ABSTRACT
Given recent advances in cancer immune therapy, specifically use of checkpoint inhibitors, understanding the link between autoimmunity and cancer is essential. Rheumatoid arthritis (RA) affects about 1% of the population, and early diagnosis is key to prevent joint damage. Management consists of disease-modifying antirheumatic drugs that alter normal immunologic pathways, which could affect malignancy growth and survival. Prolonged immune dysregulation and the resulting inflammatory response associated with development of RA may also lead to increased cancer development risk. RA has long been associated with increased risk of non-Hodgkin's lymphoma [1] and further evidence supports relationship to lung cancer [2]. This review will address the mechanisms behind cancer development and progression in RA patients, biomarkers and assess cancer risk and early detection.
Subject(s)
Arthritis, Rheumatoid/etiology , Neoplasms/pathology , Neoplasms/therapy , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Agents, Immunological/therapeutic use , Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/immunology , Biomarkers, Tumor/antagonists & inhibitors , Biomarkers, Tumor/metabolism , Disease Progression , Humans , Immunotherapy/adverse effects , Inflammation , Neoplasms/immunology , RiskABSTRACT
Coordination of intracellular Ca2+ signaling in parotid acini is crucial for controlling the secretion of primary saliva. Previous work from our lab has demonstrated acidic-organelle Ca2+ release as a participant in agonist-evoked signaling dynamics of the parotid acinar cell. Furthermore, results implicated a potential role for the potent Ca2+ releasing second messenger NAADP in these events. The current study interrogated a direct role of NAADP for Ca2+ signaling in the parotid salivary gland acinar cell. Use of live-cell Ca2+ imaging, patch-clamp methods, and confocal microscopy revealed for the first time NAADP can evoke or enhance Ca2+ dynamics in parotid acini. These results were compared with pancreatic acini, a morphologically similar cell type previously shown to display NAADP-dependent Ca2+ signals. Findings presented here may be relevant in establishing new therapeutic targets for those suffering from xerostomia produced by hypofunctioning salivary glands.
Subject(s)
Acinar Cells/metabolism , NADP/analogs & derivatives , Pancreas/pathology , Salivary Glands/pathology , Xerostomia/metabolism , Acinar Cells/pathology , Animals , Calcium Signaling , Cells, Cultured , Humans , Male , Mice , Mice, Inbred C57BL , Microscopy, Confocal , Molecular Targeted Therapy , NADP/metabolism , Patch-Clamp Techniques , Xerostomia/pathologyABSTRACT
Autonomic neural activation of intracellular Ca2+ release in parotid acinar cells induces the secretion of the fluid and protein components of primary saliva critical for maintaining overall oral homeostasis. In the current study, we profiled the role of acidic organelles in shaping the Ca2+ signals of parotid acini using a variety of imaging and pharmacological approaches. Results demonstrate that zymogen granules predominate as an apically polarized population of acidic organelles that contributes to the initial Ca2+ release. Moreover, we provide evidence that indicates a role for the intracellular messenger NAADP in the release of Ca2+ from acidic organelles following elevation of cAMP. Our data are consistent with the "trigger" hypothesis where localized release of Ca2+ sensitizes canonical intracellular Ca2+ channels to enhance signals from the endoplasmic reticulum. Release from acidic stores may be important for initiating saliva secretion at low levels of stimulation and a potential therapeutic target to augment secretory activity in hypofunctioning salivary glands.
