Aims of this study were to investigate how single-(SD) or fractionated-(MF) doses radiation changes the microenvironment in TRAMP-C1 tumors with respect to vascularity, hypoxia, and tumor-associated macrophage infiltrates, and to elucidate their potential influence on tumor growth. A murine prostate cell line, TRAMP-C1, was grown in C57Bl/6J mice to 4 mm tumor diameter and irradiated with either 25 Gy in a single dose, or 60 Gy in 15 fractions. The tumors were removed at the indicated times for assessment of changes in vascularity, hypoxia, and macrophage content, activation status and function by immunohistochemistry and molecular assays. Molecular imaging such as microMRI, microPET, sonography were also implicated to monitor the tumor microenvironment in parallel studies. Tumor growth was delayed for one week after both radiation schedules. Tumor microvascular density (MVD) progressively decreased over a 3 week period to nadirs of 25% and 40% of un-irradiated tumors for SD or MF treatment, respectively. In accord with the decrease in MVDs, mRNA levels of endothelial markers such as CD31, endoglin, and TIE decreased over the same time period after irradiation. Central dilated vessels developed surrounded by avascularized hypoxic regions that became infiltrated with aggregates of CD68+ tumor-associated macrophages (TAMs), reaching a maximum at three weeks after irradiation. Necrotic regions decreased and were more dispersed. In tumors receiving radiation, arginase (Arg-I) and cycloxygenase-2 (COX-2) mRNA expression increased within hrs to days and lasted to the end of observation. Inducible nitric oxide synthase (iNOS) mRNA was elevated only after 3 days by SD irradiation or after 10 fractions of MF irradiation. Protein expression of Arg-I, COX-2, and to a lesser extent iNOS, was increased by TAMs in irradiated tumors at 1-2 weeks. CD11b+ TAMs from un-irradiated and irradiated tumors were functionally compared by mixing them with TRAMP-C1 cells before injection into mice and measuring tumor growth rate. By day 10, tumors growing in the presence of TAMs from the irradiation group were 1.4 fold larger than those mixed with TAMs from unirradiated tumors and 1.75 fold larger than control TRAMP-C1 tumors. In conclusion, irradiation of TRAMP-C1 tumors with either SD or MF doses decreases MVD, leading to the development of disperse chronic hypoxic regions, which are infiltrated with CD68+ TAMs. CD11b+ TAMs in the post-irradiated tumor microenvironment express higher levels of Arg-1, COX-2, and iNOS, and promote early tumor growth in vivo. Approaches to interfere the development of these effects are promising strategies to enhance the efficacy of cancer radiotherapy.

Table of Contents

Chapter 1: Responses of TRAMP C-1 Tumors to High Dose Single or Multi-fractioned Radiation Therapy
Introduction………………………………………………………………………1
Materials and Methods…………………………………………………………...5
Results…………………………………………………………………………..10
Chapter 2: Assessment of Microvascular Functionality during TRAMP C-1 Tumor Development and the Responses Following Single Dose and Multi-fractioned Irradiation
Introduction……………………………………………………………………19
Materials and Methods…………………………………………………………23
Results…………………………………………………………………………..27
Chapter 3: Tumor Associated Macrophages Response to the Altered Tumor Microenvironment Following Irradiation
Introduction……………………………………………………………………..36
Materials and Methods…………………………………………………………39
Results…………………………………………………………………………..42
Chapter 4: Discussion
………………………………………………………………………………………..47
Figures:
......................................................................................................................................59
References:
………………………………………………………………………………………..99

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