Sema4C通过介导血管新生和巨噬细胞募集调控肿瘤血管生成的研究
摘要
研究背景与目的
乳腺癌是女性最常见的恶性肿瘤之一,据资料统计,发病率占全身各种恶性肿瘤的7%-10%,仅次于宫颈癌,但近年来有超过子宫颈癌的倾向,并呈逐年上升趋势。乳腺周围淋巴管网丰富,其主要转移途径为局部扩散、淋巴转移和血运转移。以往认为血运转移多发生在晚期,这一概念已被否定。研究发现有些早期乳腺癌已有血运转移。癌细胞可经淋巴途径进入静脉,也可直接侵入血循环而致远处转移。最常见的远处转移依次为肺、骨、肝。是否转移在很大程度上影响着患者术后的生存质量,因此,探讨乳腺癌通过血运转移的机制,寻找有效的分子治疗靶标,抑制乳腺癌通过血运转移,成为目前国内外分子肿瘤学研究热点。肿瘤的生长高度依赖于它的血管供应。然而,肿瘤生长需要的养分和氧气往往超过现有脉管系统为它供给的能力。因此,肿瘤的持续生长需要新的血管。这种实体肿瘤诱导的血管生成包括两个相辅相成的过程：发芽血管生成和血管新生。发芽血管生成是局部反应,涉及现有的血管。血管新生,是通过动员和募集骨髓来源细胞形成新的血管。实验室前期研究工作(激光捕获显微切割技术和生物芯片分析)获得乳腺癌组织与正常乳腺组织之间淋巴内皮细胞差异表达的基因Sema4C,并在多种癌组织和对应正常组织中检测Sema4C的表达。本研究旨在探讨Sema4C在多种体外肿瘤细胞系和体内乳腺癌组织中的表达情况,及其在肿瘤生长和肿瘤血管生成中的作用。基于Sema4C在乳腺癌组织中表达异于正常乳腺组织,从而影响乳腺癌微环境而促进肿瘤血管新生和肿瘤生长,促进肿瘤血运转移,因此,通过药物或者遗传手段控制Sema4C功能或其调节通路,将是一个振奋人心的抗乳腺癌生长和血运转移的分子治疗靶点。
方法
收集27株肿瘤细胞系及2株正常永生化细胞系,应用Trizol法抽提总mRNA,荧光实时定量PCR法检测Sema4C的表达；免疫组化EnvisionTM二步法及半定量分析方法检测乳腺癌150例,乳腺增生组织10例中Sema4C的表达,并进行相关临床病理因素分析；采用慢病毒基因干预技术,转染MDA-MB-231细胞,流式筛选后获得带有红色荧光(RFP)稳定封闭SEMA4C基因的细胞株和对照细胞株,检测这两株细胞在裸鼠体内的生长情况；应用MTT法检测两株细胞的生长情况；应用PI染色流式细胞术检测封闭SEMA4C后细胞周期的变化；收集两株细胞上清,应用Transwell体外运动实验检测肿瘤上清对血管内皮细胞和巨噬细胞的趋化；应用三维培养试验观察肿瘤细胞上清对血管内皮细胞形成管样结构能力的改变；将两株细胞上清经RayBiotech细胞因子抗体芯片筛选调控血管生成的细胞因子。
结果
1. Sema4C在29株细胞系中普遍表达,但在肿瘤细胞中的表达普遍高于正常永生化细胞；在上皮性来源的肿瘤细胞株中,侵袭转移能力强的细胞中Sema4C的表达高于侵袭转移能力弱的细胞。
2.免疫组化结果提示乳腺癌中Sema4C的表达高于正常乳腺和乳腺良性病变；并且与肿瘤血管密度高度相关。
3.实时定量PCR和Western blot结果显示,慢病毒转染的细胞株封闭SEMA4C基因的效果稳定,动物体内试验发现,封闭掉SEMA4C后的瘤体生长慢,体积小,瘤周和瘤内血管密度低,巨噬细胞减少,远处转移少。
4.MTT试验结果表明封闭SEMA4C后的MDA-MB-231细胞较对照生长速度明显减慢,光学显微镜下发下细胞形态发生变化,细胞变的肥大、核大、细胞质变少并有空泡形成；PI染色流式细胞术试验结果提示封闭SEMA4C后的细胞出现G2/M期细胞阻滞,Annexin V-FITC/PI-PE细胞凋亡染色结果无统计学差异,但β-半乳糖苷酶染色提示细胞发生衰老。
5.利用人淋巴细胞分离液分离外周血单核细胞,经GM-CSF和IL-4刺激后转化为巨噬细胞,Transwell体外实验提示封闭SEMA4C后的MDA-MB-231细胞上清趋化血管内皮细胞HUVEC和巨噬细胞能力减弱,三维培养试验证明封闭SEMA4C后的231细胞上清减弱了HUVEC的成管能力。
6.收集封闭SEMA4C后的MDA-MB-231细胞和对照MDA-MB-231上清经RayBiotech细胞因子抗体芯片分析发现,封闭SEMA4C后的MDA-MB-231细胞上清中的Angiogenin和CSF-1分泌减少,差异具有统计学意义。
结论
在细胞水平,Sema4C在肿瘤细胞系中表达普遍高于正常细胞系,特别是在乳腺癌中它的表达水平与肿瘤的转移潜能成正比；在组织水平,Sema4C在乳腺癌中的表达高于正常乳腺组织和乳腺良性病变,并且与肿瘤血管密度高度相关。
试验证实,Sema4C通过调控乳腺癌肿瘤细胞自身生长和肿瘤微环境中Angiogenin和CSF-1的表达来调控乳腺癌生长、血管生成、巨噬细胞募集和远处转移。
综上所述,首次发现Sema4C在乳腺癌组织中高表达与肿瘤血管密度高度相关,并且抵抗乳腺癌细胞衰老,促进乳腺癌微环境中Angiogenin和CSF-1分泌来促进肿瘤血管新生和血运转移。因此,Sema4C是一个振奋人心的抗乳腺癌生长和血运转移的分子靶点。
Background and Objective
