前列腺癌冷冻消融后免疫微环境改变的实验研究
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摘要
前列腺癌是男性泌尿生殖系统常见的恶性肿瘤之一。随着我国社会的发展和进步，人口老龄化、城市化、膳食结构西方化、检测技术进步与诊断水平的提高，我国前列腺癌发病率呈迅速上升趋势。由于缺乏有效的筛查机制，我国前列腺癌病例构成以中晚期为主。目前对于中晚期前列腺癌，临床尚无有效治疗方法，如何控制其转移，延长患者生存时间和提高生存质量，是当今国内外亟待解决的重大课题之一。随着临床冷冻外科技术的发展和直肠超声的应用，冷冻消融已成为治疗前列腺癌的有效方法。冷冻消融在局部控制原位肿瘤的同时，释放大量肿瘤抗原，诱导机体产生特异性抗肿瘤免疫反应。深入探讨冷冻免疫反应相关机制，寻求增强冷冻免疫反应的有效方法，有望为中晚期前列腺癌的综合治疗提供新的线索。
多不饱和脂肪酸—花生四烯酸（AA）作为一种促炎物质参与肿瘤发生与发展。环氧化酶-2（COX-2）是花生四烯酸代谢过程中的关键酶，前列腺素E2（PGE2）是其重要代谢产物之一，二者在前列腺癌的发生发展中发挥着重要作用。近年来，研究认为COX-2/PGE2在肿瘤免疫逃逸中发挥了重要作用，有望成为免疫调节的分子靶点。因此，COX-2/PGE2是否介导和调节冷冻免疫反应，从而影响肿瘤免疫微环境，是值得我们深入研究和探讨的重大课题之一。
本研究集营养与食品卫生学、卫生毒理学、肿瘤学、免疫学、基础医学等多学科理论和方法，以多不饱和脂肪酸—花生四烯酸代谢通路为切入点，观察了花生四烯酸代谢在肿瘤免疫微环境调节中的作用。在深入探讨冷冻免疫反应相关机制的基础上寻找新的线索，观察冷冻消融后COX-2/PGE2变化及肿瘤免疫微环境的改变，分析相关分子机制，进一步丰富冷冻免疫反应相关理论，为单一冷冻治疗模式向综合治疗模式的转变提供理论基础，为寻求冷冻免疫调节的分子靶点提供新的思路，试图为前列腺癌的综合治疗和早期预防提供新的理论和实践依据。
Prostate cancer (PCa) is the most common malignant tumor in male urogenital system. Recently, the incidence of prostate cancer shows a rising trend in China. Because of the absentce of effective screening schedule, middle-late prostate cancer is the majority in China. For moderate or advanced prostate cancer, little effective treatment is available. How to control the tumor metastasis; improve the overall survival (OS) and quality of life (QOL)? It is still an important issue at home and abroad. With the application and development of cryosurgery and transrecctal ultrasound, cryoablation is an important alternative in the treatment of prostate cancer. Cryoablation can be used as primary treatment or salvage treatment for the failure of radiotherapy or chemotherapy, showing a vital value in clinical treatment.
Besides of locally controlling the tumors, cryoablation can induce tumor cells to release a huge amount of tumor antigens, which can result in the specific anti-tumor immune response. Furthermore, going deeply into the related mechanisms of cryoablation immune response, and seeking a method for enhacing the cryoablation immune response could provide a novel strategy for the comprehensive treatment of moderate or advanced prostate cancer.
Regular T cell (Treg, TR) is the main inhibitive immune cell involed in tumor immunosurveillance escape. Exploring the change of immune microenvironment including Treg after cryoablation and illustrating the regulation mechanisms will be helpful for futher inhibiting immune suppressor cells and enhancing the anti-tumor immune response. It's also important for the combination of tumor immunotherapy and other treatments.
As a pro-inflammatory material, arachidonic acid is involved in the development of cancers. Cyclooxygenase-2(COX-2) is the main limiting velocity enzyme in the metabolism of arachidonic acid. And prostaglandin E2(PGE2) is one of the important metabolic products. Both of them play an important role in the progression of prostate cancer. Recently, a wide variety of evidences showed that COX-2/PGE2was involed in the tumor immunosurveillance escape. It's supposed to be a target of immunosurveillance regulation. The tumor-drived CO-2/PGE2may induce the non-regulatory T cells to transform into Tregs, and cryoablation can result in the variations of immune microenvironment. Therefore, it's an important issue for us to explore the effects of cryoablation on the COX-2/PGE2signal and tumor immune microenvironment in vivo and in vitro.
