Modulating the tumor microenvironment to increase radiation responsiveness.
Modulating the tumor microenvironment to increase radiation responsiveness.
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调节肿瘤微环境以提高辐射反应能力。
DOI：
10.4161/cbt.8.21.9988
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发表时间：
2009-11
影响因子：
3.6
通讯作者：
Maity A
中科院分区：
文献类型：
--
作者：
Karar J;Maity A
放射敏感性可能受到癌细胞内在和外在因素的影响。肿瘤细胞外在的肿瘤微环境（TME）中影响放射敏感性的因素之一是氧合。严重缺氧的细胞需要 2-3 倍高剂量的辐射才能达到与氧合良好的细胞相同水平的细胞杀伤效果。微环境中可能影响肿瘤放射敏感性的其他因素包括基质细胞对辐射的反应以及血管内皮生长因子（VEGF）和缺氧诱导因子-1（HIF-1）等因子的表达。目前有几类药物可以通过调节 TME 来增加肿瘤放射敏感性。临床前证据表明，抑制 VEGF 可能会增强放疗后的局部控制。已经假设了几种机制来解释这一现象，包括肿瘤内皮细胞的放射增敏、防止放射后新脉管系统的建立以及继发于血管正常化的氧合增加。在临床前模型中，针对 HIF-1 的药物还可增强放疗后的局部控制。这可能通过间接抑制 VEGF（HIF-1 的下游靶标）或通过不依赖 VEGF 的方式发生。当与放射治疗相结合时，EGFR 抑制剂西妥昔单抗可改善头颈癌患者的局部控制和生存率。临床前数据表明EGFR抑制剂可以增加癌细胞固有的放射敏感性。它们还可以改善肿瘤血流和氧合，这可能会增加外源性放射敏感性。可能促成这种效应的 EGFR 下游途径之一是 PI3K/Akt 途径。在临床前模型中，直接抑制该途径的药物可改善血流并增加肿瘤氧合。挑战仍然是从患者那里获得临床数据，证明 TME 的调节是生物制剂使肿瘤放射增敏的重要机制，然后利用这些信息来优化治疗。
Radiosensitivity can be influenced both by factors intrinsic and extrinsic to the cancer cell. One of the factors in the tumor microenvironment (TME) extrinsic to the cancer cell that can affect radiosensitivity is oxygenation. Severely hypoxic cells require a 2–3 fold higher dose of radiation to achieve the same level of cell killing as do well-oxygenated cells. Other elements in the microenvironment that may influence tumor radiosensitivity are the response of stromal cells to radiation and the expression of factors such as vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 (HIF-1). There are currently several classes of agents that may increase tumor radiosensitivity by modulating the TME. Pre-clinical evidence indicates that inhibition of VEGF may increase local control after radiation. Several mechanisms have been postulated to explain this including radiosensitization of tumor endothelial cells, prevention of the establishment of new vasculature post-radiation, and increased oxygenation secondary to vascular normalization. Agents targeting HIF-1 also increase local control after radiation in pre-clinical models. This may occur via indirect inhibition of VEGF, which is a downstream target of HIF-1, or by VEGF-independent means. When combined with radiation, the EGFR inhibitor cetuximab improves local control and survival in patients with head and neck cancer. Pre-clinical data indicate that EGFR inhibitors can increase the intrinsic radiosensitivity of cancer cells. They can also improve tumor blood flow and oxygenation, which may increase extrinsic radiosensitivity. One of the pathways downstream of EGFR that may contribute to this effect is the PI3K/Akt pathway. Agents that directly inhibit this pathway improve blood flow and increase tumor oxygenation in pre-clinical models. The challenge remains to obtain clinical data from patients showing that modulation of the TME is an important mechanism by which biological agents can radiosensitize tumors and then to utilize this information to optimize therapy.
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表皮生长因子受体抑制通过血管正常化调节微环境，从而提高化疗和放疗疗效。
影响因子：
3.7
作者：
Cerniglia, George J.;Pore, Nabendu;Tsai, Jeff H.;Schultz, Susan;Mick, Rosemarie;Choe, Regine;Xing, Xiaoman;Durduran, Turgut;Yodh, Arjun G.;Evans, Sydney M.;Koch, Cameron J.;Hahn, Stephen M.;Quon, Harry;Sehgal, Chandra M.;Lee, William M. F.;Maity, Amit
通讯作者：
Maity, Amit
影响因子：
11.2
作者：
Gerweck, Leo E.;Vijayappa, Shashirekha;Chen, David J.
通讯作者：
Chen, David J.
影响因子：
8.8
作者：
Diaz, R.;Nguewa, P. A.;Diaz-Gonzalez, J. A.;Hamel, E.;Gonzalez-Moreno, O.;Catena, R.;Serrano, D.;Redrado, M.;Sherris, D.;Calvo, A.
通讯作者：
Calvo, A.
影响因子：
158.5
作者：
Bonner, JA;Harari, PM;Ang, KK
通讯作者：
Ang, KK
影响因子：
3.1
作者：
AUSPRUNK, DH;FOLKMAN, J
通讯作者：
FOLKMAN, J