Human Neural Stem Cell Tropism to Metastatic Breast Cancer
Human Neural Stem Cell Tropism to Metastatic Breast Cancer
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DOI：
10.1002/stem.784
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发表时间：
2012-02-01
期刊：
影响因子：
5.2
通讯作者：
Aboody, Karen S.
中科院分区：
文献类型：
--
作者：
Zhao, Donghong;Najbauer, Joseph;Aboody, Karen S.
多器官转移是乳腺癌患者死亡的主要原因。转移性乳腺癌患者预后不良以及现有治疗方法的毒副作用要求开发有效的肿瘤选择性治疗方法。神经干细胞（NSCs）具有固有的致瘤特性，使其能够克服许多限制乳腺癌有效化疗策略的药物输送障碍。我们报道NSC对乳腺肿瘤细胞系的趋向性增加与癌细胞的侵袭性密切相关。白细胞介素6 （IL-6）是介导NSC向浸润性乳腺癌细胞趋向性的主要细胞因子。我们首次在转移性人类乳腺癌的临床前小鼠模型中表明，与原发性乳腺内脂肪垫肿瘤相比，NSCs优先靶向多器官转移的肿瘤，包括肝脏、肺、淋巴结和股骨。为了证明干细胞介导的乳腺癌治疗的概念，研究人员对NSCs进行了基因修饰，使其分泌兔羧酸酯酶（rCE），这种酶可以激活CPT-11前体药物SN-38，一种有效的拓扑异构酶I抑制剂，用于肿瘤局部化疗。体外数据表明，乳腺癌细胞暴露于分泌rce的NSCs （NSC.rCE）的条件培养基中，其对CPT-11的敏感性增加了200倍。体内，NSC对荷瘤小鼠的治疗作用。rCE细胞联合CPT-11可减少肺和淋巴结的转移性肿瘤负荷。这些数据表明，对于乳腺癌转移，nsc介导的酶/前药治疗可能比目前可用的化疗策略更有效，毒性更小。干细胞2012；30:314325。
Metastasis to multiple organs is the primary cause of mortality in breast cancer patients. The poor prognosis for patients with metastatic breast cancer and toxic side effects of currently available treatments necessitate the development of effective tumor-selective therapies. Neural stem cells (NSCs) possess inherent tumor tropic properties that enable them to overcome many obstacles of drug delivery that limit effective chemotherapy strategies for breast cancer. We report that increased NSC tropism to breast tumor cell lines is strongly correlated with the invasiveness of cancer cells. Interleukin 6 (IL-6) was identified as a major cytokine mediating NSC tropism to invasive breast cancer cells. We show for the first time in a preclinical mouse model of metastatic human breast cancer that NSCs preferentially target tumor metastases in multiple organs, including liver, lung, lymph nodes, and femur, versus the primary intramammary fat pad tumor. For proof-of-concept of stem cell-mediated breast cancer therapy, NSCs were genetically modified to secrete rabbit carboxylesterase (rCE), an enzyme that activates the CPT-11 prodrug to SN-38, a potent topoisomerase I inhibitor, to effect tumor-localized chemotherapy. In vitro data demonstrate that exposure of breast cancer cells to conditioned media from rCE-secreting NSCs (NSC.rCE) increased their sensitivity to CPT-11 by 200-fold. In vivo, treatment of tumor-bearing mice with NSC.rCE cells in combination with CPT-11 resulted in reduction of metastatic tumor burden in lung and lymph nodes. These data suggest that NSC-mediated enzyme/prodrug therapy may be more effective and less toxic than currently available chemotherapy strategies for breast cancer metastases. STEM CELLS 2012; 30:314325.