临床放射生物学的现状和未来

系统综述了临床放射生物学研究的现状，包括对放射敏感性的预测，放射治疗效价的修饰措施，放疗中正常组织损伤的防治，新的治疗手段和此学科领域的热点以及临床放射生物学未来的展望，供提高肿瘤放疗疗效基础研究和临床应用参考。     

肿瘤干细胞在肿瘤放射治疗学中的研究进展

肿瘤细胞的放射敏感性是决定放射治疗能否成功的重要因素之一.研究表明,临床上肿瘤的放射敏感性主要取决于肿瘤的组织来源、分化程度、遗传背景、大体类型以及患者的一般状况,如是否存在严重贫血和糖尿病等.而放射生物学研究提示肿瘤细胞的内在敏感性、细胞周期、增殖情况以及肿瘤细胞所处的微环境,如乏氧等是影响肿瘤放射敏感性的重要因素.随着肿瘤基础研究的深入,现在认为恶性肿瘤是一种干细胞疾病,即肿瘤来源于肿瘤干细胞(cancer stemcell,CSC)[1].近年来,先后在脑胶质瘤、乳腺癌、肺癌、黑色素瘤和前列腺癌等多种实体瘤中克隆到了肿瘤干细胞.这类细胞虽然仅占整个肿瘤细胞的一小部分,但是它们具有自我更新能力和多向分化潜能,可能是形成不同分化程度肿瘤和肿瘤不断生长的根源,是肿瘤发生、扩散和复发等过程中的"起始细胞",也可能是肿瘤治疗失败的根源所在[1-2].肿瘤干细胞概念的提出,给传统肿瘤放射治疗学带来了新进展,也带来了新的挑战.为此,本文拟对肿瘤干细胞在肿瘤放射治疗中的研究进展作一综述.     

放射肿瘤学：抗癌基因与放射敏感性关系研究进展

提高肿瘤放射敏感性是放射治疗的关键。从总体角度，细胞水平研究肿瘤放射敏感性未能给临床提供足够的信息。抗癌基因，特别是Ｐ＾５３及其相关基因与放射敏感性关系的研究为提高放射治疗效果提供了新的思路和方法。     

肿瘤乏氧细胞与放射治疗相关性研究进展

肿瘤内乏氧细胞的存在导致肿瘤对放射线的抗拒性,至今仍是肿瘤放射治疗与放射生物学研究的热点课题。近年来,对肿瘤乏氧细胞的形成机制及其对肿瘤放射治疗的影响有了更深入地研究,其中肿瘤乏氧细胞的分子影像学研究为肿瘤生物适形放射治疗的临床试验提供了可靠的研究平台。     

p16基因与肿瘤放射敏感性关系的研究进展

放射治疗是肿瘤治疗的主要手段之一,而肿瘤细胞的放射敏感性是决定放疗疗效的关键因素之一,大量的研究表明细胞周期调控是影响细胞辐射敏感性的重要因素之一,p16基因与细胞周期调控有关,人类75％的癌细胞株有p16基因的缺失或突变,其低表达与肿瘤细胞增殖、辐射抵抗密切相关。随着分子生物学技术的发展,对癌基因和抑癌基因研究日益深入,为从基因水平上治疗肿瘤和增加放射敏感性提供了新的希望。现将p16基因其在肿瘤放射敏感性方面的研究进展综述如下。     

双硫仑抗肿瘤活性及在放射生物学中的研究进展

双硫仑（disulfiram,DSF）为临床广泛应用的抗酗酒药物。然而,近年来的一些研究表明,DSF具有极强的抗肿瘤活性,已有临床试验报道其可提高肿瘤患者生存率;并对其抗肿瘤的分子机制进行了深入的阐述。另外,放射生物学研究发现DSF可以减轻射线对机体正常细胞的损伤,并通过其与铜离子形成复合物、抑制肿瘤干细胞、抑制泛素-蛋白酶体活性等机制增强肿瘤细胞的放疗敏感性,极有希望作为放化疗的辅助用药,提高放化疗疗效。本文详细论述了双硫仑抗肿瘤临床研究现状、分子机制,在肿瘤放射生物学中的研究及其应用前景。     

鼻咽癌细胞系放射敏感性的异质性

鼻咽癌多发于我国南方 ,放射治疗为首选治疗手段。鼻咽癌患者放射治疗后 5年生存率为 34%～ 5 3% ,多数死于局部复发和 或远处转移。肿瘤细胞群中存在放射敏感性差的亚群是复发和转移的主要原因 ,更有效的治疗方案的设计应针对这些放射抵抗的细胞。本室已从鼻咽癌细胞系ＣＮＥ 2Ｚ中分离出 2 5个单克隆株 ,这些克隆株在倍增时间、细胞分裂指数、成瘤率、体外侵袭能力、转移能力和途径等方面存在异质性[1 ] 。为分离出放射敏感性不同的细胞亚系并研究产生放射抵抗的机理 ,本实验对这 2 5个克隆株中生物学特性差异较大的 10个克隆作进一步研究…     

