STRESS INDUCED BYSTANDER EFFECT IN CANCER TREATMENT

肿瘤耐药性和抗癌治疗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，肿瘤的反应也涉及旁分泌效应，包括肿瘤细胞之间的相互作用、与间质的相互作用以及与远处组织释放的因子的相互作用。在这里，我们提出了一个研究计划，旨在确定细胞-细胞通讯在药物和放射治疗中的作用和机制。它是基于两条线的初步观察。首先，利用基因抑制元件(GSE)技术，发现无处不在的动蛋白重链(UKHC)基因是一种药物敏感基因，其缺失会导致一种不寻常的耐药类型。最近发现，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，导致负的旁分泌调节(旁观者效应)，影响邻近细胞的生长。初步数据显示，Kinesin介导的耐药性是由旁观者效应的调节决定的，这表明Kinesin参与了P53依赖的应激诱导的生长抑制因子的分泌。目前的计划致力于表征应激诱导的旁观者效应在肿瘤抗癌治疗反应中的作用，确定决定这一现象的因素，并分析P53和激动素介导的分泌放松调控的分子机制和后果。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诱导的旁观者效应的作用，(Ii)分析在药物或放射治疗的细胞群体中Kinesin功能参与P53依赖的旁观者效应的参与，(Iii)鉴定参与应激诱导的Kinesin介导的旁观者效应的细胞蛋白，以及(Iv)决定应激诱导的旁观者效应在肿瘤治疗敏感性和耐药性以及确定这种形式的治疗反应的分子决定因素中的细胞因子(S)的分离和鉴定。

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.