Objectives:To confirm the efficacy of cryoablation for prostate cancer, observe the immune microenvironment viriation after cryoablation, analyze the change of PGE2and the related fators during cryoablation, explore the possible mechanisms of COX-2/PGE2involed in the immune regulation, and provide the decision basis for clinical treatment.
Methods:Firstly, we observed the changes of tumor microenvironment after cryoablation in vivo and in vitro. Then we adopted enzyme linked immunosorbent assay (ELISA) to test the plasma PGE2, TGF-β1and IL-2in proste cancer patients and RM-1tumor-bearing mice. Western blot assay was used to test the E-cadherin, MMP-2and MMP-9protein changes after cryoablation, Transwell matrigel invasion assay and migration experiments were adopted to evaluate the adhesive and invasive abilities of tumor cells. We also detected the PGE2, TGF-β and IL-2in the culture supernatant of PC-3cell line. Realtime PCR and western blot was used to compare the mRNA and protein change of COX-2in PC-3cell line before or after cryoablation. The mixed culture of tumor cell and human peripheral blood lymphocyte was used to imitate the vivo environments. Then we detected the PGE2, TGF-β and IL-2in the culture supernatant by ELISA, evaluated the Foxp3+T lymphocyte proportion by flow cytometry, and compared the Foxp3mRNA and protein of T lymphocyte by realtime-PCR and western blot. All in all, we evaluated the effect on the Treg cell in the tumor environments by cryoablation directly.
Quantity-One software was used to analyze the gray value of the stip. Graphpad prim5, Excel and Adobe Photoshop were used to draw and operate the figures. SPSS16.0software was used to analysis. For continuous variables, x±S was used to depict their central tendency. Paried t test was used to compare their differences between two paried groups. T test was used to compare their differences between two independent groups. For the comparison among several groups, variance analysis or rank sum test was used. The overall survival between two groups was analyzed by Kaplan-Meier.P＜0.05was respresentive of statistical significance.
Results:The positive rate of COX-2was77.2%in the pathological tissue of prostate cancer.33cases showed a high-expressed, while24cases were loew-expressed. There was no siginificant difference in the overall survival between two goups (high-expressed group and low-expressed group). One month after cryoablation, the peripheral CD4+T cell group and NK cell was higher than before the operation, while the Treg cell was lower than before. CD8+T cell was not different before and afer cryoablation. Three days after cryoablation, the plasma PGE2declined obviously, but showed a recovery at7day. However, the plasma TGF-β1was lower at3day and7day than before, with a step by step decline trendency. For IL-2, the plasma level ascended at3day but descended at7day, with a trendecy of "saddle pattern".7day and14d after cryoablation, in prosate cancer-beared RM-1mice, the plasma PGE2and TGF-β1level declined significantly, but the IL-2level rised. The Treg proportion of spleen in RM-1model was significantly declined after cryoablation. The exotic celecoxib, with a dose of25μM and50μM, was added into the culture medium. Then the PGE2level in the cell culture supernatant decreased siginificantly. However, the TGF-β1in the cell culture supernatant was not affected by the exotic celecoxib. After two freezes thawing cycles, the prosate cancer cell line (PC-3cell) showed a siginificant increase in the proportion of apoptosis and necrosis. The invasion and migration abilities of PC-3cell line declined after cryoablation. Correspondingly, the E-cadherin protein was up-regulated, while the MMP-2and MMP-9proteins were down-regulated, which resulted in a declined invasion and migration ablities of tumor cell. Similarly, the mRNA and protein level of COX-2was also declined. After cryoablation, the PGE2and TGF-β1level in the PC-3cell culture supernatant decreased significantly. The co-cultrue of cryoablated PC-3cell and T cell didn't show a significant effect on the T cell survival and apopotosis. After co-cultrue, the number of Foxp3positive T lymphocyte was increased, and the mRNA and protein level of Foxp3was higher than that in co-cultrue of control PC-3cell and T cell. The PGE2level in the culture supernatant of co-cultrue of cryoablated PC-3cell and T cell was lower than that in co-cultrue of control PC-3cell and T cell. However, the IL-2showed a contrary change. The TGF-β1level in the co-cultrue system was not different between cryoablated PC-3cell group and control PC-3cell group.