抗癌基因与放射敏感性关系研究进展

提高肿瘤放射敏感性是放射治疗的关键。从总体角度,细胞水平研究肿瘤放射敏感性未能给临床提供足够的信息。抗癌基因,特别是P~(53)及其相关基因与放射敏感性关系的研究为提高放射治疗效果提供了新的思路和方法。     

NADH对正常肝细胞株L02辐射后p53和bax表达的影响

放射治疗在于最大程度地杀伤肿瘤细胞和尽可能地减小正常组织细胞的损伤。但临床上往往对正常组织造成损伤，从而限制了肿瘤的放射治疗剂量的提高，特别是对于亚临床病灶的放射治疗。为此，减小正常组织细胞的放射损伤成为放射生物学研究的重要领域。本研究通过还原型辅酶NADH对辐射诱导的细胞凋亡及其凋亡信号传递分子p53、bax表达的影响，探讨NADH抗辐射诱导的细胞凋亡作用及其作用机理。     

由SABR再论放射敏感性

随着现代放射治疗技术进步,放疗已由过去二维时代进入三维和四维时代,治疗精度大幅度提高,分割模式也发生了深刻变革。从传统放射治疗发展到以三维适形放射治疗（3D-CRT）和调强放射治疗（IMRT）为代表的聚焦照射,提高了肿瘤靶区剂量,减少了正常组织的损伤。同时随着影像引导技术进步,治疗机与影像引导结合,每次治疗前通过影像扫描技术获得肿瘤靶区位置信息,或用4D影像引导技术精确地将射线投射到目标靶点,达到立体定向体部放射治疗（stereotactic body radiation therapy,SBRT）/立体定向消融放疗（stereotactic ablative radiotherapy,SABR）的目的,放射治疗完全进入精准、高效和低毒时代。高剂量、大分割照射已经取得令人信服和可喜的疗效,传统放射生物学理论已无法解释这种照射模式抗肿瘤细胞作用机制。传统放疗认为,肿瘤有敏感与不敏感之分,但是,进入SABR时代,肿瘤对其治疗均反应良好,放射治疗学迫切需要建立新的放射生物学学说和体系,在传统放射生物学理论基础上,更好地阐明新技术原理、作用机制,并建立与传统放射生物学内在联系,为临床普及和推广消融放疗技术奠定理论基础。     

Caveolin-1: a novel prognostic biomarker of radioresistance in cancer

Purpose: Caveolin-1 is a membrane protein highly expressed in many tumors and plays an important role in tumor progression and metastasis. This review describes the structure of the Caveolin-1 protein and its pre-clinical and clinical significance, demonstrating that Caveolin-1 is a novel biomarker for radioresistance which has the promising potential to improve the clinical outcome of cancer patients undergoing radiation treatment.

Summary: Targeted radiation therapy has shown immense benefits for cancer treatment. However, one of the major challenges for effective clinical outcome of radiation therapy for cancer patients is the development of radioresistance during radiation treatment. As a consequence, radiation therapy becomes a less effective modality for successful clinical outcome. Furthermore, a radioresistant tumor has the ability to repair its genome, and therefore becomes more aggressive and metastasizes. The plausible mechanisms for tumor radioresistance include the rapid DNA repair, somatic mutations in tumor oncogenes, aberrant activation of kinase pathways, and changes in the tumor microenvironment including tumor hypoxia, tumor vasculature, and cancer stem cells. Caveolin-1 is significantly upregulated in certain cancer cells and aberrantly mediates downstream signaling mechanisms. Notably, numerous recent research reports have shown the role of Caveolin-1 in tumor radioresistance and poor treatment outcome. Thus, Caveolin-1 could be a novel prognostic biomarker to monitor tumor radioresistance in cancer patients undergoing radiation therapy.

Conclusions: Caveolin-1 has the promising potential to become a novel prognostic biomarker to monitor tumor radioresistance and radiation response specifically in the prostate, pancreas, and lung cancer.     

