Protecting spermatogonial stem cells from chemotherapy-induced damage for fertility preservation in childhood cancer

近几十年来，儿童癌症发病率急剧上升（自1960年以来为38%），目前每500名成年人中就有1人（英国约35000人）是儿童癌症的幸存者。发病率的增加，加上治愈率的显著提高（5年生存率约为80%），导致年轻成年人经历癌症治疗的后续健康影响的增加。确保这一新的和不断扩大的患者群体的长期健康是儿科肿瘤学临床需求最紧迫的领域之一。不孕症发生在大多数接受高剂量化疗的男性中，这些化疗药物被称为烷基化剂。烷基化剂通常用于儿童癌症，越来越多地用于非恶性疾病的干细胞移植。与男性的情况不同，精子冷冻保存不是保持这些男孩生育能力的一种选择，因为他们的睾丸在儿童时期无法制造精子。因此，目前还没有确定的临床选择来预防接受化疗的青春期前男孩不孕。在接受癌症治疗的儿童中，生育能力的保存取决于睾丸中精原干细胞（SSC）的存活。这些干细胞会在青春期后的男性体内产生精子。在接受癌症治疗的儿童中，保留生育能力的实验方法可能包括在患者接受治疗之前对睾丸进行活检，并将其储存起来以备将来使用，尽管迄今为止还没有开发出使用这种方法恢复生育能力的方法。此外，这需要进行侵入性手术，可能有重新引入恶性细胞的风险，并且可能需要人工生殖技术来恢复生育能力。因此，在化疗期间制定保护睾丸的策略将代表儿童癌症临床护理的重大进步。此次更新的目的是利用在奖学金初期产生的关于SSC发展，化疗诱导损伤机制和确定对睾丸细胞具有“化学保护”作用的药物的理解。这些“化学保护”药物将进入共培养和体内研究，以证明其有效性和安全性，以便将来进行旨在保持癌症儿童生育能力的临床试验。我们预计，这种更新将是发展治疗方法的又一重要步骤，这种治疗方法将使接受化疗的男孩保持生育能力。

Childhood cancer rates have increased dramatically (38% since 1960) over recent decades and currently 1 in 500 adults (~35000 in UK) is a survivor of childhood cancer. The increasing incidence, coupled with remarkable improvements in cure rates (>80% 5-year survival), have resulted in an increase in young adults experiencing subsequent health effects of their cancer treatment. Ensuring long-term health of this new and expanding patient cohort is one of the most pressing areas of clinical need in paediatric oncology. Infertility occurs in the majority of males receiving high-dose chemotherapy with drugs known as alkylating agents. Alkylating agents are used commonly in childhood cancer and increasingly for stem cell transplant in non-malignant disorders. Unlike the situation in men, semen cryopreservation is not an option to preserve fertility in these boys as their testicles are not capable of making sperm in childhood. As a result, there is currently no established clinical option to prevent infertility in prepubertal boys receiving chemotherapy. Preservation of fertility in children receiving cancer treatment is dependent on survival of the spermatogonial stem cells (SSC) in the testicle. These stem cells will generate sperm in males after puberty. Experimental approaches for fertility preservation in children undergoing cancer treatment could include taking a biopsy of the testicle before the patient receives their treatment and storing it for future use to restore fertility, although no methods to restore fertility using this approach have been developed so far. In addition, this requires invasive surgery, could carry a risk of re-introducing malignant cells and may require artificial reproductive techniques to restore fertility. Therefore, developing strategies to protect the testicles during chemotherapy treatment would represent a major advance for the clinical care of children with cancer. The aim of this renewal is to use the understanding generated during the intial period of the Fellowship regarding SSC development, mechanisms of chemotherapy-induced damage and drugs identified as having 'chemo-protective' effects on testicular cells. These 'chemo-protective' drugs will be taken forward into co-culture and in-vivo studies to demonstrate their efficacy and safety in order that future clinical trials aimed at preserving fertility in children with cancer can be performed. We anticipate that this renewal will be another important step towards development of treatments that will preserve fertility in boys receiving chemotherapy treatment.