CXCL12 Retargeting of an Oncolytic Adenovirus Vector to the Chemokine CXCR4 and CXCR7 Receptors in Breast Cancer.
CXCL12 Retargeting of an Oncolytic Adenovirus Vector to the Chemokine CXCR4 and CXCR7 Receptors in Breast Cancer.
复制标题
趋化因子CXCL12：溶瘤腺病毒载体对乳腺癌中趋化因子受体CXCR4和CXCR7的重靶向作用
DOI：
10.4236/jct.2021.126029
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发表时间：
2021-06
期刊：
影响因子：
--
通讯作者：
Mathis JM
中科院分区：
文献类型：
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作者：
O'Bryan SM;Mathis JM
乳腺癌是60岁以下女性中最常被诊断出的癌症，也是60岁以上女性中第二常被诊断出的癌症。虽然在开发针对乳腺癌的靶向疗法方面已经取得了重大进展，但晚期乳腺癌仍然具有较高的死亡率，5年生存率较低。因此，目前的疗法在治疗乳腺癌晚期方面是不足的；迫切需要新的治疗方法来应对晚期乳腺癌的复杂性。溶瘤病毒疗法已被探索作为一种能够全身给药、靶向癌细胞且不损害正常组织的治疗方法。特别是，溶瘤腺病毒由于其易于操作、生产且已证明具有临床安全性，已被用作病毒载体。在这项研究中，我们设计了一种溶瘤腺病毒来靶向趋化因子受体CXCR4和CXCR7。CXCR4和CXCR7的过度表达与乳腺癌的发生、存活、进展和转移有关。这两种受体都与配体CXCL12（SDF - 1）结合，CXCL12已被确定在乳腺癌细胞的转移中起关键作用。这项研究将一种与CXCL12融合的T4纤突蛋白整合到腺病毒纤维的尾部结构域中，以使载体重新靶向CXCR4和CXCR7趋化因子受体。我们表明，与野生型对照载体相比，修饰后的病毒能更有效地靶向并感染过度表达CXCR4和CXCR7的乳腺癌细胞。此外，用修饰后的嵌合纤维替代野生型纤维和球部结构并未干扰溶瘤能力。总体而言，这项研究的结果证明了将腺病毒载体重新靶向趋化因子受体阳性肿瘤的可行性。
Breast cancer is the most frequently diagnosed cancer in women under 60, and the second most diagnosed cancer in women over 60. While significant progress has been made in developing targeted therapies for breast cancer, advanced breast cancer continues to have high mortality, with poor 5-year survival rates. Thus, current therapies are insufficient in treating advanced stages of breast cancer; new treatments are sorely needed to address the complexity of advanced-stage breast cancer. Oncolytic virotherapy has been explored as a therapeutic approach capable of systemic administration, targeting cancer cells, and sparing normal tissue. In particular, oncolytic adenoviruses have been exploited as viral vectors due to their ease of manipulation, production, and demonstrated clinical safety profile. In this study, we engineered an oncolytic adenovirus to target the chemokine receptors CXCR4 and CXCR7. The overexpression of CXCR4 and CXCR7 is implicated in the initiation, survival, progress, and metastasis of breast cancer. Both receptors bind to the ligand, CXCL12 (SDF-1), which has been identified to play a crucial role in the metastasis of breast cancer cells. This study incorporated a T4 fibritin protein fused to CXCL12 into the tail domain of an adenovirus fiber to retarget the vector to the CXCR4 and CXCR7 chemokine receptors. We showed that the modified virus targets and infects CXCR4- and CXCR7-overexpressing breast cancer cells more efficiently than a wild-type control vector. In addition, the substitution of the wild-type fiber and knob with the modified chimeric fiber did not interfere with oncolytic capability. Overall, the results of this study demonstrate the feasibility of retargeting adenovirus vectors to chemokine receptor-positive tumors.