Low dose aspirin blocks breast cancer-induced cognitive impairment in mice

Cancer patients with non-central nervous system tumors often suffer from cognitive impairment. While chemotherapy has long been attributed as the cause of these memory, learning and concentration difficulties, we recently observed cognitive impairment in cancer patients prior to treatment. This suggests the cancer alone may be sufficient to induce cognitive impairment, however the mechanisms are unknown. Here, we show that we can experimentally replicate the clinical phenomenon of cancer-associated cognitive impairment and we identify inflammation as a causal mechanism. We demonstrate that a peripheral tumor is sufficient to induce memory loss. Using an othotopic mouse model of breast cancer, we found that mice with 4T1.2 or EO771 mammary tumors had significantly poorer memory than mice without tumors. Memory impairment was independent of cancer-induced sickness behavior, which was only observed during the later stage of cancer progression in mice with high metastatic burden. Tumor-secreted factors were sufficient to induce memory impairment and pro-inflammatory cytokines were elevated in the plasma of tumor-bearing mice. Oral treatment with low-dose aspirin completely blocked tumor-induced memory impairment without affecting tumor-induced sickness or tumor growth, demonstrating a causal role for inflammation in cognitive impairment. These findings suggest that anti-inflammatories may be a safe and readily translatable strategy that could be used to prevent cancer-associated cognitive impairment in patients.

伴非中枢神经系统肿瘤的癌症患者常出现认知功能障碍。长期以来，化疗被认为是此类记忆、学习及注意力障碍的诱因，但我们近期在接受治疗前的癌症患者中也观察到了认知功能障碍。这提示仅肿瘤本身即可诱发认知功能障碍，但其具体机制尚不明确。本研究中，我们成功在实验中复现了肿瘤相关认知功能障碍的临床表型，并证实炎症是其致病机制。我们证实外周肿瘤足以引发记忆损伤：通过构建乳腺癌原位小鼠模型，我们发现携带4T1.2或EO771乳腺肿瘤的小鼠，其记忆能力显著弱于无肿瘤小鼠。记忆障碍与癌症诱导的病态行为无关，此类病态行为仅在肿瘤负荷较高的小鼠的肿瘤进展后期才可被观测到。肿瘤分泌的因子足以诱发记忆障碍，且荷瘤小鼠血浆中的促炎细胞因子水平显著升高。口服低剂量阿司匹林可完全阻断肿瘤诱导的记忆障碍，且不影响肿瘤诱导的病态行为或肿瘤生长，这进一步证实了炎症在认知功能障碍中的致病作用。本研究结果提示，抗炎疗法或可成为一种安全且易于转化的临床策略，用于预防患者的肿瘤相关认知功能障碍。