Responses of Tumor Microenvironment during Fractionated Radiotherapy (RT)

Although radiotherapy (RT) is a front-line treatment for many types of tumors, there is still a need to identify novel ways to improve its effectiveness in advanced-stage diseases. Increasing evidence has shown that in addition to the intrinsic radiosensitivity of tumor cells, other components in the tumors such as vascular damage and inflammatory cells also play an important role in tumor killing and regrowth. Compared to numerous works done in normal tissues, much less studies have been done in the responses of tumors microenvironment following in vivo RT. In the clinics multiple, small-dose (fractionated) treatments lasting for 6-8 weeks is the standard protocol for curative RT, but most of the animal studies in tumors were done by RT with single dose or limited fraction number (usually 2-10). To our best literature search, no human study and animal model have shown how and when the tumor microenvironment respond to radiation damage during fractionated RT. It is unknown if the changes of microenvironment by early radiation doses will stimulate regrowth of the surviving tumor clones or enhance killing effects of the following radiation dose. Knowing these changes and their roles will have strong impacts on our treatment strategy to enhance tumor control by RT. The overall aim of this project is to use a murine tumor model to investigate the responses of tumor microenvironment during and after in vivo fractionated radiotherapy (RT) and to examine the possibility of manipulating these responses to enhance the RT effects on tumor growth. Our pilot studies have found macrophages and their associated molecules such as cytokines, arginase I and COX-2 were involved in tumor regrowth following single, high dose RT. We will use these findings as our starting-point and propose to make a series of studies in the tumor microenvironment during and after fractionated RT. Our studies will include discovery of the molecular and histological changes, exploration of the mechanism, and manipulation of these responses to improve tumor control by RT. This project will be a pioneer work in this very important issue in cancer treatment. The specific aims of this project are to: 1. Set up an animal tumor model and radiation system for fractionated radiotherapy (RT). 2. Serially study the gross, histological, cellular and molecular changes in the tumor during and after fractionated treatment. 3. Identify the roles of macrophages and non-macrophage cells in the molecular responses, and explore the role of macrophages on tumor growth. 4. Test the possibility of using drugs to manipulate the tumor microenvironment and observe their effects on tumor growth.

Project ID:PC9609-3956
External Project ID:NSC96-2628-B182-021-MY2