Biomathematical Approaches to Cancer

描述（由申请人提供）：在癌症通路上的中间细胞克隆，如腺瘤性息肉和肝灶改变，经常在人类和动物中观察到。这些病变提供了对癌变过程早期阶段的认识。由于部分转化细胞的克隆扩增可以大大增加癌症的可能性，因此对这些病变的定量了解是了解癌症发病率的关键。该项目的总体目标是在多阶段癌变范式下继续发展数学、统计和计算工具，用于对恶性肿瘤途径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，估计病变的起始率，以及组成病变的部分转化细胞的细胞分裂和凋亡率。这种早期病变的信息通常可以从启动促进实验中获得，特别是在啮齿动物的肝脏中。在以前的工作中，已经建立了恶性肿瘤通路中中间病变的数量和大小分布的数学表达式，并用于分析大鼠肝脏的启动-促进实验。本提案计划根据新的生物学信息扩展这项工作。除了继续对啮齿动物肝脏病灶进行分析外，本研究还将研究人类结肠和巴雷特食管患者的中间病变，巴雷特食管是食管腺癌的高风险前兆。除了在多阶段癌变范式中与克隆生长模型相关的数学和统计问题外，肝脏局灶分析和Barrett食管病变分析都存在各种各样的问题。认识到建模是一个反复的过程，这项工作的组成部分将与实验家和人类生物学家合作，特别是图宾根大学啮齿动物肝脏系统专家迈克尔·施瓦茨博士，结肠癌专业流行病学家约翰·波特博士和西雅图巴雷特食道项目主任布莱恩·里德博士。分析的结果将用于帮助产生与生物学相关的问题和假设，并计划进一步的实验和研究，这反过来又将导致更精确的模型。

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.