骨肉瘤的缺氧微环境与放疗增敏进展

Hypoxic Microenvironment of Osteosarcoma and Radiotherapy Sensitization

放疗是恶性肿瘤重要的辅助治疗手段,但骨肉瘤对放疗不是十分敏感,存在一定的放疗抵抗。即相对于对放射线敏感的肿瘤(如视网膜母细胞瘤、鼻咽癌、卵巢癌中的无性细胞瘤、睾丸精原细胞瘤、肾胚胎瘤、恶性淋巴瘤等)来讲,同等或更大的放射剂量也难以达到敏感肿瘤所能有的局部控制率。许多研究表明,低剂量分次放疗(2 Gy/次,共60 Gy)的5年局部控制率为40%~68%,但5年的局部控制率和生存率并没有相关性。近几年,骨肉瘤具有固有的放疗抵抗性的概念已经受到多项研究的质疑,有的骨肉瘤的放疗效果要好于黑色素瘤,而黑色素瘤是公认的放疗抵抗肿瘤。此外,若采取大分割治疗(总量不变,提高每次的放疗剂量),虽然骨肉瘤对普通X射线不算敏感,但其对质子和重离子治疗应答率明显提高。因此选择适当的患者、采取合适的放疗方法可以提高放疗效果。放疗抵抗的直接原因是肿瘤细胞对DNA损伤的修复能力和耐受能力,这和肿瘤的异质性有关。许多研究表明低氧微环境是放疗抵抗最重要的环境因素。首先,缺氧微环境为肿瘤细胞产生放疗抵抗提供重要的发生条件,缺氧微环境刺激细胞产生低氧诱导因子(Hypoxia inducible factors,HIF),缺氧预处理可增加骨肉瘤细胞的放疗抵抗,缺氧诱导因子(HIF-1、HIF-2)、自噬相关因子(LC3-Ⅱ)在骨肉瘤组织中高表达,若敲除HIF基因后,细胞自噬水平和凋亡显著升高,但抑制自噬后,细胞凋亡并没有减少,说明细胞在缺氧微环境中主要通过HIF实现放化疗抵抗。放疗后DNA损伤的修复能力也是放疗抵抗的机制之一,通过长时间监测DNA损伤的修复蛋白γ-H2AX和53BP1,即可评估DNA损伤的修复情况。针对引起放疗抵抗的原因,改变肿瘤缺氧微环境是放疗增敏的有效手段,主要有增加氧供应和研究靶向缺氧细胞的化学增敏药物。高压氧舱可提供高压氧环境,直接增加肿瘤组织的含氧量,但患者依从性较差,增敏效果不确切。结合尼克酰胺(针对急性缺氧)与慢性缺氧改良剂(如O 2和CO 2气体的混合物)可明显改善肿瘤组织的急慢性缺氧环境,从而增强放疗的效果。此外,有人提出热疗是克服放疗抵抗、增加放疗敏感性的有效方法,研究证明放疗同时把瘤组织加热到43℃可显著提高放疗效果。未来,骨肉瘤的放疗将在放疗增敏研究的基础上,结合立体定向放疗、质子放疗和重离子放疗等先进技术手段,低剂量、高精准,和手术治疗及化疗有机结合,实现更好的治疗效果。

Radiotherapy is an important adjuvant treatment for malignant tumors,but osteosarcoma is not very sensitive to radiotherapy,furthermore,there is a certain radiotherapy resistance.Radiation doses,equivalent to or larger than radiation-sensitive tumors needed(such as retinoblastoma,nasopharyngeal carcinoma,ovarian cancer in ovarian cancer,testicular seminoma,renal embryonal tumor,malignant lymphoma,etc.),are not enough to achieve local control rates.Many studies have shown that the 5-year local control rate of low-dose fractionated radiothe-rapy for osteosarcoma(2 Gy/time,total 60 Gy)is 40%—68%,but there is no correlation between 5-year local control rate and survival rate.However,the concept of osteosarcoma with inherent radiotherapy resistance has been questioned by many studies.Some osteosarcoma have better radiotherapy effects than melanoma,while melanoma is recognized as a radiotherapy-resistant tumor.In addition,if a large fractionated radiotherapy is taken(the total amount is unchanged,increasing the dose of each radiotherapy),although osteosarcoma is not sensitive to ordinary X-rays,its response rate to proton and heavy ion treatment is significantly improved.Therefore,choosing the appropriate patient and adopting appropriate radiotherapy methods can improve the radiotherapy effect.The direct cause of radiotherapy resistance is the ability of tumor cells to repair DNA damage,which is related to tumor heterogeneity.Many studies have shown that hypoxic microenvironment is the most important environmental factor for radiotherapy resistance.First,the hypoxic mic-roenvironment provides an important condition for the development of radiotherapy resistance in tumor cells.Hypoxic microenvironment stimulates cells to produce hypoxia-inducible factors(HIF).Hypoxic preconditioning can increase the radiotherapy resistance of osteosarcoma cells.Hypo-xia-inducible factor(HIF-1,HIF-2)and autophagy-related factor(LC3-II)are highly expressed in osteosarcoma tissues.If HIF gene is knocked out,autophagy level and apoptosis are significantly increased,but inhibiting autophagy,the apoptosis did not decrease,indicating that the cells were resistant to chemoradiotherapy mainly through HIF-2 in the hypoxic microenvironment.The repair of DNA damage can be assessed by monitoring DNA damage repair proteinsγ-H2AX and 53BP1 for a long time.Therefore,changing the tumor hypoxia microenvironment is an effective means of radiosensitization.The hyperbaric oxygen chamber can provide a hyperbaric oxygen environment and directly increase the oxygen content of the tumor tissue,but the patient compliance is poor and the sensitization effect is not accurate.The combination of nicotinamide(for acute hypoxia)and chronic hypoxia improvers(such as a mixture of O 2 and CO 2 gases)can significantly improve the acute and chronic anoxic environment of tumor tissue,thereby enhancing the effect of radiotherapy.In addition,it has been suggested that hyperthermia is an effective method to overcome radiotherapy resistance and increase the sensitivity of radiotherapy.Studies have shown that radiotherapy can also be significantly improved by heating the tumor tissue to 43℃.In the future,radiotherapy for osteosarcoma will be based on radiotherapy sensitization research,combined with advanced techniques such as stereotactic radiotherapy,proton radiotherapy and heavy ion radiotherapy and organic combination of surgical treatment and chemotherapy,to achieve better treatment effect at a low dose and high precision.