Beta-adrenergic Signaling in the Development and Progression of Pulmonary and Pancreatic Adenocarcinoma

Abstract

Small airway epithelial cells from, which most pulmonary adenocarcinomas (PACs) derive, and pancreatic duct epithelia, from which pancreatic ductal adenocarcinomas (PDACs) originate, share the ability to synthesize and release bicarbonate. This activity is stimulated in both cell types by the α7nicotinic acetylcholine receptor (α7nAChR)-mediated release of noradrenaline and adrenaline, which in turn activate β-adrenergic receptor (β-AR) signaling, leading to the cAMP-dependent release of bicarbonate. The same signaling pathway also stimulates a complex network of intracellular signaling cascades which regulate the proliferation, migration, angiogenesis and apoptosis of PAC and PDAC cells. The amino acid neurotransmitter γ-aminobutyric acid (GABA) serves as the physiological inhibitor of this cancer stimulating network by blocking the activation of adenylyl cyclase. This review summarizes experimental, epidemiological and clinical data that have identified risk factors for PAC and PDAC such as smoking, alcoholism, chronic non neoplastic diseases and their treatments as well as psychological stress and analyzes how these factors increase the cancer-stimulating effects of this regulatory cascade in PAC and PDAC. This analysis identifies the careful maintenance of balanced levels in stimulatory stress neurotransmitters and inhibitory GABA as a key factor for the prevention of PDAC and suggests the marker-guided use of beta-blockers, GABA or GABA-B receptor agonists as well as psychotherapeutic or pharmacological stress reduction as important tools that may render currently ineffective cancer intervention of PAC and PDAC more successful.

Beta-Blocker Drug Use and Survival among Patients with Pancreatic Adenocarcinoma

“…The inconsistency of results between and within cancer types could be due to not only heterogeneity in tumor biology, but also methodological variations, including differences in exposure definitions and population selection. There may also be influences of variation in type and duration (10,45) of b-blocker use in earlier studies.…”

Elucidating the role of incidental use of beta-blockers in patients with metastatic brain tumors in controlling tumor progression and survivability

“…Our findings are consistent with the results of previous preclinical studies looking at cancers in different organs and the effect of beta-blockers in their control. [7,[16][17][18][19] These results are coherently supported by beta-adrenergic signaling mechanism that regulates various cellular processes of cancer cell growth and development including tumor cell proliferation; extracellular matrix invasion and cell migration; matrix metalloproteinase activation; expression of angiogenic growth factors; and angiogenesis in several types of tumor, including those from lung, breast, colon, melanoma, prostate, pancreas, etc. [6,7,20,21] Control of local tumor growth is critical in the management of neoplasms.…”

The Neuro-Psychological Axis of Pancreatic Cancer as a Novel Target for Intervention

“…It is thus not surprising, that beta-blockers did not have significantly different effects on a variety of cancers than other antihypertensive agents [94]. Moreover, the chronic use of selective b1-AR antagonists can lead to compensatory hyperactivity of the β2-AR [97,98], a phenomenon that was predicted to have potentially deleterious effects on PDAC that is predominantly regulated by β2-ARs [99]. Significant reductions in survival from prostate cancer and PDAC (both of which are primarily regulated by β2-ARs) in a study with 75% of patients using β1-AR antagonists as compared to other hypertensive agents (none of which selectively blocks β1-ARs) unfortunately support this hypothesis [94].…”