文章：

放疗后肿瘤微环境：耐药与复发机制

The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence

原文发布日期：2015-06-24

DOI: 10.1038/nrc3958

类型: Review Article

开放获取: 否

要点：

1. Radiotherapy is a common treatment option for cancer patients. However, many aspects of the tumour microenvironment (TME) can render a tumour resistant to radiotherapy de novo or can lead it to recur with a worse prognosis following therapy.
2. Normal tissue toxicity limits the dose of radiotherapy that can be safely delivered.
3. Combination strategies are required in order to achieve better tumour control.
4. Radiotherapy-mediated immunogenic cell death (ICD) can elicit an immune response, but antitumour immunity may be limited owing to the presence of radioresistant suppressor cell types in the TME. Combining radiotherapy and immunomodulatory treatments may overcome adaptive immune suppression and holds great promise both locally in the primary tumour and abscopally.
5. Hypoxia has a crucial role in radioresistance owing to reduced oxygen-mediated fixation of DNA damage and hypoxia induced factor 1α (HIF1α)-mediated cell survival. Attempts to increase oxygen delivery, normalize tumour vessels, inhibit HIF1α and prevent the recruitment of bone marrow-derived cells (BMDCs) required for vasculogenesis are all being tested to reduce tumour hypoxia, improve radiotherapy responses and prevent tumour recurrence after therapy.
6. Tumour irradiation induces a wound healing response that is characterized by inflammation, cancer-associated fibroblast (CAF) modulation and extracellular matrix (ECM) remodelling, which may facilitate tumour recurrence. Targeting the initial inflammatory response may counteract attempts to boost the immune-mediated antitumour response following radiotherapy. Therefore, reducing ECM remodelling by inhibiting growth factors, receptor kinases or matrix enzymes may be more effective in preventing the post-irradiation stiffening of the TME that could facilitate tumour spread.
7. Careful scheduling of tumour reoxygenation strategies with radiotherapy will be required to maximize tumour control. Subsequent inclusion of immunomodulatory and anti-fibrotic treatments should be considered to maximize therapeutic benefits and to prevent post-irradiation tumour recurrence and metastasis.

要点翻译：

1. 放射治疗是癌症患者的常用治疗方案。然而，肿瘤微环境（TME）的诸多因素可导致肿瘤对放疗产生原发抗拒，或在治疗后复发且预后更差。
2. 正常组织毒性限制了可安全实施的放疗剂量。
3. 需要采用联合策略以实现更好的肿瘤控制。
4. 放疗介导的免疫原性细胞死亡（ICD）可激发免疫反应，但由于TME中存在放射抗拒的抑制性细胞类型，抗肿瘤免疫可能受限。放疗与免疫调节治疗相结合可克服适应性免疫抑制，在原发性肿瘤局部和远端效应方面均具有广阔前景。
5. 缺氧在放射抗拒中起关键作用，其机制包括氧介导的DNA损伤固定作用减弱，以及缺氧诱导因子1α（HIF1α）介导的细胞存活。目前正在尝试通过增加氧输送、正常化肿瘤血管、抑制HIF1α及阻断血管生成所需的骨髓来源细胞（BMDCs）募集来减轻肿瘤缺氧，改善放疗反应并预防治疗后肿瘤复发。
6. 肿瘤照射会诱发以炎症、癌症相关成纤维细胞（CAF）调节和细胞外基质（ECM）重塑为特征的伤口愈合反应，这可能促进肿瘤复发。靶向初始炎症反应可能会抵消放疗后增强免疫介导的抗肿瘤反应的尝试。因此，通过抑制生长因子、受体激酶或基质酶来减少ECM重塑，可能更有效预防照射后TME硬化而促进肿瘤扩散。
7. 需要精心规划肿瘤再氧合策略与放疗的时序安排，以最大化肿瘤控制。后续应考虑纳入免疫调节和抗纤维化治疗，以最大限度提升疗效，并预防照射后肿瘤复发和转移。

英文摘要：

Radiotherapy plays a central part in curing cancer. For decades, most research on improving treatment outcomes has focused on modulating radiation-induced biological effects on cancer cells. Recently, we have better understood that components within the tumour microenvironment have pivotal roles in determining treatment outcomes. In this Review, we describe vascular, stromal and immunological changes that are induced in the tumour microenvironment by irradiation and discuss how these changes may promote radioresistance and tumour recurrence. We also highlight how this knowledge is guiding the development of new treatment paradigms in which biologically targeted agents will be combined with radiotherapy.

摘要翻译： 

放疗在癌症治愈中占据核心地位。数十年来，改善治疗效果的研究大多聚焦于调控癌细胞辐射诱导的生物效应。近来，我们逐渐认识到，肿瘤微环境中的组分在决定治疗结局方面具有关键作用。本文综述了照射引起的肿瘤微环境中血管、基质及免疫学变化，并探讨这些变化如何促进放射抵抗与肿瘤复发。我们还强调，这些认知正指引新型治疗范式的开发，其中生物靶向药物将与放疗联合应用。

原文链接：

The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence