Table 3. Effects and potential underlying mechanisms of distress on cancer treatment in preclinical studies.
↑, increase; ↓, decrease; →, causal; E, epinephrine; MCL-1, myeloid cell leukemia 1; BAD, Bcl-xL/Bcl-2–associated death promoter; ISO, isoprenaline; PLC, phospholipase C; PKC, protein kinase C; CREB, cAMP response element-binding protein; DUSP1, dual-specificity protein phosphatase-1; JNK, c-Jun N-terminal kinase; Chk1, checkpoint kinase 1; NSCLC, non–small cell lung cancer; APC, antigen-presenting cells; GzmB, granzyme B; LKB1, liver kinase B1.
| Treatments | Role of stress | Cancer type | Model | Stress | Specific effects or pathway | Reference |
| Chemotherapy | ||||||
| Cisplatin | Antiapoptosis | Pancreatic cancer | Mice | Cold stress (22°C versus 30°C) |
β2-AR → ↑anti-apoptotic molecules (MCL-1, BCL-2, and BCL-XL) |
(42) |
| PI3K inhibitor, bicalutamide | Antiapoptosis | Prostate cancer | Mice | Immobilization stress; stress hormone (E) |
β2-AR/PKA/BAD antiapoptotic signaling pathway |
(27) |
| Paclitaxel, cisplatin, or docetaxel | Antiapoptosis | Ovarian cancer | Cell lines; mice | Stress hormones (NE); β-AR agonist (ISO); restraint stress |
β2-AR/cAMP/PLC/PKC/CREB→ ↑DUSP1 → ↓JNK-mediated phosphorylation of c-Jun |
(75) |
| Cisplatin | DNA damage | Epithelial ovarian cancer | Cell lines | Stress hormone (NE) | β2-AR → ↑DNA double strand breaks | (37) |
| Paclitaxel | DNA damage | Triple-negative breast cancer | Cell lines; mice | Stress hormones (cortisol, NE);restraint stress |
Stress hormone → DNA damage → ATR/Chk1/p21 → tumor cell cycle halt in the G1 phase. (Paclitaxel targets cells in S phase) |
(76) |
| Immunotherapy | ||||||
| Immunogenic cell death inducer; tumor vaccination, anti–PD-1 mAb |
Immunosuppression | NSCLC; fibrosarcomas; colorectal cancer | Mice | Repeated social defeat stress; acute restraint stress |
GC → ↑Tsc22d3 → ↓type I IFN responses in DC, activation of IFN-γ+ T cell |
(22) |
| Tumor vaccination | Immunosuppression | Melanoma | Mice | Social disruption stress | Stress→ ↓DC function and migration to draining lymph nodes, APC priming→↓IFN-γ + CD8+ T cell, CTL-mediated target cell killing |
(29) |
| CpG-C | Immunosuppression | Mammary carcinoma; colon tumor with liver metastasis; melanoma |
Rats and mice | Wet cage stress | Stress → β2-AR, GR, COX-2 → ↓ cytotoxicity of NK cells by CpG-C |
(33) |
| Anti–PD-1 mAb, anti–4-1BB mAb | Immunosuppression | B cell lymphoma | Mice | β-AR agonist (ISO) | β2-AR → ↓proliferation, IFN-γ production, and cytolytic killing capacity of antigen-specific CD8+ T cells. | (54) |
| Anti–PD-1 mAb | Immunosuppression | Mammary carcinoma; melanoma | Mice | Cold stress (22°C versus 30°C) |
β-AR → ↓the ratio of effector CD8+ T cell and CD4+ regulatory T cell ratio (IFN+ CD8+ T cell: Treg); ↑PD-1 expression in effector CD8+ TILs |
(77) |
| Radiotherapy | ||||||
| Local irradiation | Immunosuppression | Colon tumors; melanoma; mammary carcinoma |
Mice | Cold stress (22°C versus 30°C) |
β2-AR → ↓CD8+ T cell migration (CXCR3/CXCL9) and function (T-bet, IFN-γ, TNF-α, and GzmB) |
(80) |
| Irradiation | EMT | Lung cancer | Mice | Exposure to a conspecific mouse receiving inescapable foot shocks |
β2-AR → ↑Biomarker of EMT expressed in tumor: ↑Wnt1, Drosha, and vimentin, ↓E-cadherin |
(30) |
| Irradiation | Immunosuppression | Colon adenocarcinoma | Mice | Cold stress (22°C versus 30°C) |
β2-AR → ↓the percentage of IFN-γ+
GzmB+ CD4+ and CD8+ in tumor |
(79) |
| Targeted therapy | ||||||
| Sunitinib | Angiogenesis | Colorectal cancer; colon carcinoma |
Mice | Chronic restraint stress; stress hormone (NE) |
β-AR/cAMP/PKA → ↑VEGF, IL-8 | (23) |
| EGFR-TKIs | NSCLC | Cell lines; mice | Stress hormone (NE) | β2-AR/PKC/LKB1/CREB → IL-6– mediated EGFR TKI resistance |
(83) | |