Epigenetic therapy inhibits metastases by disrupting premetastatic niches.
Epigenetic therapy inhibits metastases by disrupting premetastatic niches.
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DOI：
10.1038/s41586-020-2054-x
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发表时间：
2020-03
期刊：
影响因子：
64.8
通讯作者：
Brock MV
中科院分区：
文献类型：
--
作者：
Lu Z;Zou J;Li S;Topper MJ;Tao Y;Zhang H;Jiao X;Xie W;Kong X;Vaz M;Li H;Cai Y;Xia L;Huang P;Rodgers K;Lee B;Riemer JB;Day CP;Yen RC;Cui Y;Wang Y;Wang Y;Zhang W;Easwaran H;Hulbert A;Kim K;Juergens RA;Yang SC;Battafarano RJ;Bush EL;Broderick SR;Cattaneo SM;Brahmer JR;Rudin CM;Wrangle J;Mei Y;Kim YJ;Zhang B;Wang KK;Forde PM;Margolick JB;Nelkin BD;Zahnow CA;Pardoll DM;Housseau F;Baylin SB;Shen L;Brock MV
手术后癌症复发仍然是一个尚未解决的临床问题。骨髓来源的髓样细胞有助于形成转移前微环境，这是将肿瘤细胞播散到移植远端部位所必需的。目前，还没有有效的干预措施来防止转移前微环境的形成。在这里，我们表明，手术切除原发性肺癌，乳腺癌和食管癌后，低剂量辅助表观遗传治疗破坏了转移前微环境，并通过其对髓源性抑制细胞（MDSC）的选择性作用抑制肺转移。在小鼠肺转移模型中，MDSC是原发性肿瘤切除后转移前微环境形成的关键因素。使用低剂量DNA甲基转移酶和组蛋白去乙酰化酶抑制剂、5-氮杂胞苷（Aza）和恩替诺特的辅助表观遗传疗法通过下调CCR 2和CXCR 2抑制MDSC的运输以及通过促进MDSC分化成更像间质性巨噬细胞的表型来破坏转移前生态位。与化疗相比，转移前肺中MDSC积累减少可产生更长的无病生存期和总生存期。我们的数据表明，即使在原发性肿瘤切除后，MDSC也有助于转移前壁龛的发展和残留肿瘤细胞的沉降。低剂量佐剂表观遗传修饰剂的组合，破坏这种转移前微环境，抑制转移，可能代表一种新的癌症辅助治疗方法。
Cancer recurrence after surgery remains an unresolved clinical problem. Bone marrow-derived myeloid cells contribute in forming the premetastatic microenvironment required for disseminating tumour cells to engraft distant sites. Presently, there are no effective interventions that prevent premetastatic microenvironment formation. Here, we show that after surgical removal of primary lung, breast, and esophageal cancers, low dose adjuvant epigenetic therapy disrupts the premetastatic microenvironment and inhibits lung metastases by its selective effect on myeloid derived suppressor cells (MDSCs). In murine pulmonary metastases models, MDSCs are key factors in premetastatic microenvironment formation after primary tumour resection. Adjuvant epigenetic therapy, using low dose DNA methyltransferase and histone deacetylase inhibitors, 5-azacytidine (Aza) and entinostat, disrupts the premetastatic niche by inhibiting the trafficking of MDSCs through the downregulation of CCR2 and CXCR2, and by promoting MDSC differentiation into a more interstitial macrophage-like phenotype. Decreased MDSCs accumulation in the premetastatic lung produces longer disease-free and overall survival compared to chemotherapy. Our data demonstrate that even after primary tumour removal, MDSCs contribute to the development of premetastatic niches and settlement of residual tumour cells. A combination of low dose adjuvant epigenetic modifiers that disrupts this premetastatic microenvironment and inhibits metastases may represent a novel adjuvant approach to cancer.
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DOI：
10.1084/jem.193.11.1303
发表时间：
2001-06-04
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Dieckmann D;Plottner H;Berchtold S;Berger T;Schuler G
通讯作者：
Schuler G
影响因子：
17.1
作者：
Highfill SL;Cui Y;Giles AJ;Smith JP;Zhang H;Morse E;Kaplan RN;Mackall CL
通讯作者：
Mackall CL
影响因子：
45.3
作者：
Pignon, Jean-Pierre;Tribodet, Helene;Le Chevalier, Thierry
通讯作者：
Le Chevalier, Thierry
影响因子：
45.3
作者：
Kris, Mark G.;Gaspar, Laurie E.;Weyant, Michael
通讯作者：
Weyant, Michael
影响因子：
45.3
作者：
Allum, William H.;Stenning, Sally P.;Langley, Ruth E.
通讯作者：
Langley, Ruth E.