In a PLoS One study, perhaps the first in the area of hematological tumors, and specifically leukemia, Shelly Inbar and colleagues from the Neuroimmunology Research Unit, Department of Psychology, Tel Aviv University, Israel, demonstrate marked adverse effects of stress hormones and prostaglandin E2 (PGE2) on survival rates of leukemic animals.
An increasing body of evidence indicates that psychological stress might be linked to the onset, expression or progression of several human malignancies such as tumors of the breast, skin, reproductive system and the gastrointestinal tract.
It appears that the activation of the sympathetic nervous system (SNS) and the hypothalamic–pituitary–adrenal (HPA) axis play a central role in cancer progression, through suppression of cell-mediated immunity and/or through direct effects of catecholamines and prostaglandins (PGs) on tumor growth.
To date, these issues have not been directly addressed in the context of leukemia.
In the PLoS One study the authors report that in rats already bearing leukemia (for two or six days) exposure to a combination of epinephrine and corticosterone significantly decreased survival rates. When these stress hormones were administered simultaneously with leukemia cells, an approximate 3-fold decrease in survival rates was evident. PGE2 and epinephrine by themselves caused similar effects, while corticosterone alone had smaller and non-significant effects.
Searching for mediating mechanisms, the authors found that each of the stress factors transiently suppressed NK activity against CRNK-16 and YAC-1 lines on a per NK basis.
Furthermore, a short paradigm of swim stress markedly reduced survival rates of the CRNK-16 challenged rats, whereas a prolonged administration of the beta-blocker nadolol or the COX inhibitor indomethacin significantly improved survival rates.
Previous research indicates that patients undergoing treatment for hematological malignancies experience high levels of anxiety and depression, and that these two psychological factors are strongly linked to profound cellular immunity suppression through the release of stress hormones.
Thus, as discussed by the authors, this study provides further insights into stress-tumor interactions, and underlines the importance of considering stress responses in the clinical setting of leukemia treatment, specifically addressing the potential beneficial effects of beta-blockers and COX inhibitors.
Thus, according to the authors of this study, patients with hematological malignancies, which often exhibit diminished NK activity, may benefit from extended β-blockade and COX inhibition.
In a study published in Brain, Behavior, and Immunity, in 2012, Donald M. Lamkin et al. tested the hypothesis that stress-induced sympathetic nervous system (SNS) activation and signaling might affect acute lymphoblastic leukemia (ALL) progression. In an orthotopic mouse model, Nalm-6 human pre-B ALL cells were transduced with the luciferase gene for longitudinal bioluminescent imaging and injected i.v. into male SCID mice for bone marrow engraftment.
The investigators found that chronic restraint stress significantly increased Nalm-6 ALL tumor burden and dissemination in a well-established mouse xenograft model of the most prevalent form of human pediatric leukemia. When restraint-stressed mice were treated with the non-selective β-adrenergic antagonist, propranolol, the authors observed that this drug significantly abrogated stress-enhanced ALL progression by the end of the stress period.
Thus, these experiments indicated that stress effects were mediated by β-adrenergic signaling in vivo, but no evidence was found that those in vivo growth and dissemination effects stemmed from direct stimulation of Nalm-6 ALL cell proliferation by β-adrenergic signaling. Thus, as per the authors, the effect of chronic stress on ALL progression in the present model appears to be indirectly mediated by other host cell types that interact with Nalm-6 human ALL cells. Such effects could potentially include SNS regulation of anti-tumor immune responses and/or SNS regulation of bone marrow stromal cells.
Moreover, according to the investigators, an indirect pathway by which β-adrenergic signaling may affect ALL cell biology involves sympathetic innervation of the stem cell niche in bone marrow. SNS activity regulates both endogenous circadian mobilization and pharmacological cytokine-prompted mobilization of normal (non-leukemic) progenitor cells through β-adrenergic signaling in adjacent stromal cells.
In conclusion, this study indicates that chronic stress can enhance the progression of human pre-B cell acute lymphoblastic leukemia in an orthotopic mouse model through an indirect pathway that is regulated by β-adrenergic signaling.
A 2018 study by Barbara L. Andersen et al.demonstrated that in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) psychological stress is related to heightened levels of cellular, cytokine, and chemokine markers that are associated with progressive disease. In these patients stress predicted higher absolute lymphocyte counts (ALCs), and higher levels of tumor necrosis factor-α (TNF)-α, interleukin (IL)-16 and the chemokine (C-C motif) ligand 3 (CCL3).
As discussed by the authors of this study, the association between stress and TNF-α is particularly important in CLL, because malignant cells release TNF-α spontaneously, and TNF-α increases their proliferation and viability. As per IL-16, it has been suggested that IL-16 may mediate communications between B cells and T cells within lymph node follicles, and IL-16 may suppresses effector T-cell function. Regarding CCL3 it has been hypothesized that increased CCL3 secretion may induce the trafficking and homing of T cells to CLL cells in tissue microenvironments.
In conclusion, previous research has examined stress associations in animal models, but this study is perhaps the first to demonstrate that stress covaries with 4 key biomarkers in patients with CLL.
In the study, a chronic restraint stress mouse model was established to evaluate the effect of stress on AML. The authors found that mice under chronic stress exhibited significantly increased liver and spleen infiltration of leukemic cells and poorer overall survival. This was accompanied by elevated cellular NLR family pyrin domain containing 3 (NLRP3) and interleukin-1β (IL-1β) in the liver or bone marrow, and secreted IL-1β in the plasma, indicating the activation of inflammasomes under chronic restraint stress. Thus, chronic stress may promote AML progression via the high mobility group box 1 (HMGB1) – NLRP3 – IL-1β dependent mechanism.