Conclusions:
(1) The rate of apoptosis/necrosis increased sharply after cryoablation. The invasion and migirtion ablility was weakend by cryoablation, with an upregualtion of E-cadherin and a downregulation of MMP-2and MMP-9.(2) The peripheral CD4+T cell group and NK cell were higher than before cryoablation, while the Treg cell was lower than before.(3) The COX-2mRNA and protein and PGE2concerntration declined obviously after cryoablation, which reversed the immune inhibition by PGE2.(4) Cryoablation may suppress the TGF-β1production and weaken its effect on IL-2through COX-2/PGE2pathway. Cryoablation also may lead to the decline of Treg cells through the pathway, which play a role on the tumor immune microenvironments.
多不饱和脂肪酸—花生四烯酸（AA）作为一种促炎物质参与肿瘤发生与发展。环氧化酶-2（COX-2）是花生四烯酸代谢过程中的关键酶，前列腺素E2（PGE2）是其重要代谢产物之一，二者在前列腺癌的发生发展中发挥着重要作用。近年来，研究认为COX-2/PGE2在肿瘤免疫逃逸中发挥了重要作用，有望成为免疫调节的分子靶点。因此，COX-2/PGE2是否介导和调节冷冻免疫反应，从而影响肿瘤免疫微环境，是值得我们深入研究和探讨的重大课题之一。
本研究集营养与食品卫生学、卫生毒理学、肿瘤学、免疫学、基础医学等多学科理论和方法，以多不饱和脂肪酸—花生四烯酸代谢通路为切入点，观察了花生四烯酸代谢在肿瘤免疫微环境调节中的作用。在深入探讨冷冻免疫反应相关机制的基础上寻找新的线索，观察冷冻消融后COX-2/PGE2变化及肿瘤免疫微环境的改变，分析相关分子机制，进一步丰富冷冻免疫反应相关理论，为单一冷冻治疗模式向综合治疗模式的转变提供理论基础，为寻求冷冻免疫调节的分子靶点提供新的思路，试图为前列腺癌的综合治疗和早期预防提供新的理论和实践依据。
Prostate cancer (PCa) is the most common malignant tumor in male urogenital system. Recently, the incidence of prostate cancer shows a rising trend in China. Because of the absentce of effective screening schedule, middle-late prostate cancer is the majority in China. For moderate or advanced prostate cancer, little effective treatment is available. How to control the tumor metastasis; improve the overall survival (OS) and quality of life (QOL)? It is still an important issue at home and abroad. With the application and development of cryosurgery and transrecctal ultrasound, cryoablation is an important alternative in the treatment of prostate cancer. Cryoablation can be used as primary treatment or salvage treatment for the failure of radiotherapy or chemotherapy, showing a vital value in clinical treatment.
Besides of locally controlling the tumors, cryoablation can induce tumor cells to release a huge amount of tumor antigens, which can result in the specific anti-tumor immune response. Furthermore, going deeply into the related mechanisms of cryoablation immune response, and seeking a method for enhacing the cryoablation immune response could provide a novel strategy for the comprehensive treatment of moderate or advanced prostate cancer.
Regular T cell (Treg, TR) is the main inhibitive immune cell involed in tumor immunosurveillance escape. Exploring the change of immune microenvironment including Treg after cryoablation and illustrating the regulation mechanisms will be helpful for futher inhibiting immune suppressor cells and enhancing the anti-tumor immune response. It's also important for the combination of tumor immunotherapy and other treatments.
As a pro-inflammatory material, arachidonic acid is involved in the development of cancers. Cyclooxygenase-2(COX-2) is the main limiting velocity enzyme in the metabolism of arachidonic acid. And prostaglandin E2(PGE2) is one of the important metabolic products. Both of them play an important role in the progression of prostate cancer. Recently, a wide variety of evidences showed that COX-2/PGE2was involed in the tumor immunosurveillance escape. It's supposed to be a target of immunosurveillance regulation. The tumor-drived CO-2/PGE2may induce the non-regulatory T cells to transform into Tregs, and cryoablation can result in the variations of immune microenvironment. Therefore, it's an important issue for us to explore the effects of cryoablation on the COX-2/PGE2signal and tumor immune microenvironment in vivo and in vitro.
Objectives:To confirm the efficacy of cryoablation for prostate cancer, observe the immune microenvironment viriation after cryoablation, analyze the change of PGE2and the related fators during cryoablation, explore the possible mechanisms of COX-2/PGE2involed in the immune regulation, and provide the decision basis for clinical treatment.
