Local and transient gene expression primes the liver to resist cancer metastasis.
Local and transient gene expression primes the liver to resist cancer metastasis.
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DOI：
10.1126/scitranslmed.aag2306
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发表时间：
2016-11-09
影响因子：
17.1
通讯作者：
Huang L
中科院分区：
文献类型：
--
作者：
Goodwin TJ;Zhou Y;Musetti SN;Liu R;Huang L
肝脏是胃肠癌转移的主要部位，并且是在许多其他原发性癌症（包括乳腺癌、肺癌和胰腺癌）中高度易受转移建立的位置。目前的标准治疗通常包括原发性肿瘤切除和全身给予强效但有毒的化疗药物，使中位生存率得到最小的改善。趋化因子CXCL 12是激活CXCR 4+癌细胞的迁移/存活途径和将免疫抑制细胞募集到炎症区域的关键因素。因此，降低肝脏内的CXCL 12浓度具有降低肝脏内的肿瘤和免疫抑制细胞活化/迁移的潜力。然而，由于与抗CXCL 12疗法的全身施用相关的脱靶毒性，CXCL 12陷阱的瞬时和肝脏特异性表达是必要的。为了应对这一挑战，我们开发了一种脂质磷酸钙纳米颗粒，其优化用于将编码工程化CXCL 12蛋白陷阱的质粒DNA递送至肝细胞的细胞核。这种pCXCL 12-trap制剂产生短暂（4天）的肝脏特异性表达，这大大降低了两种侵袭性肝转移模型（包括结肠直肠癌[CT-26（FL 3）]和乳腺癌（4 T1））中肝转移的发生。在侵袭性人结肠直肠肝转移模型（HT-29）中的后续研究比全身给予CXCL 12蛋白陷阱更有效地减少了肝转移的建立，并且达到了与强效CXCR 4拮抗剂（AMD 3100）的高剂量方案相当的水平。
The liver is the primary site of metastasis for gastrointestinal cancers and is a location highly susceptible to the establishment of metastasis in numerous other primary cancers, including breast, lung, and pancreatic cancers. The current standard of care typically consists of primary tumor resection and systemic administration of potent but toxic chemotherapeutics, yielding a minimal improvement in the median survival rate. CXCL12, a chemokine, is a key factor for activating the migration/survival pathways of CXCR4+ cancer cells and for recruiting immunosuppressive cells to areas of inflammation. Therefore, reducing CXCL12 concentrations within the liver has the potential to decrease tumor and immunosuppressive cell activation/migration within the liver. However, because of off-target toxicities associated with systemic administration of anti-CXCL12 therapies, transient and liver-specific expression of a CXCL12 trap is necessary. To address this challenge, we developed a lipid calcium phosphate nanoparticle optimized for delivering plasmid DNA, encoding an engineered CXCL12 protein trap, to the nucleus of liver hepatocytes. This pCXCL12-trap formulation yielded transient (4 days) liver-specific expression, which greatly decreased the occurrence of liver metastasis in two aggressive liver metastasis models, including colorectal [CT-26(FL3)] and breast (4T1) cancers. Subsequent studies in an aggressive human colorectal liver metastasis model (HT-29) decreased the establishment of liver metastasis more effectively than did systemic administration of the CXCL12 protein trap and to a level comparable to a high-dose regimen of a potent CXCR4 antagonist (AMD3100).
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影响因子：
7.4
作者：
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通讯作者：
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作者：
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影响因子：
9.3
作者：
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通讯作者：
Wei LX
影响因子：
3.2
作者：
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通讯作者：
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