Targeting the AKT/cyclin D1 pathway to overcome intrinsic and acquired radioresistance of tumors for effective radiotherapy

Purpose: Radiotherapy (RT) is a powerful tool in the treatment of cancer, having the advantage of preserving normal tissues. Clinical outcomes of RT are significantly improved by technological advances, enabling increased radiation doses directed very specifically to a tumor. However, tumor radioresistance remains a major impediment to effective RT. We have shown that human tumor cells surviving after repeated exposure to fractionated radiation (FR) of X-rays for 1 month have acquired radioresistance through constitutive activation of AKT and downstream cyclin D1 nuclear retention. Tumor radioresistance is also proposed to be an intrinsic characteristic of cancer stem cells (CSC), whose efficient DNA repair is thought to confer this phenotype. We have isolated radioresistant CD133-positive cells following exposure to long-term FR. These cells exhibited the CSC phenotype with activation of the AKT/cyclin D1 pathway. In this review, I summarize our current understanding of the molecular mechanisms underlying tumor radioresistance and propose a strategy for overcoming radioresistance by targeting the AKT/cyclin D1 pathway.

Conclusion: Two different mechanisms: acquired radioresistance of surviving tumor cells after RT and intrinsic radioresistance of CSC are associated with tumor radioresistance. Inhibition of the AKT pathway results in radiosensitization of both types of tumor radioresistance.     

肿瘤干细胞与辐射抗性的研究进展

放射治疗是治疗肿瘤的常规手段,而辐射抗性的产生是限制放射治疗广泛应用的重要因素之一。笔者简述了辐射耐受乳腺癌和多形性成角质母细胞瘤的特异性肿瘤干细胞特征的研究进展,为与放射治疗相结合的肿瘤靶向治疗提供新的研究思路。     

小鼠肝癌H22细胞中不同干性亚群的分选与鉴定

 目的 利用干细胞中乙醛脱氢酶（ALDH）高表达的特性分选并鉴定肿瘤细胞中存在的ALDH high 、ALDH low 及ALDH neg 细胞亚群。 方法 以流式细胞术检测小鼠肝癌H22、人胃癌BGC-823、结肠癌LS-174T、肝癌SMMC-7721细胞及胰腺癌SW-1990和Panc-1细胞系中ALDH+细胞的表达;在确定ALDH阳性表达的细胞中,以ALDH表达的高低差异,将细胞分选并定义为ALDH high 、ALDH low 、ALDH neg 细胞亚群;对分选出的3种细胞亚群进行CD133/CD44表型及细胞周期分析。 结果 （1）在小鼠肝癌H22细胞、人结肠癌LS-174T细胞、胰腺癌SW-1990细胞和Panc-1细胞中存在着ALDH阳性表达,而在人胃癌BGC-823细胞和肝癌SMMC-7721细胞中未见ALDH表达;（2）在小鼠肝癌H22细胞中能明确分选出存在荧光差异的3群细胞即ALDH high 、ALDH low 和ALDH neg 细胞亚群;（3）H22的ALDH high 、ALDH low 、ALDH neg  3个亚群中CD133/CD44表达存在差异,其表达比例依次减少;（4）H22细胞中ALDH high 亚群主要处于G 0/G 1期,ALDH low 亚群处于S期,而ALDH neg 亚群处于G 2/M期。 结论 在肿瘤细胞中存在着介乎于肿瘤干细胞与终末肿瘤细胞之间的特异性亚群,该亚群为肿瘤治疗提供了新的方向。     

Dexamethasone-Induced Enhancement of Resistance to Ionizing Radiation and Chemotherapeutic Agents in Human Tumor Cells

BACKGROUND: Dexamethasone-induced changes in radioresistance have previously been observed by several authors. Here, we examined effects of dexamethasone on resistance to ionizing radiation in 10 additional human cell lines and strains, and on resistance to carboplatin and paclitaxel in 13 fresh tumor samples. MATERIAL AND METHODS: Eight human carcinoma cell lines, a glioblastoma cell line and a strain of normal human diploid fibroblasts were arbitrarily chosen for these in-vitro studies. Effects on radiosensitivity were assessed using a conventional colony formation assay. Effects on resistance to the drugs were investigated prospectively (ATP cell viability assay) using 13 fresh tumor samples from consecutive patients operated for ovarian cancer within the context of a Swiss nation-wide randomized prospective clinical trial (SAKK 45/94). RESULTS: Dexamethasone promoted proliferation of 1 of the cell lines without affecting radiosensitivity, while it completely inhibited proliferation of another cell line (effects on radiosensitivity could thus not be examined). Furthermore, dexamethasone induced enhanced radioresistance in 1 of the 8 carcinoma cell lines examined. In the glioblastoma cell line, there was no effect on growth or radioresistance, nor in the fibroblasts. Treatment with dexamethasone enhanced resistance of the malignant cells to carboplatin in 4 of the 13 fresh tumor samples examined, while no enhancement in resistance to paclitaxel was observed. CONCLUSIONS: In agreement with previous reports, we found that dexamethasone may induce radioresistance in human carcinoma cells. Including the published data from the literature, dexamethasone induced enhancement in radioresistance in 4 of 12 carcinoma cell lines (33%), but not in 3 glioblastoma cell lines, nor in 3 fibroblast strains. Dexamethasone also induced enhanced resistance to carboplatin with a similar probability in fresh samples of ovarian cancer evaluated prospectively (in 4 of 13 samples; 31%). We worry that induction of resistance by corticosteroids given to patients undergoing either radiotherapy or chemotherapy with agents causing DNA damage might be associated with a reduced clinical responsiveness in a significant fraction of patients with a carcinoma.     