Methods:Firstly, we observed the changes of tumor microenvironment after cryoablation in vivo and in vitro. Then we adopted enzyme linked immunosorbent assay (ELISA) to test the plasma PGE2, TGF-β1and IL-2in proste cancer patients and RM-1tumor-bearing mice. Western blot assay was used to test the E-cadherin, MMP-2and MMP-9protein changes after cryoablation, Transwell matrigel invasion assay and migration experiments were adopted to evaluate the adhesive and invasive abilities of tumor cells. We also detected the PGE2, TGF-β and IL-2in the culture supernatant of PC-3cell line. Realtime PCR and western blot was used to compare the mRNA and protein change of COX-2in PC-3cell line before or after cryoablation. The mixed culture of tumor cell and human peripheral blood lymphocyte was used to imitate the vivo environments. Then we detected the PGE2, TGF-β and IL-2in the culture supernatant by ELISA, evaluated the Foxp3+T lymphocyte proportion by flow cytometry, and compared the Foxp3mRNA and protein of T lymphocyte by realtime-PCR and western blot. All in all, we evaluated the effect on the Treg cell in the tumor environments by cryoablation directly.
Quantity-One software was used to analyze the gray value of the stip. Graphpad prim5, Excel and Adobe Photoshop were used to draw and operate the figures. SPSS16.0software was used to analysis. For continuous variables, x±S was used to depict their central tendency. Paried t test was used to compare their differences between two paried groups. T test was used to compare their differences between two independent groups. For the comparison among several groups, variance analysis or rank sum test was used. The overall survival between two groups was analyzed by Kaplan-Meier.P＜0.05was respresentive of statistical significance.
Results:The positive rate of COX-2was77.2%in the pathological tissue of prostate cancer.33cases showed a high-expressed, while24cases were loew-expressed. There was no siginificant difference in the overall survival between two goups (high-expressed group and low-expressed group). One month after cryoablation, the peripheral CD4+T cell group and NK cell was higher than before the operation, while the Treg cell was lower than before. CD8+T cell was not different before and afer cryoablation. Three days after cryoablation, the plasma PGE2declined obviously, but showed a recovery at7day. However, the plasma TGF-β1was lower at3day and7day than before, with a step by step decline trendency. For IL-2, the plasma level ascended at3day but descended at7day, with a trendecy of "saddle pattern".7day and14d after cryoablation, in prosate cancer-beared RM-1mice, the plasma PGE2and TGF-β1level declined significantly, but the IL-2level rised. The Treg proportion of spleen in RM-1model was significantly declined after cryoablation. The exotic celecoxib, with a dose of25μM and50μM, was added into the culture medium. Then the PGE2level in the cell culture supernatant decreased siginificantly. However, the TGF-β1in the cell culture supernatant was not affected by the exotic celecoxib. After two freezes thawing cycles, the prosate cancer cell line (PC-3cell) showed a siginificant increase in the proportion of apoptosis and necrosis. The invasion and migration abilities of PC-3cell line declined after cryoablation. Correspondingly, the E-cadherin protein was up-regulated, while the MMP-2and MMP-9proteins were down-regulated, which resulted in a declined invasion and migration ablities of tumor cell. Similarly, the mRNA and protein level of COX-2was also declined. After cryoablation, the PGE2and TGF-β1level in the PC-3cell culture supernatant decreased significantly. The co-cultrue of cryoablated PC-3cell and T cell didn't show a significant effect on the T cell survival and apopotosis. After co-cultrue, the number of Foxp3positive T lymphocyte was increased, and the mRNA and protein level of Foxp3was higher than that in co-cultrue of control PC-3cell and T cell. The PGE2level in the culture supernatant of co-cultrue of cryoablated PC-3cell and T cell was lower than that in co-cultrue of control PC-3cell and T cell. However, the IL-2showed a contrary change. The TGF-β1level in the co-cultrue system was not different between cryoablated PC-3cell group and control PC-3cell group.
Conclusions:
(1) The rate of apoptosis/necrosis increased sharply after cryoablation. The invasion and migirtion ablility was weakend by cryoablation, with an upregualtion of E-cadherin and a downregulation of MMP-2and MMP-9.(2) The peripheral CD4+T cell group and NK cell were higher than before cryoablation, while the Treg cell was lower than before.(3) The COX-2mRNA and protein and PGE2concerntration declined obviously after cryoablation, which reversed the immune inhibition by PGE2.(4) Cryoablation may suppress the TGF-β1production and weaken its effect on IL-2through COX-2/PGE2pathway. Cryoablation also may lead to the decline of Treg cells through the pathway, which play a role on the tumor immune microenvironments.
引文
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