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

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 rate, lower microvscular density (MVD), higher necrotic and hypoxic fraction than in non-irradiated tissues, a phenomenon known as the tumor bed effect (TBE). In addition, we also found great numbers of tumor-associated macrophages (TAM) aggregated in the hypoxic regions of tumors with TBE. These aggregated TAMs promote tumor re-growth via secretion of angiogenic factors. The vasculatures in tumors with TBE were mainly formed by vasculogenesis and resistant to following radiation and antiangiogenic therapy. These preliminary results indicate vascular responses and TAM are key players in tumor re-growth after radiation therapy. Based on these preliminary results, we presented a proposal to investigate the profile of chemokines released from tumors which links to functions of TAM on tumor vasculature and the formation of tumor microenvironment, and test the possibility to improve tumor control by targeting TAM last year. The original proposal was intended for 3 years of project with 3 specific aims, but it was funded for only one year with some concerns of last year’s reviewers. In last 6 months, we not only published the preliminary results in International journal of radiation biology [1], but also performed the first aim using another tumor model to prove the hypothesis that tumors with different chemokine profiles growing from pre-irradiated tissues display different microenvironments and have different vascular formation mechanism. These results further solidify our hypothesis that tumor-derived chemokines play essential role on the formation of tumor microenvironment, in particular the composition of TAM. We are therefore asking the reviewer committee to continue this study to finish another two specific aims. They are 1. Study the role of tumor-related chemokines on formation of tumor microenvironment from pre-irradiated tissue 2. Study the role of TAM on tumor regrowth after radiation therapy. The accomplishment of these two aims not only advances our knowledge on tumor microenvironment formation mechanism in pre-irradiated tissues, but also improves our treatment planning for recurrent tumor after radiation therapy.

Project ID:PC10408-2332
External Project ID:MOST104-2314-B182-024