放射抗拒性肿瘤细胞株构建研究进展

约70%的恶性肿瘤患者需要放射治疗,局部复发和转移是治疗失败的主要模式,放射抗拒性是重要的因素之一。明确潜在的放射抗拒相关机制至关重要,通过放射线构建放射抗拒性肿瘤细胞株是关键的工作基础。根据分割剂量、照射次数及不同分割剂量组合方式等因素的不同,归纳出4种典型的照射模式：常规照射模式、反复照射模式、梯度照射模式和其他照射模式。不同的照射模式在总照射剂量、构建周期上不同,肿瘤细胞的生物学特性也存在差异。梯度照射模式随着细胞株放射抗拒性增强而逐步提高分割剂量,较好地平衡了分割剂量和照射后细胞恢复至指数期时间,优于其他3种照射模式。临床相关放射抗拒性细胞株具备放射抗拒性表型的同时,保持与亲本细胞株相同的基因型,是未来肿瘤放射抗拒性研究的重要方向。     

前列腺癌干细胞分离方法研究进展

前列腺癌是男性泌尿系统中常见的恶性肿瘤,极易发展为激素难治性前列腺癌而难以治愈。近年来的研究认为前列腺癌干细胞是前列腺癌发生、发展、转移和复发的根源,针对前列腺癌干细胞的靶向治疗可能是根治前列腺癌的有效途径,但这些细胞所占比例极小,几乎难以检测到,目前的研究难点就在于前列腺癌干细胞的分离技术效率较低。故拟深入研究前列腺癌干细胞的功能,首先必须有效地分离前列腺癌干细胞。该文就目前前列腺癌干细胞的几种主要分离方法的研究进展及存在的问题进行综述,包括基于前列腺癌干细胞表面标志物的荧光激活细胞分选法、磁性激活细胞分选法和基于前列腺癌干细胞生物特性的侧群细胞筛选法、体外无血清聚球筛选法。     

肿瘤干细胞的MR可视化研究进展

干细胞示踪技术为目前研究的热点。肿瘤干细胞具有无限增殖能力及多向分化潜能,在启动肿瘤形成和生长中起着决定性的作用,利用其表面特异性标志物可分离、培养肿瘤干细胞。 MR成像可视化示踪肿瘤干细胞,可实时监控细胞的存活、增殖、迁移等生物学过程,这些研究能够为恶性肿瘤的靶向治疗,以及无创追踪肿瘤干细胞的体内行为提供支持。     

Cancer stem cells and radioresistance

Abstract

Purpose: Radiation therapy has made significant contributions to cancer treatment. However, despite continuous improvements, tumor recurrence and therapy resistance still occur in a high proportion of patients. One underlying reason for this radioresistance might be attributable to the presence of cancer stem cells (CSC). The purpose of this review is to discuss CSC-specific mechanisms that confer radiation resistance.

Conclusions: We focus our discussions on breast cancer and glioblastoma multiforme (GBM) and conclude that both CSC-intrinsic and CSC-extrinsic factors as well as adaptive responses in CSC caused by irradiation and microenvironmental changes all make contributions to CSC-mediated radioresistance. Our discussions emphasize CSC as novel therapeutic targets in order to potentiate radiotherapy efficacy.     

环状RNA作为肿瘤标志物及其在肿瘤放疗中应用的研究进展

放疗是肿瘤综合治疗的重要手段之一,但放疗抵抗是影响肿瘤患者放疗疗效及预后的一大难题。由于肿瘤细胞放疗抵抗的机制十分复杂,所以至今还未找到特别有效的调控放疗敏感性的开关分子。环状RNA（circRNA）是一类通过反式剪接使得 3' 末端与 5' 末端共价结合的闭合circRNA分子,具有丰度高、结构稳定和特异性强等特征。circRNA参与肿瘤的发生、发展、侵袭和转移等过程,可以作为新型肿瘤分子标志物和潜在的治疗靶点。此外,circRNA在受照后的肿瘤细胞中存在差异性表达,并可作为微小RNA（miRNA）的海绵,调控与肿瘤放疗抵抗相关的miRNA及其下游信号通路,使其有望成为攻克肿瘤放疗抵抗的突破口。笔者综述了circRNA作为新型肿瘤标志物及其在肿瘤放疗中应用的研究进展。