Regulation of nonsmall‐cell lung cancer stem cell like cells by neurotransmitters and opioid peptides

Abstract

Non small-cell lung cancer (NSCLC) is the leading type of lung cancer and has a poor prognosis. We have shown that chronic stress promoted NSCLC xenografts in mice via stress neurotransmitter-activated cAMP signaling downstream of beta-adrenergic receptors and incidental beta-blocker therapy was reported to improve clinical outcomes in NSCLC patients. These findings suggest that psychological stress promotes NSCLC whereas pharmacologically or psychologically induced decreases in cAMP may inhibit NSCLC. Cancer stem cells are thought to drive the development, progression and resistance to therapy of NSCLC. However, their potential regulation by stress neurotransmitters has not been investigated. In the current study, epinephrine increased the number of cancer stem cell like cells (CSCs) from three NSCLC cell lines in spheroid formation assays while enhancing intracellular cAMP and the stem cell markers sonic hedgehog (SHH), aldehyde dehydrogenase-1 (ALDH-1) and Gli1, effects reversed by GABA or dynorphin B via Gαi-mediated inhibition of cAMP formation. The growth of NSCLC xenografts in a mouse model of stress reduction was significantly reduced compared with mice maintained under standard conditions. Stress reduction reduced serum levels of corticosterone, norepinephrine and epinephrine while the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and opioid peptides increased. Stress reduction significantly reduced cAMP, VEGF, p-ERK, p-AKT, p-CREB, p-SRc, SHH, ALDH-1 and Gli1 in xenograft tissues whereas cleaved caspase-3 and p53 were induced. We conclude that stress neurotransmitters activate CSCs in NSCLC via multiple cAMP-mediated pathways and that pharmacologically or psychologically induced decreases in cAMP signaling may improve clinical outcomes in NSCLC patients.

Comparing Patient-Derived Xenograft and Computational Response Prediction for Targeted Therapy in Patients of Early-Stage Large Cell Lung Cancer

“…Nevertheless, one major disadvantage is that the average timeframe for generating response data from PDX would not be less than 15 days, in this study, 25 days. Furthermore, recent studies provided compelling evidence about the strong impact of social distress on the tumor growth in PDXs (40,41). Stress-related signaling cascades such as adenylyl cyclase/cAMP/PKA signaling (42), MAPK-ERK signaling (40), and Hedgehog signaling (41) may confound the treatment effects of interest.…”

“…So far, we did not check how the infrastructure of the MSM or the algorithms used for the FCA may be biased with respect to different backgrounds regarding cancer biology and implementation of treatment effects, because all mice were housed under the same standard facility condition we would not expect a noticeable stress effect. However, the stress-related signaling cascades such as adenylyl cyclase/ cAMP/PKA signaling (42), MAPK/ERK signaling (40), and Hedgehog signaling (41) are well implemented in the MSM model. To settle this question, we started a project in which patient, PDX, and model-based response can be compared and quality differences between MSM-based and PDX-based response prediction can be quantified.…”

Molecular challenges of neuroendocrine tumors (Review)

“…Thus, based on the evidence there is no indication of beneficial effect in NETs for cotreatment with everolimus (146). The resistance of treatments also can be explained by presence of the cancer stem cells, which is very controvercial issue for NETs and there is not much evidence for the presence of CSC in these tumors, however some of dual targeted therapies reported to prevent drug resistance (147)(148)(149)(150)(151). There is evident lack of reliable biomarkers for correct treatment selection, although there are some for specific NETs, like CDX-2, for example, which is highly specific for metastatic and ileal NETS (14,152).…”

Cancer Stem Cells: Foe or Reprogrammable Cells for Efficient Cancer Therapy?

“…In this regard, the attainment of cardiogenesis in the presence of either chemical agents or physical stimulation encompasses the transcription and protein expression of endorphin peptides [33]. These molecules, besides their role in cardiogenesis [55][56][57], have long been shown to act as negative regulators for the development and spreading of different types of cancer [82][83][84][85][86][87].…”