Tani Tetsuya, Oikawa Masayoshi, Misaka Tomofumi, Ishida Takafumi, Takeishi Yasuchika
Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan.
Department of Community Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan.
JACC CardioOncol. 2023 Nov 6;6(1):55-66. doi: 10.1016/j.jaccao.2023.10.002. eCollection 2024 Feb.
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.
This study aimed to investigate the impact and underlying mechanisms of myocardial infarction (MI)-induced heart failure on tumor cell growth.
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.
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.
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.
流行病学调查表明，心力衰竭患者的癌症发病率较高；然而，心脏疾病在癌症进展中的因果作用仍不清楚。
本研究旨在探讨心肌梗死（MI）诱导的心力衰竭对肿瘤细胞生长的影响及其潜在机制。
通过将乳腺肿瘤来源的4T1细胞植入因左前降支结扎导致心肌梗死的BALB/c小鼠中，构建同基因小鼠模型。
与假手术小鼠相比，心肌梗死小鼠的肿瘤体积、肿瘤重量增加，肿瘤组织中Ki67阳性增殖细胞增多。此外，肿瘤组织的RNA测序分析显示，心肌梗死小鼠中与肿瘤进展相关的通路显著富集，尤其是PI3K-AKT通路。在心肌梗死小鼠的肿瘤组织中观察到PI3K-AKT信号上游调节因子原肌球蛋白受体激酶A（TRKA）磷酸化上调。我们还观察到循环神经生长因子（NGF）水平升高，NGF是TRKA的配体，心肌梗死后心肌中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磷酸化。值得注意的是，小干扰RNA或化学抑制剂GW441756抑制TRKA可有效阻断这些作用。给予GW441756可抑制心肌梗死小鼠的肿瘤体积和细胞增殖。
我们的研究表明，心肌梗死通过NGF-TRKA通路促进乳腺肿瘤生长。因此，抑制TRKA可能是心肌梗死后并发心力衰竭的乳腺癌患者的一种治疗策略。
