Biomathematical Approaches to Cancer

描述(申请人提供)：在人类和动物中经常观察到致癌途径上的中间细胞的克隆，例如腺瘤性息肉和改变的肝脏病灶。这些病变提供了对致癌过程的早期阶段的洞察。由于部分转化的细胞的克隆性扩张会显著增加癌症的可能性，因此对这些损伤的定量了解是了解癌症发生率的关键。该项目的广泛目标是在多阶段癌症发生的范例内继续开发数学、统计和计算工具，用于对癌变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，估计病变的起始率，以及构成病变的部分转化细胞的细胞分裂和凋亡率。关于这种早期病变的信息通常可以从启动促进实验中获得，特别是在啮齿类动物的肝脏中。在以前的工作中，已经建立了致癌途径上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。这项提案计划根据新的生物信息延长这项工作。除了继续对啮齿类动物的肝脏病灶进行分析外，这里提出的研究还将调查人类结肠和Barrett‘s食道患者的中间病变，Barrett’s食道是食管腺癌的高风险前驱疾病。除了与多阶段癌变范式中的克隆生长模型相关的数学和统计学问题外，对肝脏病灶的分析和对Barrett‘s食道病变的分析都存在各种问题。认识到建模是一个迭代过程，这项工作的一个组成部分将是与实验者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。分析的结果将被用来帮助产生与生物学相关的问题和假说，并计划进一步的实验和研究，这反过来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.