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Rac1-regulated endothelial radiation response stimulates extravasation and metastasis that can be blocked by HMG-CoA reductase inhibitors.

Hamalukic M, Huelsenbeck J, Schad A, Wirtz S, Kaina B, Fritz G - PLoS ONE (2011)

Bottom Line: IR-stimulated TC-EC adhesion was blocked by the HMG-CoA reductase inhibitor lovastatin.Glycyrrhizic acid from liquorice root, which acts as a Sialyl-Lewis X mimetic drug, and the Rac1 inhibitor NSC23766 also reduced TC-EC adhesion.To examine the in vivo relevance of these findings, tumorigenic cells were injected into the tail vein of immunodeficient mice followed by total body irradiation (TBI).

View Article: PubMed Central - PubMed

Affiliation: Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

ABSTRACT
Radiotherapy (RT) plays a key role in cancer treatment. Although the benefit of ionizing radiation (IR) is well established, some findings raise the possibility that irradiation of the primary tumor not only triggers a killing response but also increases the metastatic potential of surviving tumor cells. Here we addressed the question of whether irradiation of normal cells outside of the primary tumor augments metastasis by stimulating the extravasation of circulating tumor cells. We show that IR exposure of human endothelial cells (EC), tumor cells (TC) or both increases TC-EC adhesion in vitro. IR-stimulated TC-EC adhesion was blocked by the HMG-CoA reductase inhibitor lovastatin. Glycyrrhizic acid from liquorice root, which acts as a Sialyl-Lewis X mimetic drug, and the Rac1 inhibitor NSC23766 also reduced TC-EC adhesion. To examine the in vivo relevance of these findings, tumorigenic cells were injected into the tail vein of immunodeficient mice followed by total body irradiation (TBI). The data obtained show that TBI dramatically enhances tumor cell extravasation and lung metastasis. This pro-metastatic radiation effect was blocked by pre-treating mice with lovastatin, glycyrrhizic acid or NSC23766. TBI of mice prior to tumor cell transplantation also stimulated metastasis, which was again blocked by lovastatin. The data point to a pro-metastatic trans-effect of RT, which likely rests on the endothelial radiation response promoting the extravasation of circulating tumor cells. Administration of the widely used lipid-lowering drug lovastatin prior to irradiation counteracts this process, likely by suppressing Rac1-regulated E-selectin expression following irradiation. The data support the concern that radiation exposure might increase the extravasation of circulating tumor cells and recommend co-administration of lipid-lowering drugs to avoid this adverse effect of ionizing radiation.

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Radiation response of normal tissue is sufficient for provoking lung metastasis.A, B: Rag2−/− Balb/c mice that have been pre-treated or not with lovastatin (Lova) for 4 days (10 mg/kg, p.o.) were irradiated with 4 Gy before tumorigenic (non-irradiated) CHO-K1 cells (2×106) were injected into the tail vein. 3–4 weeks later, formation of lung metastases was analyzed. A, representative morphological and histopathological pictures demonstrating the pro-metastatic effect of TBI; B, quantitative analysis of tumor area in lung sections. Con, non-irradiated control; IR, TBI with 4 Gy. ** p≤0.01; *** p≤0.001 (n = 4–8 mice). C, D: 2×106 human colon carcinoma cells (HT29) were injected into the tail vein of CB-17 SCID mice which have been pretreated or not with lovastatin (Lova) for 4 days (10 mg/kg, p.o.). Immediately after injection of the tumor cells, animals were irradiated with 2.5 Gy. 3–4 weeks later, lung metastases were analyzed by calculating the tumor area as described in Methods. C, representative morphological and histopathological pictures illustrating the IR effect; D, quantitative analysis of percent (%) tumor area in lung sections. Con, non-irradiated control; IR, total body irradiation with 2.5 Gy; nd, no tumor cells detectable. * p≤0.05 (n = 3–4 mice). See also Figure S4.
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pone-0026413-g004: Radiation response of normal tissue is sufficient for provoking lung metastasis.A, B: Rag2−/− Balb/c mice that have been pre-treated or not with lovastatin (Lova) for 4 days (10 mg/kg, p.o.) were irradiated with 4 Gy before tumorigenic (non-irradiated) CHO-K1 cells (2×106) were injected into the tail vein. 3–4 weeks later, formation of lung metastases was analyzed. A, representative morphological and histopathological pictures demonstrating the pro-metastatic effect of TBI; B, quantitative analysis of tumor area in lung sections. Con, non-irradiated control; IR, TBI with 4 Gy. ** p≤0.01; *** p≤0.001 (n = 4–8 mice). C, D: 2×106 human colon carcinoma cells (HT29) were injected into the tail vein of CB-17 SCID mice which have been pretreated or not with lovastatin (Lova) for 4 days (10 mg/kg, p.o.). Immediately after injection of the tumor cells, animals were irradiated with 2.5 Gy. 3–4 weeks later, lung metastases were analyzed by calculating the tumor area as described in Methods. C, representative morphological and histopathological pictures illustrating the IR effect; D, quantitative analysis of percent (%) tumor area in lung sections. Con, non-irradiated control; IR, total body irradiation with 2.5 Gy; nd, no tumor cells detectable. * p≤0.05 (n = 3–4 mice). See also Figure S4.

