Aging and CNS Myeloid Cell Depletion Attenuate Breast Cancer Brain Metastasis.
Aging and CNS Myeloid Cell Depletion Attenuate Breast Cancer Brain Metastasis.
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DOI：
10.1158/1078-0432.ccr-21-1549
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发表时间：
2021-08-01
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在年轻患者中诊断出的乳腺癌通常具有侵袭性。由于年轻和老年患者的原发性乳腺肿瘤具有相似的突变模式，我们假设年轻宿主微环境促进更具侵袭性的转移性疾病。将三阴性或管腔型B乳腺癌细胞系并排注射到年轻小鼠和老年小鼠中，以量化肺、肝和脑转移。通过流式细胞术分析转移性和幼稚的年轻和年老小鼠脑。使用抗体或集落刺激因子-1受体（CSF-1 R）抑制剂耗尽免疫群体，并进行脑转移测定。确定对骨髓细胞群、星形胶质细胞增生和神经炎症反应的影响。在四种三阴性或管腔型B乳腺癌模型中，年轻小鼠宿主的脑转移是老年小鼠宿主的2- 4倍;未观察到年龄对肝或肺转移的影响。老年大脑，幼稚或转移，包含较少的居民中枢神经系统髓样细胞。使用CSF-1 R抑制剂耗竭髓样细胞，包括小胶质细胞和浸润性巨噬细胞，优先降低幼龄小鼠的脑转移负荷。CSF-1 R抑制在年轻小鼠中的下游效应在髓细胞数量、星形胶质细胞增生的诱导和神经炎症反应中的脑信号蛋白3A分泌方面与老年脑相似。宿主微环境因素有助于三阴性和腔型B乳腺癌脑转移的侵袭性。CSF-1 R抑制剂可能对年轻的脑转移患者有希望。
Breast cancer diagnosed in young patients is often aggressive. Because primary breast tumors from young and older patients have similar mutational patterns, we hypothesized that the young host microenvironment promotes more aggressive metastatic disease. Triple-negative or luminal B breast cancer cell lines were injected into young and older mice side-by-side to quantify lung, liver, and brain metastases. Young and older mouse brains, metastatic and naïve, were analyzed by flow cytometry. Immune populations were depleted using antibodies or a colony-stimulating factor-1 receptor (CSF-1R) inhibitor, and brain metastasis assays were conducted. Effects on myeloid populations, astrogliosis, and the neuroinflammatory response were determined. Brain metastases were 2- to 4-fold higher in young as compared with older mouse hosts in four models of triple-negative or luminal B breast cancer; no age effect was observed on liver or lung metastases. Aged brains, naïve or metastatic, contained fewer resident CNS myeloid cells. Use of a CSF-1R inhibitor to deplete myeloid cells, including both microglia and infiltrating macrophages, preferentially reduced brain metastasis burden in young mice. Downstream effects of CSF-1R inhibition in young mice resembled that of an aged brain in terms of myeloid numbers, induction of astrogliosis, and Semaphorin 3A secretion within the neuroinflammatory response. Host microenvironmental factors contribute to the aggressiveness of triple-negative and luminal B breast cancer brain metastasis. CSF-1R inhibitors may hold promise for young brain metastasis patients.
DOI：
10.1186/bcr2908
发表时间：
2011-06-24
期刊：
Breast cancer research : BCR
影响因子：
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作者：
van der Hage JA;Mieog JS;van de Velde CJ;Putter H;Bartelink H;van de Vijver MJ
通讯作者：
van de Vijver MJ