The Roles of Tumor-Associated Macrophage and Chemokines in Tumors with Tumor Bed Effect

The growth and therapeutic responses of tumors are influenced by tumor microenvironments. Our previous works on a mouse prostate cancer (TRAMP-C1) model have found that tumor transplants in pre-irradiated (pre-IR) tissues have shown longer growth delay, lower microvscular density (MVD), higher necrotic and hypoxic fraction than in non-irradiated tissues, a phenomenon known as the tumor bed effect (TBE). Besides, a large amount of tumor-associated macrophages (TAM) were found to aggregate in the hypoxic regions in tumors growing from pre-IR tissues and most of the vasculatures were mainly formed by vasculogenesis. These vasculatures had tightly-adhered pericytes and were resistant to radiation and antiangiogenic therapy, which explains why recurrent tumors after radiotherapy are less responsive to salvage radiotherapy or chemotherapy in clinics (Int. J. Radiat. Oncol. Biol. Phys., 2011). We also found a similar tumor microenvironment in multi-fractioned irradiated tumors in which TAMs could promote tumor growth via secretion of COX-2, an angiogenic factor (Int. J. Radiat. Oncol. Biol. Phys., 2007). These two papers indicate vascular responses and immune cells are key players in tumor growth. Our ongoing studies showed that TBE varies between tumors. B16 tumor from a mouse melanoma cell line showed a vascular morphology distinct from TRAMP-C1 tumor, extremely low number of TAMs and greater delay of tumor growth than TRAMP-C1 tumors if growing in the pre-irradiated tissue. Based on our previous and ongoing studies, we hypothesize that TAM infiltration plays an important role in the intrinsic tumor characteristics such as density and phenotype of vasculature, and TBE effects. The phenotype of TAMs in the tumor microenvironment should play a direct role to regulate the angiogenic mechanism. The overall aim of this project is to use tumors with different characteristics in vascular phenotype and TAMs to study the roles of tumor-associated macrophage in tumor bed effect. This project will provide us important information for development of methods to predict behaviors of recurring tumors after radiotherapy, and design better treatment modality to against these tumors. The specific of this project are to: 1. Study the global differences in microenvironments and mechanism of vascular formation between different types of tumors growing from pre-irradiated tissues 2. Study the chemotactic activity of tumors and the role of TAM in different tumors growing from pre-irradiated tissues 3. Explore the effects of targeting TAM in different tumors growing from pre-irradiated tissues

Project ID:PC10309-0118
External Project ID:MOST103-2314-B182-062