STRESS INDUCED BYSTANDER EFFECT IN CANCER TREATMENT

肿瘤对抗癌治疗的抗性和敏感性的研究在很大程度上限于分析细胞对治疗的反应的内在机制。 然而，肿瘤反应还涉及旁分泌效应，包括肿瘤细胞彼此之间、与间质之间以及与远处组织释放的因子之间的相互作用。 在这里，我们提出了一个研究计划，旨在确定药物和放射治疗中细胞间通讯的作用和机制。 它基于两条初步意见。 首先，通过使用遗传抑制元件（GSE）技术，普遍存在的驱动蛋白重链（uKHC）被确定为药物敏感基因，其失调导致一种不寻常的耐药性。 最近，发现正常和肿瘤细胞在应激条件下以p53依赖性方式分泌生长抑制因子，引起负旁分泌调节（“旁观者效应”），影响邻近细胞的生长。 初步数据显示，驱动蛋白介导的耐药性是由旁观者效应的调制，表明驱动蛋白参与p53依赖性应激诱导的生长抑制剂的分泌。 目前的计划致力于表征肿瘤对抗癌治疗的反应中应激诱导的旁观者效应的作用，确定这种现象的因素，并分析p53和驱动蛋白介导的分泌失调的分子机制和后果。 具体目标包括：（i）建立实验方法和模型系统以研究体外和体内应激依赖性旁观者效应的作用，（ii）分析药物或辐射处理的细胞群体中p53依赖性旁观者效应中驱动蛋白功能的参与，（iii）鉴定参与应激诱导的驱动蛋白介导的旁观者效应的细胞蛋白，和（iv）在肿瘤敏感性和对治疗性治疗的抗性中以及在鉴定这种形式的治疗反应的分子决定因素中，确定应激诱导的旁观者效应的细胞因子的分离和表征。

Studies of tumor resistance and sensitivity to anti-cancer therapy is largely limited to the analysis of intrinsic mechanisms of cell response to treatment. However, tumor response also involves paracrine effects, including interactions of tumor cells with each other, with the stroma and with factors released by distant tissues. Here we propose a program of studies that is aimed at the determination of the role and mechanisms of cell-cell communication in drug and radiation treatment. It is based on two lines of preliminary observations. First, by using the genetic suppressor element (GSE) technology, ubiquitous kinesin heavy chain (uKHC) was identified as a drug-sensitivity gene, deregulation of which results in an unusual type of drug resistance. More recently, it was found that normal and tumor cells under conditions of stress secrete in a p53-dependent manner growth inhibitory factors causing negative paracrine regulation ("bystander effect"), affecting growth of neighboring cells. Preliminary data were generated showing that kinesin-mediated drug resistance is determined by modulation of the bystander effect, suggesting that kinesin participates in p53-dependent stress-induced secretion of growth inhibitors. Current program is devoted to characterization of the role of stress-induced bystander effect in tumor response to anticancer treatment, identification of factors determining this phenomenon and the analysis of molecular mechanisms and consequences of deregulation of p53- and kinesin-mediated secretion. Specific aims include: (i) the establishment of experimental approaches and model systems to study the role of stress- dependent bystander effect in vitro and in vivo, (ii) the analysis of involvement of the kinesin function in the p53-dependent bystander effect in drug- or radiation- treated cell populations, (iii) identification of cellular proteins involved in stress-induced kinesin-mediated bystander effect, and (iv) isolation and characterization of cellular factor(s) determining stress- induced bystander effect in tumor sensitivity and resistance to therapeutic treatments and in identification of molecular determinants of this form of therapy response.