Biomathematical Approaches to Cancer

描述（由申请人提供）：在人类和动物中经常观察到癌症途径上的中间细胞克隆，例如腺瘤性息肉和改变的肝病灶。这些病变提供了对致癌过程的最早阶段的见解。由于部分转化的细胞的克隆扩增可以大大增加癌症的概率，因此对这些病变的定量理解是理解癌症发生率的关键。该项目的广泛目标是在多阶段致癌作用的范例内继续开发数学、统计和计算工具，用于对恶性肿瘤途径上的早期病变进行定量分析。这些分析的基本目标是研究这些病变的时间演变，估计病变的起始速率，以及构成病变的部分转化细胞的细胞分裂和凋亡速率。这种早期病变的信息通常是从启动促进实验，特别是在啮齿动物liver.In以前的工作中，数学表达式已经开发的中间病变的数量和大小分布的恶性肿瘤的途径，并用于分析启动促进实验在大鼠肝脏。该提案计划根据新的生物信息扩展这项工作。除了继续对啮齿动物肝病灶进行分析外，本文提出的研究还将研究人类结肠和Barrett食管患者的中间病变，Barrett食管是食管腺癌的高风险前驱疾病。除了与克隆生长模型在多阶段癌变的范例中相关的数学和统计问题之外，肝病灶的分析和巴雷特食管病变的分析都存在不同的问题。认识到建模是一个反复的过程，这一努力的一个组成部分将是与实验学家和人类生物学家的合作，特别是蒂宾根大学的啮齿动物肝脏系统专家Michael施瓦茨博士，结肠癌专家流行病学家John Potter博士和西雅图巴雷特食管项目主任Brian Reid博士。分析结果将用于帮助生成生物学相关问题和假设，并计划进一步的实验和研究，这反过来将导致更完善的模型。

DESCRIPTION (provided by applicant): Clones of intermediate cells on the pathway to cancer, such as adenomatous polyps and altered hepatic foci, are often observed in humans and animals. These lesions provide insights into the earliest stages of the carcinogenic process. Because clonal expansion of cells that are partially transformed can increase the probability of cancer substantially, a quantitative understanding of these lesions is key to understanding cancer rates. The broad objective of this project is to continue the development of mathematical, statistical and computational tools, within the paradigm of multistage carcinogenesis, for the quantitative analyses of early lesions on the pathway to malignancy. The fundamental goals of these analyses are to study the temporal evolution of these lesions, to estimate the rate of initiation of the lesions, and the rates of cell division and apoptosis of the partially transformed cells that comprise the lesion. Information on such early lesions is typically available from initiation-promotion experiments, particularly in the rodent liver.In previous work mathematical expressions have been developed for the number and size distribution of intermediate lesions on the pathway to malignancy and used for analyses of initiation-promotion experiments in rat liver. This proposal plans to extend this work in light of new biological information. In addition to continuing work on analyses of liver foci in rodents, the research proposed here will investigate intermediate lesions in the human colon and in patients with Barrett's esophagus, a high-risk precursor condition for adenocarcinoma of the esophagus. In addition to the mathematical and statistical problems associated with clonal growth models within the paradigm of multistage carcinogenesis, both analyses of liver foci and analyses of lesions in Barrett's esophagus present diverse problems. Recognizing that modeling is an iterative process an integral part of this effort will be collaboration with experimentalists and human biologists, in particular Dr. Michael Schwarz, University of Tubingen, an expert on the rodent liver system, Dr. John Potter, an epidemiologist with expertise on colon cancer and Dr. Brian Reid, Director of the Seattle Barrett's Esophagus Project. The results of analyses will be used to help generate biologically relevant questions and hypotheses and to plan further experiments and studies, which, in turn, will lead to more refined models.