Hematology/Oncology, Department of Medicine, University of California, Irvine, CA, USA.
Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
Neurosci Lett. 2021 Jan 23;744:135601. doi: 10.1016/j.neulet.2020.135601. Epub 2020 Dec 30.
We examined the association between endogenous opioid β-endorphin, cancer progression and pain in a transgenic mouse model of breast cancer, with a rat C3(1) simian virus 40 large tumor antigen fusion gene (C3TAg). C3TAg mice develop ductal epithelial atypia at 8 weeks, progression to intra-epithelial neoplasia at 12 weeks, and invasive carcinoma with palpable tumors at 16 weeks. Consistent with invasive carcinoma at 4 months of age, C3TAg mice demonstrate a significant increase in hyperalgesia compared to younger C3TAg or control FVBN mice without tumors. Our data show that the growing tumor contributes to circulating β-endorphin. As an endogenous ligand of mu opioid receptor, β-endorphin has analgesic activity. Paradoxically, we observed an increase in pain in transgenic breast cancer mice with significantly high circulating and tumor-associated β-endorphin. Increased circulating β-endorphin correlates with increasing tumor burden. β-endorphin induced the activation of mitogenic and survival-promoting signaling pathways, MAPK/ERK 1/2, STAT3 and Akt, observed by us in human MDA-MB-231 cells suggesting a role for β-endorphin in breast cancer progression and associated pain.
我们研究了内源性阿片 β-内啡肽、癌症进展和疼痛之间的关系，使用了一种乳腺癌的转基因小鼠模型，该模型带有大鼠 C3(1)猴 SV40 大肿瘤抗原融合基因（C3TAg）。C3TAg 小鼠在 8 周时出现导管上皮异型增生，12 周时发展为上皮内瘤变，16 周时出现可触及肿瘤的浸润性癌。与 4 个月大时的浸润性癌一致，C3TAg 小鼠与没有肿瘤的年轻 C3TAg 或对照 FVBN 小鼠相比，表现出明显的痛觉过敏增加。我们的数据表明，生长中的肿瘤导致循环β-内啡肽增加。作为μ阿片受体的内源性配体，β-内啡肽具有镇痛活性。矛盾的是，我们观察到转基因乳腺癌小鼠的疼痛增加，其循环和肿瘤相关β-内啡肽显著升高。增加的循环β-内啡肽与肿瘤负荷的增加相关。β-内啡肽诱导促有丝分裂和生存促进信号通路 MAPK/ERK1/2、STAT3 和 Akt 的激活，我们在人 MDA-MB-231 细胞中观察到这一点，表明β-内啡肽在乳腺癌进展和相关疼痛中起作用。
