentration of [Ca2+]i ranges between 10 and 100 nM, reaching up to a 100 fold increase upon the Ca2+ entry into the cells from the extracellular space or its release from the internal Ca2+ stores (endoplasmic reticulum and mitochondria). [Ca2+]i homeostasis is maintained in the cell by a Ca2+ influx and efflux mechanism, in which the inositol-1,4,5 triphosphate receptor (InsP3R) and the ryanodine receptor (RYR) play an important role in regulating the influx mechanism. Signalling pathways involved in association to neuroblastoma includes growth factors like Epidermal Growth factor (EGF), Insulin-like Growth Factor (IGF), Nerve Growth factor (NGF), Platelet-derived Growth Factor (PDGF) and Vascular Endothelial Growth Factor (VEGF). Activation of these growth factor signalling pathways, activates a cascade of downstream signalling molecules including PI3K/AKT, ALK and FAK as intermediate kinases to MYCN, NF-KB and p53 as important transcription factors involved in the development of neuroblastoma. [Ca2+]i and PI3K/AKT pathway interactions lead to a loop of continuous activation of this cascade, while the activation of ALK and FAK leads to the activation of calmodulins and CaM dependent protein kinase kinase. Several studies confers the role of [Ca2+]i in inducing differentiation, proliferation and apoptosis in neuroblastoma. This poster explains in detail on the intracellular pathways that regulate differentiation, proliferation and apoptosis in neuroblastoma and the mechanism by which the [Ca2+]i homeostasis is maintained in the cells. Calcium-Sensing Receptor (CaSR), a G-protein coupled receptor is a vital mediator protein that sustains the cellular responses and determines the cell fate in response to the external Ca2+ concentration between 0.05-5 mM from a proliferative stage to a stage of quiescence and differentiation. CaSR activation is often associated with an up regulated expression of parathyroid hormone related peptide (PTHrP), which has a role in inducing hyperglycemia in cancer cells. It is conferred that these CaSR exerts tumour suppressor functions in neuroblastoma and is found in differentiated favourable neuroblastoma tumours. Evidences suggest that in neuroblastoma cells, common chemotherapeutic drugs like arsenic trioxide (As2O3), cisplatin (CDDP) and trimethytin chloride (TMT) that are used in treatment of cancer interferes with the [Ca2+]i homeostasis and induce apoptosis. It suggests a promising role for targeting [Ca2+]i for the development of a new drug. Thus, in a nut shell, we elucidate the intracellular mechanisms that are associated with the development of neuroblastoma with the key focus on the [Ca2+]i along with possibility of development of a new drug target in the treatment of neuroblastoma.


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