■流行病学调查表明,心力衰竭患者的癌症发病率较高;然而,心脏病对癌症进展的因果作用尚不清楚.
■本研究旨在探讨心肌梗死(MI)引起的心力衰竭对肿瘤细胞生长的影响和潜在机制。
■我们通过将乳腺肿瘤来源的4T1细胞植入患有由左前降支结扎导致的MI的BALB/c小鼠中,产生了同基因小鼠模型。
■患有MI的小鼠表现出肿瘤体积增加,肿瘤重量,与假手术小鼠相比,肿瘤组织中Ki67阳性增殖细胞。此外,在肿瘤组织中的RNA测序分析显示与肿瘤进展相关的通路显著富集,特别是MI小鼠中的PI3K-AKT途径。原肌球蛋白受体激酶A(TRKA)磷酸化上调,PI3K-AKT信令的上游调节器,在MI小鼠的肿瘤组织中观察到。我们还观察到循环神经生长因子(NGF)水平升高,TRKA的配体,MI后心肌中NGF表达增加。在体外实验中,NGF刺激导致细胞增殖增加,以及TRKA和AKT的磷酸化。值得注意的是,小干扰RNA或化学抑制剂GW441756对TRKA的抑制作用可有效阻断这些作用。GW441756的施用导致MI小鼠中肿瘤体积和细胞增殖的抑制。
■我们的研究表明MI通过NGF-TRKA途径促进乳腺肿瘤生长。因此,抑制TRKA可能是同时经历MI后心力衰竭的乳腺癌患者的治疗策略.
UNASSIGNED: Epidemiological investigations suggest that patients with heart failure have a higher incidence of cancer; however, the causal role of cardiac disease on cancer progression remains unclear.
UNASSIGNED: This study aimed to investigate the impact and underlying mechanisms of myocardial infarction (MI)-induced heart failure on tumor cell growth.
UNASSIGNED: We generated a syngeneic mouse model by implanting mammary tumor-derived 4T1 cells into BALB/c mice with MI resulting from ligation of the left anterior descending artery.
UNASSIGNED: Mice with MI exhibited increased tumor volume, tumor weight, and Ki67-positive proliferative cells in the tumor tissue compared with the sham-operated mice. Furthermore, RNA sequencing analysis in the tumor tissue revealed significant enrichment of pathways related to tumor progression, particularly the PI3K-AKT pathway in the MI mice. Upregulation of tropomyosin receptor kinase A (
TRKA) phosphorylation, an upstream regulator of PI3K-AKT signaling, was observed in the tumor tissue of the MI mice. We also observed elevated levels of circulating nerve growth factor (NGF), a ligand of
TRKA, and increased NGF expressions in the myocardium after MI. In in vitro experiments, NGF stimulation led to increased cell proliferation, as well as phosphorylation of
TRKA and AKT. Notably, inhibition of
TRKA by small interfering RNA or the chemical inhibitor GW441756 effectively blocked these effects. Administration of GW441756 resulted in the suppression of tumor volume and cell proliferation in the MI mice.
UNASSIGNED: Our study demonstrates that MI promotes mammary tumor growth through the NGF-
TRKA pathway. Consequently, inhibiting TRKA could represent a therapeutic strategy for breast cancer patients concurrently experiencing heart failure after MI.