Institute for Health and Sport, Victoria University, Melbourne, Australia.
Department of Physiology and Cell Biology, University of Nevada, Reno, USA.
BMC Cancer. 2023 Oct 12;23(1):971. doi: 10.1186/s12885-023-11410-3.
Cancer cells express immunosuppressive molecules, such as programmed death ligands (PD-L)1 and PD-L2, enabling evasion from the host's immune system. Cancer cells synthesize and secrete acetylcholine (ACh), acting as an autocrine or paracrine hormone to promote their proliferation, differentiation, and migration.
We correlated the expression of PD-L1, PD-L2, cholinergic muscarinic receptor 3 (M3R), alpha 7 nicotinic receptor (α7nAChR), and choline acetyltransferase (ChAT) in colorectal cancer (CRC) tissues with the stage of disease, gender, age, risk, and patient survival. The effects of a muscarinic receptor blocker, atropine, and a selective M3R blocker, 4-DAMP, on the expression of immunosuppressive and cholinergic markers were evaluated in human CRC (LIM-2405, HT-29) cells.
Increased expression of PD-L1, M3R, and ChAT at stages III-IV was associated with a high risk of CRC and poor survival outcomes independent of patients' gender and age. α7nAChR and PD-L2 were not changed at any CRC stages. Atropine and 4-DAMP suppressed the proliferation and migration of human CRC cells, induced apoptosis, and decreased PD-L1, PD-L2, and M3R expression in CRC cells via inhibition of EGFR and phosphorylation of ERK.
The expression of immunosuppressive and cholinergic markers may increase the risk of recurrence of CRC. These markers might be used in determining prognosis and treatment regimens for CRC patients. Blocking cholinergic signaling may be a potential therapeutic for CRC through anti-proliferation and anti-migration via inhibition of EGFR and phosphorylation of ERK. These effects allow the immune system to recognize and eliminate cancer cells.
癌细胞表达免疫抑制分子，如程序性死亡配体（PD-L）1 和 PD-L2，使其能够逃避宿主的免疫系统。癌细胞合成并分泌乙酰胆碱（ACh），作为自分泌或旁分泌激素，促进其增殖、分化和迁移。
我们将结直肠癌（CRC）组织中 PD-L1、PD-L2、毒蕈碱型 M3 受体（M3R）、α7 烟碱型受体（α7nAChR）和胆碱乙酰转移酶（ChAT）的表达与疾病分期、性别、年龄、风险和患者生存相关联。评估了毒蕈碱受体阻滞剂阿托品和选择性 M3R 阻滞剂 4-DAMP 对人 CRC（LIM-2405、HT-29）细胞中免疫抑制和胆碱能标志物表达的影响。
III-IV 期 PD-L1、M3R 和 ChAT 表达增加与 CRC 高风险和不良生存结局相关，与患者性别和年龄无关。在任何 CRC 分期，α7nAChR 和 PD-L2 均未改变。阿托品和 4-DAMP 通过抑制 EGFR 和 ERK 磷酸化，抑制人 CRC 细胞的增殖和迁移，诱导细胞凋亡，并降低 CRC 细胞中 PD-L1、PD-L2 和 M3R 的表达。
免疫抑制和胆碱能标志物的表达可能会增加 CRC 复发的风险。这些标志物可用于确定 CRC 患者的预后和治疗方案。通过抑制 EGFR 和 ERK 磷酸化，阻断胆碱能信号可能是 CRC 的一种潜在治疗方法，可通过抗增殖和抗迁移发挥作用。这些作用使免疫系统能够识别和消除癌细胞。