Mentions: In order to elucidate whether TBI was effective in stimulating metastasis when the animals, but not the tumor cells were irradiated, mice were irradiated first and thereafter tumor cells were transplanted. As shown in Fig. 4A, TBI of animals followed by transplantation of non-irradiated tumor cells also resulted in enhanced formation of lung metastases as compared to mice that have not been pre-irradiated. When the animals were pre-treated with lovastatin before they were subjected to TBI and then received non-irradiated tumor cells, the formation of lung metastases was reduced (Fig. 4B). These findings show that the pro-metastatic effect of TBI is a trans-effect, i.e. it is due to a radiation response of the normal tissue that stimulates the metastatic properties of the tumor cells. It is reasonable to suggest that this occurs via transient activation of pro-adhesive endothelial functions. Pre-treatment of mice with lovastatin is sufficient to block this pro-adhesive radiation response of the endothelium and, therefore, antagonizes IR-mediated extravasation of tumor cells and formation of lung metastases.


Rac1-regulated endothelial radiation response stimulates extravasation and metastasis that can be blocked by HMG-CoA reductase inhibitors.

Hamalukic M, Huelsenbeck J, Schad A, Wirtz S, Kaina B, Fritz G - PLoS ONE (2011)

Radiation response of normal tissue is sufficient for provoking lung metastasis.A, B: Rag2−/− Balb/c mice that have been pre-treated or not with lovastatin (Lova) for 4 days (10 mg/kg, p.o.) were irradiated with 4 Gy before tumorigenic (non-irradiated) CHO-K1 cells (2×106) were injected into the tail vein. 3–4 weeks later, formation of lung metastases was analyzed. A, representative morphological and histopathological pictures demonstrating the pro-metastatic effect of TBI; B, quantitative analysis of tumor area in lung sections. Con, non-irradiated control; IR, TBI with 4 Gy. ** p≤0.01; *** p≤0.001 (n = 4–8 mice). C, D: 2×106 human colon carcinoma cells (HT29) were injected into the tail vein of CB-17 SCID mice which have been pretreated or not with lovastatin (Lova) for 4 days (10 mg/kg, p.o.). Immediately after injection of the tumor cells, animals were irradiated with 2.5 Gy. 3–4 weeks later, lung metastases were analyzed by calculating the tumor area as described in Methods. C, representative morphological and histopathological pictures illustrating the IR effect; D, quantitative analysis of percent (%) tumor area in lung sections. Con, non-irradiated control; IR, total body irradiation with 2.5 Gy; nd, no tumor cells detectable. * p≤0.05 (n = 3–4 mice). See also Figure S4.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3198428&req=5

