Partial Recovery from Tumor Bed Effects: Two Distinct Tumor Microenvironments with Different Responses to Therapy

Tumors growing in pre-irradiated tissues (pre-IR tumors) had a prolonged latency period and retarded growth rate as compared with non-IR tumors, a phenomenon known as tumor bed effects (TBE). The aim of this study is compare the structures, functions and involvement of bone marrow (BM) stem cells in the vasculatures of small pre-IR and non-IR tumors. Murine TRAMP-C1 prostate tumor cells transplanted into shank were used as a model and 25 Gy was given before tumor implantation for pre-IR tumors. For 3-4 mm size tumors, pre-IR tumors had decreases of microvascular density (MVD) and increases of hypoxic area than size-matched non-IR tumors. However, vasculatures in the pre-IR tumors were larger, and better perfused, as measured by Hoechst 33342 dye, than non-IR tumors, In the non-IR tumors, only 16.5% ± 7.1% CD-31 positive endothelial cells were covered with α-SMA positive pericyte, significantly lower than 91% ± 13% in pre-IR tumors. The behaviors of PDGFR positive cells are similar to those of α-SMA positive cells, with a tight coupling with endothelial cells and larger size in dilated vessels. These results suggested the vasculatures in small pre-IR tumors are more mature than those in control tumors. Three approaches were used to investigate if BM-derived cells are involved in the vascular formation in the pre-IR tumors; they are: 1. Co-injection of GFP-bone marrow derived cells (GFP-BMs) and TRAMP-C1 tumors. 2. Inoculation of tumors into GFP-BM-transplanted wide-type mice. 3.Continuous i.v. injection of GFP-BMs during tumor growth. The results from these three approaches clearly showed CD31-positive endothelial cells were co-localized with GFP positive cells in pre-IR tumors but not in non-IR tumors, and the percentage was highest for the first approach and lowest for the third approach. The conclusions from this study are that vasculatures in the pre-IR tumors are more mature than non-IR tumors, and BM-derived cells are involved in the vascular formation in the small pre-IR tumors. Vasculogenesis plays an important role in the pre-IR tumors and blockade of this pathway may decrease tumor relapse in the irradiated tissues.