Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA.
Department of Neurosurgery, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
Nat Commun. 2020 Dec 9;11(1):6311. doi: 10.1038/s41467-020-20144-w.
Blood-borne metastasis to the brain is a major complication of breast cancer, but cellular pathways that enable cancer cells to selectively grow in the brain microenvironment are poorly understood. We find that cultured circulating tumor cells (CTCs), derived from blood samples of women with advanced breast cancer and directly inoculated into the mouse frontal lobe, exhibit striking differences in proliferative potential in the brain. Derivative cell lines generated by serial intracranial injections acquire selectively increased proliferative competency in the brain, with reduced orthotopic tumor growth. Increased Hypoxia Inducible Factor 1A (HIF1A)-associated signaling correlates with enhanced proliferation in the brain, and shRNA-mediated suppression of HIF1A or drug inhibition of HIF-associated glycolytic pathways selectively impairs brain tumor growth while minimally impacting mammary tumor growth. In clinical specimens, brain metastases have elevated HIF1A protein expression, compared with matched primary breast tumors, and in patients with brain metastases, hypoxic signaling within CTCs predicts decreased overall survival. The selective activation of hypoxic signaling by metastatic breast cancer in the brain may have therapeutic implications.
血源性脑转移是乳腺癌的主要并发症，但癌症细胞在大脑微环境中选择性生长的细胞途径仍知之甚少。我们发现，从晚期乳腺癌女性的血液样本中培养的循环肿瘤细胞（CTCs），并直接接种到小鼠额叶中，在大脑中的增殖潜力存在显著差异。通过颅内连续注射产生的衍生细胞系在大脑中选择性地获得了更高的增殖能力，而原位肿瘤生长减少。与增强的大脑增殖相关的缺氧诱导因子 1A（HIF1A）相关信号与增强的增殖相关，并且 shRNA 介导的 HIF1A 抑制或药物抑制 HIF 相关糖酵解途径选择性地损害脑肿瘤生长，而对乳腺肿瘤生长的影响最小。在临床标本中，脑转移瘤的 HIF1A 蛋白表达水平高于匹配的原发性乳腺癌，并且在脑转移瘤患者中，CTCs 内的缺氧信号预示着总生存期的降低。转移性乳腺癌在大脑中选择性激活缺氧信号可能具有治疗意义。