pone-0026413-g004: Radiation response of normal tissue is sufficient for provoking lung metastasis.A, B: Rag2−/− Balb/c mice that have been pre-treated or not with lovastatin (Lova) for 4 days (10 mg/kg, p.o.) were irradiated with 4 Gy before tumorigenic (non-irradiated) CHO-K1 cells (2×106) were injected into the tail vein. 3–4 weeks later, formation of lung metastases was analyzed. A, representative morphological and histopathological pictures demonstrating the pro-metastatic effect of TBI; B, quantitative analysis of tumor area in lung sections. Con, non-irradiated control; IR, TBI with 4 Gy. ** p≤0.01; *** p≤0.001 (n = 4–8 mice). C, D: 2×106 human colon carcinoma cells (HT29) were injected into the tail vein of CB-17 SCID mice which have been pretreated or not with lovastatin (Lova) for 4 days (10 mg/kg, p.o.). Immediately after injection of the tumor cells, animals were irradiated with 2.5 Gy. 3–4 weeks later, lung metastases were analyzed by calculating the tumor area as described in Methods. C, representative morphological and histopathological pictures illustrating the IR effect; D, quantitative analysis of percent (%) tumor area in lung sections. Con, non-irradiated control; IR, total body irradiation with 2.5 Gy; nd, no tumor cells detectable. * p≤0.05 (n = 3–4 mice). See also Figure S4.
Mentions: In order to elucidate whether TBI was effective in stimulating metastasis when the animals, but not the tumor cells were irradiated, mice were irradiated first and thereafter tumor cells were transplanted. As shown in Fig. 4A, TBI of animals followed by transplantation of non-irradiated tumor cells also resulted in enhanced formation of lung metastases as compared to mice that have not been pre-irradiated. When the animals were pre-treated with lovastatin before they were subjected to TBI and then received non-irradiated tumor cells, the formation of lung metastases was reduced (Fig. 4B). These findings show that the pro-metastatic effect of TBI is a trans-effect, i.e. it is due to a radiation response of the normal tissue that stimulates the metastatic properties of the tumor cells. It is reasonable to suggest that this occurs via transient activation of pro-adhesive endothelial functions. Pre-treatment of mice with lovastatin is sufficient to block this pro-adhesive radiation response of the endothelium and, therefore, antagonizes IR-mediated extravasation of tumor cells and formation of lung metastases.

Bottom Line: IR-stimulated TC-EC adhesion was blocked by the HMG-CoA reductase inhibitor lovastatin.Glycyrrhizic acid from liquorice root, which acts as a Sialyl-Lewis X mimetic drug, and the Rac1 inhibitor NSC23766 also reduced TC-EC adhesion.To examine the in vivo relevance of these findings, tumorigenic cells were injected into the tail vein of immunodeficient mice followed by total body irradiation (TBI).

View Article: PubMed Central - PubMed

Affiliation: Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

ABSTRACT
Radiotherapy (RT) plays a key role in cancer treatment. Although the benefit of ionizing radiation (IR) is well established, some findings raise the possibility that irradiation of the primary tumor not only triggers a killing response but also increases the metastatic potential of surviving tumor cells. Here we addressed the question of whether irradiation of normal cells outside of the primary tumor augments metastasis by stimulating the extravasation of circulating tumor cells. We show that IR exposure of human endothelial cells (EC), tumor cells (TC) or both increases TC-EC adhesion in vitro. IR-stimulated TC-EC adhesion was blocked by the HMG-CoA reductase inhibitor lovastatin. Glycyrrhizic acid from liquorice root, which acts as a Sialyl-Lewis X mimetic drug, and the Rac1 inhibitor NSC23766 also reduced TC-EC adhesion. To examine the in vivo relevance of these findings, tumorigenic cells were injected into the tail vein of immunodeficient mice followed by total body irradiation (TBI). The data obtained show that TBI dramatically enhances tumor cell extravasation and lung metastasis. This pro-metastatic radiation effect was blocked by pre-treating mice with lovastatin, glycyrrhizic acid or NSC23766. TBI of mice prior to tumor cell transplantation also stimulated metastasis, which was again blocked by lovastatin. The data point to a pro-metastatic trans-effect of RT, which likely rests on the endothelial radiation response promoting the extravasation of circulating tumor cells. Administration of the widely used lipid-lowering drug lovastatin prior to irradiation counteracts this process, likely by suppressing Rac1-regulated E-selectin expression following irradiation. The data support the concern that radiation exposure might increase the extravasation of circulating tumor cells and recommend co-administration of lipid-lowering drugs to avoid this adverse effect of ionizing radiation.

Show MeSH
Related in: MedlinePlus