Table 1.
Responses of the various cellular components of the tumor stroma to diverse radiation regimens.
| Cell type | Tumor type | Experimental model | Radiation schemes | Effects | Reference |
|---|---|---|---|---|---|
| Endothelial cells | AVM (no tumor) | Human specimens | 15–50 Gy × 1 | Damage to EC is the earliest change after irradiation; >75% size reduction in AVM (Arterio-Venous Malformation) | (70) |
| Brain metastasis | In silico | 20 Gy × 1 | Occlusion of ≥99% of vessels within 1 year post-RT Vascular effect calculated to contribute by 19–33% of overall effect | (59) | |
| Sarcoma Melanoma | In vivo In vitro | 10 Gy × 1 | In vitro: EC apoptosis above 10 Gy In vivo: apoptosis induced in ECs above 15 Gy (local RT) | (61) | |
| – | In vivo | (a) 8–13 Gy | (a) Threshold-value for induction of EC-apoptosis, 1–6 h post-WBR | (63) | |
| (b) >17–18 Gy | (b) Endothelial-independent GI damage activated; 8–24 h post-WBR | ||||
| Sarcoma Melanoma | Xenografts in asmase+/+ or −/−mice | 13.5 Gy × 1 WBR | Anti-VEGFR2 given (0.5–2 h) before RT upregulates ceramide levels, resulting in enhanced apoptotic fraction of ECs. Anti-angiogenic effect fails without elevated ceramide levels | (64) | |
| – | Xenograft and human specimens | (a) <5 Gy | (a) Tumor vasculature preserved or improved | (13) | |
| (b) 5–10 Gy | (b) Mild vascular damage | ||||
| (c) <10 Gy | (c) Severe vascular damage, indirect tumor cell death | ||||
| Immune cells | Sarcoma | Mice | 10 Gy × 3 | Complete tumor regression by combining DC-immunotherapy and high-dose RT; no effect as single therapies | (160) |
| Melanoma Sarcoma | Mice | 8.5 Gy × 5 | Local and systemic anti-tumor response by combining DC administration and local oligo-fractionated RT | (161) | |
| Melanoma | Mice | 15 Gy × 1 | Increased accumulation of effector CD8+ T-cells upon local RT | (131) | |
| 3 Gy × 5 | Stronger immune-responses by single high-dose RT | ||||
| Melanoma | In vitro | (1, 4, 10, 25) Gy × 1 | A marked increase in cell-surface MHC class-I expression observed at higher doses (10–25 Gy) over a period of 3 days | (108) | |
| Colon cancer | Mice/humans | 10 Gy × 1 | Danger signals released by dying cells after RT as key events for mounting adaptive immune-responses | (117) | |
| Breast cancer | |||||
| Sarcoma | |||||
| Melanoma | Mice | (15–25) Gy × 1 | Local and systemic anti-tumor effects after ablative RT depends on CD8+ T-cell activation | (12) | |
| Lung | |||||
| Melanoma | Mice | 25 Gy × 1 | Local ablative RT trigger intratumoral production of IFN-β, resulting in enhanced cross-priming ability of DCs and tumor regression | (134) | |
| Colon | Mice | 10 Gy × 1 | High-dose RT elicits tumor-specific immunity by activation of tumor-associated DCs and CD8+ T-cells, but not via CD4+ or macrophages | (135) | |
| Lung | |||||
| Melanoma | |||||
| Normal fibroblasts | Normal fibroblasts | In vitro | (0.5, 2, 5, 15, 50) Gy × 1 | Normal fibroblasts (NFs) survive a radiation dose of 50 Gy Human NFs exposed to 15 Gy resulted in the highest number of | (140) |
| up- and down-regulated genes, peaking at 24 and 48 h post-IR | |||||
| Squamous cell carcinoma | In vitro | 12 Gy 24 Gy | Irradiated NFs promoted growth and invasion of non-irradiated SCC tumor cells. 12 Gy induced the greatest invasion. TGF-β expressed only by irradiated fibroblasts | (162) | |
| Skin fibroblasts | In vitro | 0.5 Gy × 1 10 Gy × 1 | Persistent DNA-damage signaling only at 10 Gy. High-dose induction of irreversible cell senescence and initiation of cytokine response | (147) | |
| Lung | Primary lung fibroblasts | (5, 15, 20, 25) Gy × 1 | Cytokine production by NFs exposed to escalating RT doses. RT doses above 15 Gy triggers enhanced expression of TGF-β | (138) | |
| IL-6, IL-8, and MCP-1 expression by NF unchanged post-RT | |||||
| Lung | In vitro In vivo | 4 Gy × 12 | Human NFs become senescent after an accumulative dose of 50 Gy, and turn pro-tumorigenic by increased expression of MMP1 | (145) | |
| Cancer-associated fibroblasts | Pancreatic cancer | Co-cultures: CAFs + adeno-carcinoma cells | 5 Gy 10 Gy | Enhanced invasiveness of pancreatic cancer cells co-cultured with irradiated CAFs, blocked by antagonist to HGF. Secreted HGF-levels unchanged after high-dose RT; bFGF-levels enhanced | (157) |
| Pancreatic cancer | In vitro In vivo | 100 Gy × 1 | Conditioned medium from human pancreatic stellate cells protects pancreatic tumor cells from radiation-induced apoptosis | (163) | |
| Breast cancer | Primary CAF cultures | 30 Gy × 1 | Breast CAFs and normal fibroblasts (NF) exhibit high radio-resistance. CAFs proliferate faster than NFs, and express higher levels of the tumor protecting factor Survivin | (144) | |
| Pancreatic cancer | Tumor-derived primary cells and cell lines | 3.5 Gy × 3 | Pancreatic stellate cells promote radioprotection of cancer cells in a β1-integrin dependent manner, and stimulate proliferation of pancreatic cancer cells in direct co-culture | (164) | |
| Non-small cell lung cancer (NSCLC) | In vitro human primary CAFs | (2, 6, 12, 18) Gy × 1 | >12 Gy permanent DDR and induction of cellular senescence | (146) | |
| At ablative RT doses: reduction of proliferative and migratory abilities. Induction of cell surface focal contacts | |||||
| NSCLC | In vitro human primary CAFs | 18 Gy × 1 | Secretome-analysis after ablative RT: reduced expression of angiogenic factors SDF-1, Angiopoietin-1, TSP-1; elevated levels of bFGF; unchanged levels of HGF, IL-6, IL-8, Il-1β, and TNF-α | (14) |