The ultimate goal of radiation therapy is to reduce or eliminate tumor burden while sparing normal tissues from long-term injury. However, tumor resistance becomes increasingly aware. In addition, local recurrence of primary tumors and distant metastasis are the leading causes of death in many cancer patients. Herein the high intrinsic sensitivity of normal tissues to ionizing radiation often precludes the application of curative radiation doses. Therefore, further research effort is needed to understand the complex interactions of tumors within their microenvironment and their surrounding (normal) tissue. This is prerequisite for the development of strategies that could either result in normal tissue protection or tumor sensitization to radiation therapy. Concerning normal tissue protection, the vascular compartment gained attraction, because the endothelial cells were known to be critical determinants of the radiation response and in particular of radiation toxicity in healthy tissues. Own work of the laboratory could show that radiation-induced vascular damage and dysfunction in normal lung tissue supports extravasation of pre-metastatic immune cells and of circulating tumor cells into previously irradiated lung. The pro-invasive cellular activities were accompanied by radiation-induced senescence of bronchial-alveolar epithelial cells and up-regulation of the senescence-associated secretory phenotype (SASP) factor chemokine C-C motif ligand 2 (CCL2), also known as monocyte chemoattractant protein-1 (MCP-1). In the first work/manuscript, it was hypothesized that this factor with angiogenic activities leads to the stimulation of the hitherto quiescent endothelial cells of the normal tissue upon radiation, which then results in vascular dysfunction (acute effect) and severe endothelial cell loss (late complication). Here, it could be shown that inhibition of CCL2 secreted by irradiated and senescent epithelial cells leads to protection of the vascular components in normal tissue. In more detail, deficiency of the corresponding CCL2 receptor CCR2 or specific inhibition of CCL2 with the inhibitor Bindarit significantly rescued the radiation-induced vascular impairments and subsequent endothelial cell loss. By limiting the radiation-induced endothelial barrier dysfunction, extravasation of circulating immune and tumor cells was significantly reduced and thus inflammation and metastasis were limited. In addition, radiation-induced fibrosis progression was reduced by CCL2 signaling inhibition. Thus, CCL2 signaling inhibition that countered acute and chronic effects of normal tissue toxicity upon radiation treatment is a promising radioprotective strategy. The vascular compartment is also of potential interest concerning tumor sensitization to radiation therapy. Previous work of the lab revealed that a downregulation of the membrane protein caveolin-1 (CAV1) in endothelial cells resulted in a more activated, angiogenic phenotype which was associated with an increased sensitivity to radiation treatment. In general, CAV1 emerged as a potential biomarker of tumor progression and resistance in numerous solid human tumors and could thus serve as a potential target for sensitizing malignant cells to therapy. Especially, alterations of CAV1 expression in tumor cells and the corresponding microenvironment were shown to be linked to tumor progression and resistance e.g. in prostate cancer. In the second and third work, it was investigated how a differential CAV1 expression in tumor and stromal cells affected the radiation response of tumors, with a focus on prostate cancer. Whereas a downregulation of CAV1 in radio-resistant CAV1-expressing endothelial and prostate cancer cells resulted in radio-sensitization, CAV1-deficiency in stromal fibroblasts resulted in a more activated, radio-resistant fibroblast phenotype. In particular, CAV1-deficient fibroblasts mediated therapy resistance of prostate cancer xenografts by protecting tumor cells from apoptosis induction. The apoptosis inhibiting protein TP53-regulated inhibitor of apoptosis 1 (TRIAP1), known as p53-inducible cell-survival factor, was identified as a CAV1-dependent secreted factor of activated fibroblast contributing to elevated tumor growth and radiation therapy resistance in vitro and vivo. Moreover, staining of human prostate cancer tissue revealed an increase in TRIAP1 expression in advanced tumor samples. Conclusively, blocking TRIAP1 activity and avoiding drug resistance may offer a promising drug development strategy to inhibit resistance-promoting CAV1-dependent signals. In the fourth work, the influence of CAV1 in the radiation response of endothelial cells as well as tumor cells was linked to the ASMase/ceramide pathway. Mechanistically, a reduced CAV1 content of angiogenic and thus more radio-sensitive endothelial cells was linked to increased ceramide levels, in particular to the apoptosis-prone C16 ceramide, resulting from an increased ASMase activity in CAV1-deficient endothelial cells and increased levels of ceramide synthases that were responsible for the generation of C16. The more radio-resistant prostate cancer cells, which were characterized by a CAV1 upregulation bear more long chain ceramides (C24, C24:1), which were shown to scavenge the apoptosis-inducing effects of C16 ceramide. Taken together, the present thesis was able to contribute to a better understanding how the tumor-surrounding normal tissue reacts to radiation therapy, and thus provides the basis for the development of radio-protective strategies. Furthermore, mechanistic insights in the stromal-epithelial crosstalk were achieved and molecular targets to possibly improve the outcome of radiotherapy were identified.