Perivascular cell-derived extracellular vesicles stimulate colorectal cancer revascularization after withdrawal of antiangiogenic drugs.
Perivascular cell-derived extracellular vesicles stimulate colorectal cancer revascularization after withdrawal of antiangiogenic drugs.
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血管周围细胞衍生的细胞外囊泡在停用抗血管生成药物后刺激结直肠癌血运重建
DOI：
10.1002/jev2.12096
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发表时间：
2021-05
影响因子：
16
通讯作者：
Zhang D
中科院分区：
文献类型：
--
作者：
Huang M;Chen M;Qi M;Ye G;Pan J;Shi C;Yang Y;Zhao L;Mo X;Zhang Y;Li Y;Zhong J;Lu W;Li X;Zhang J;Lin J;Luo L;Liu T;Tang PM;Hong A;Cao Y;Ye W;Zhang D
抗血管生成酪氨酸激酶抑制剂（AA-TKI）已成为结直肠癌（CRC）的一种有前途的治疗策略。在临床实践中，很大比例的癌症患者由于复发性毒性、经济负担或获得性耐药而暂时停止AA‐TKI治疗。然而，AA‐TKI停药诱导的肿瘤血运重建经常发生，阻碍了AA‐ TKI的临床应用。在此，本研究表明，肿瘤血管周围细胞介导AA‐TKI治疗停药后的肿瘤血管重建。血管周围细胞的药理学抑制和基因消融在很大程度上减弱了AA‐TKI停止实验环境中CRC血管化的反弹效应。从机制上讲，肿瘤血管周围细胞衍生的细胞外载体（TPC-EV）含有Gas 6，Gas 6通过激活Axl通路促进内皮祖细胞（EPC）的募集，用于肿瘤血管重建。Gas 6沉默和Axl抑制剂通过损害EPC募集显著抑制肿瘤血管再生。因此，瑞戈非尼与Axl抑制剂的联合治疗通过抑制肿瘤生长改善了小鼠转移性CRC模型的总体存活率。总之，这些数据揭示了在脱AA TKI诱导的肿瘤血运重建中血管周围细胞的新机制，并表明阻断Axl信号传导可能提供一种有吸引力的抗癌方法，用于维持持久的血管生成抑制作用，以改善抗血管生成药物在CRC中的治疗结果。
Antiangiogenic tyrosine kinase inhibitors (AA‐TKIs) have become a promising therapeutic strategy for colorectal cancer (CRC). In clinical practice, a significant proportion of cancer patients temporarily discontinue AA‐TKI treatment due to recurrent toxicities, economic burden or acquired resistance. However, AA‐TKI therapy withdrawal‐induced tumour revascularization frequently occurs, hampering the clinical application of AA‐TKIs. Here, this study demonstrates that tumour perivascular cells mediate tumour revascularization after withdrawal of AA‐TKI therapy. Pharmacological inhibition and genetic ablation of perivascular cells largely attenuate the rebound effect of CRC vascularization in the AA‐TKI cessation experimental settings. Mechanistically, tumour perivascular cell‐derived extracellular vehicles (TPC‐EVs) contain Gas6 that instigates the recruitment of endothelial progenitor cells (EPCs) for tumour revascularization via activating the Axl pathway. Gas6 silence and an Axl inhibitor markedly inhibit tumour revascularization by impairing EPC recruitment. Consequently, combination therapy of regorafenib with the Axl inhibitor improves overall survival in mice metastatic CRC model by inhibiting tumour growth. Together, these data shed new mechanistic insights into perivascular cells in off‐AA‐TKI‐induced tumour revascularization and indicate that blocking the Axl signalling may provide an attractive anticancer approach for sustaining long‐lasting angiostatic effects to improve the therapeutic outcomes of antiangiogenic drugs in CRC.
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影响因子：
8
作者：
Busato A;Bonafede R;Bontempi P;Scambi I;Schiaffino L;Benati D;Malatesta M;Sbarbati A;Marzola P;Mariotti R
通讯作者：
Mariotti R
DOI：
10.1073/pnas.1814874116
发表时间：
2019-04-09
影响因子：
11.1
作者：
Liu, Chang;Ge, Hui-Min;Yan, Biao
通讯作者：
Yan, Biao
影响因子：
20.3
作者：
Franco, Marcela;Roswall, Pernilla;Pietras, Kristian
通讯作者：
Pietras, Kristian
影响因子：
50.3
作者：
Cooke VG;LeBleu VS;Keskin D;Khan Z;O'Connell JT;Teng Y;Duncan MB;Xie L;Maeda G;Vong S;Sugimoto H;Rocha RM;Damascena A;Brentani RR;Kalluri R
通讯作者：
Kalluri R
DOI：
10.1073/pnas.1121146109
发表时间：
2012-05-08
影响因子：
11.1
作者：
Hayakawa, Kazuhide;Pham, Loc-Duyen D.;Lo, Eng H.
通讯作者：
Lo, Eng H.