Sunitinib facilitates metastatic breast cancer spreading by inducing endothelial cell senescence.
Sunitinib facilitates metastatic breast cancer spreading by inducing endothelial cell senescence.
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舒尼替尼通过诱导内皮细胞衰老促进转移性乳腺癌扩散
DOI：
10.1186/s13058-020-01346-y
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发表时间：
2020-09-29
期刊：
影响因子：
--
通讯作者：
Zhang W
中科院分区：
文献类型：
--
作者：
Wang D;Xiao F;Feng Z;Li M;Kong L;Huang L;Wei Y;Li H;Liu F;Zhang H;Zhang W
舒尼替尼是一种受体酪氨酸激酶（RTK）抑制剂，靶向多种受体，如血管内皮生长因子受体（VEGFRs），于2006年被批准用于癌症治疗。然而，它在治疗某些癌症，特别是转移性乳腺癌（MBC）方面并不成功，而且这种“舒尼替尼耐药”的机制尚不清楚。在这里，我们研究了舒尼替相关的低生存获益是否由于舒尼替诱导的内皮细胞（EC）损伤或EC衰老。方法以小鼠乳腺癌细胞4t1作为主要的乳腺肿瘤模型，其产生的高转移性实体瘤可自发转移到肺部，与人类高转移性乳腺癌非常相似。衰老相关β-半乳糖苷酶（SA-β-Gal，免疫组化[IHC]染色）、P16、P53、P57（免疫印迹）作为细胞衰老的标志物。一个包含25个衰老相关趋化因子的蛋白质阵列和transwell趋化试验被用来检测舒尼替尼是否增加炎症趋化因子的分泌，从而通过趋化作用吸引肿瘤细胞。采用流式细胞术和免疫组化检测舒尼替尼诱导的衰老内皮细胞是否募集癌症相关的炎性骨髓细胞。最后，采用自发转移模型监测舒尼替尼是否引起“转移前生态位”的形成，促进MBC向肺部转移。结果舒尼替尼诱导衰老样内皮细胞（EC）表型。炎症趋化因子分泌和VCAM1表达在衰老的ECs中显著增加，导致肿瘤细胞（TC）趋化和TC/EC相互作用。同时，EC衰老导致EC连接松动，促进TC通过内皮屏障转运。舒尼替尼诱导的衰老内皮细胞也招募了与癌症相关的骨髓细胞，形成了一个“转移前生态位”样的微环境。分子水平和组织环境的改变最终导致远处转移的增加。结论虽然舒尼替尼是直接针对EC设计的，但具有讽刺意味的是，肿瘤转移的增加可能是由于舒尼替尼“正确”地发挥了其作用。我们的研究结果表明，在使用舒尼替尼和其他直接针对内皮细胞的抗血管生成药物之前，我们应该仔细权衡利弊。
BackgroundSunitinib, a receptor tyrosine kinase (RTK) inhibitor that targets multiple receptors such as vascular endothelial growth factor receptors (VEGFRs), was approved for cancer treatment in 2006. However, it was unsuccessful in treating certain cancers, particularly metastatic breast cancer (MBC), and the mechanism underlying this “sunitinib resistance” remains unclear. Herein, we investigated whether the sunitinib-associated inferior survival benefit in MBC was due to sunitinib-induced endothelial cell (EC) injury or EC senescence.Methods4T1 murine breast cancer cells were used as the main breast tumor model for it produces a highly metastatic solid tumor that can spontaneously metastasize to the lung, which closely mimics highly metastatic human breast cancer. Senescence-associated β-galactosidase (SA-β-Gal, immunohistochemistry [IHC]-staining), P16, P53, and P57 (immunoblotting) were used as markers of cell senescence. A protein array containing 25 senescence-associated chemokines and the transwell chemotaxis assay were used to examine whether sunitinib increases inflammatory chemokine secretion which attracts tumor cells via chemokinesis. Flow cytometry and IHC were used to detect whether the sunitinib-induced senescent ECs recruit cancer-associated inflammatory myeloid cells. Finally, the spontaneous metastatic model was used to monitor whether sunitinib causes the formation of “pre-metastatic niche” which promotes MBC to metastasize to the lungs.ResultsWe demonstrated that sunitinib induced a senescence-like endothelial cell (EC) phenotype. Inflammatory chemokine secretion and VCAM1 expression were significantly increased in senescent ECs, resulting in tumor cell (TC) chemotaxis and TC/EC interactions. Meanwhile, EC senescence caused loosening of EC junctions, facilitating TC transmigration through the endothelial barrier. Sunitinib-induced senescent ECs also recruited cancer-associated myeloid cells to form a “pre-metastatic niche”-like microenvironment. Alterations at the molecular level and in the tissue environment ultimately led to an increase in distant metastasis.ConclusionAlthough sunitinib was designed to target the EC directly, the increase in tumor metastasis may ironically be due to sunitinib “correctly” playing its role. Our findings suggest that we should carefully weigh the pros and cons before using sunitinib and other antiangiogenic drugs that directly target the ECs.
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影响因子：
7.7
作者：
King GL;Park K;Li Q
通讯作者：
Li Q
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
4.8
作者：
Heimburg, Jamie;Yan, Jun;Rittenhouse-Olson, Kate
通讯作者：
Rittenhouse-Olson, Kate
影响因子：
15.9
作者：
Elgendy, Mohamed;Abdel-Aziz, Amal Kamal;Minucci, Saverio
通讯作者：
Minucci, Saverio
影响因子：
9.8
作者：
Coppé JP;Patil CK;Rodier F;Sun Y;Muñoz DP;Goldstein J;Nelson PS;Desprez PY;Campisi J
通讯作者：
Campisi J