STRESS INDUCED BYSTANDER EFFECT IN CANCER TREATMENT

肿瘤对抗癌治疗的耐药性和敏感性的研究在很大程度上局限于对细胞对治疗反应的内在机制的分析。然而，肿瘤反应还涉及旁分泌效应，包括肿瘤细胞之间、与基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-细胞通讯的作用和机制。它是基于两行初步观察。首先，利用基因抑制元件（GSE）技术，确定了无处不在的激酶蛋白重链（uKHC）是一种药物敏感基因，解除其管制会导致一种不同寻常的耐药类型。最近，研究发现正常细胞和肿瘤细胞在应激条件下以p53依赖的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，kinesin介导的耐药是通过调节旁观者效应来决定的，这表明kinesin参与了p53依赖性应激诱导的生长抑制剂分泌。目前的项目致力于描述应激诱导的旁观者效应在肿瘤对抗癌治疗的反应中的作用，确定决定这一现象的因素，分析p53和激酶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来研究体外和体内应激依赖性旁观者效应的作用，（ii）分析在药物或辐射处理的细胞群体中p53依赖性旁观者效应中激酶功能的参与，（iii）鉴定与应激诱导的激酶介导的旁观者效应有关的细胞蛋白，（iv）在肿瘤敏感性和抗治疗性中确定应激诱导的旁观者效应的细胞因子的分离和表征，以及确定这种形式的治疗反应的分子决定因素。

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.