Breast cancer is the most common malignant tumor in women. According to data about malignant tumor incidences, breast cancer consists of approximately7-10%of total tumor cases, ranking only beneath that of cervical cancer; however, there is an increasing tendency for breast cancer to surpass cervical cancer in the occurrence rate in recent years. The notion that metastasis of tumor cells via vessels has been revised, which is substituted with the finding that breast cancer cell can spread through vascular pathway at the early stage of the cancer development. At their entrance into vessels, tumor cell can subsequently translocate to lung, bone marrow, liver, etc. Since metastasis is a main determinant factor in the diagnosis of tumor patients, finding the efficient therapeutic target for inhibiting metastasis becomes the most interest task for researchers in this prominent field. Tumor growth is highly dependent on its vascular supply. However, tumor growth often exceeds the ability of the existing vasculature to supply it with nutrients and oxygen. Continued tumor growth therefore requires new blood vessels. This induction of angiogenesis by solid tumors encompasses two complementary processes:sprouting angiogenesis and neovascularization. Sprouting angiogenesis is a local response, involving existing blood vessels. Neovascularization, or vasculogenesis, is the de novo formation of new blood vessels through the mobilization and recruitment of bone marrow-derived cells (BMDCs). Our previous data, acquired from laser scanning microscopy and bio-CHIP analysis, showed that the Sema4C gene expression in breast cancer tissues differs from that in normal breast tissues. In this study, the author aimed to investigate the expression pattern of Sema4C in various tumor cell lines and breast cancer tissues, as well as its role in promoting tumor vasculargenesis. In view of the probable role of Sema4C in affecting the tumor vasculargenesis and tumor development, manipulation of a certain target for modulating the Sema4C function will be of considerable interest in the perspective of finding a therapeutic method.
Method
The author tested the Sema4C mRNA expression levels in as much as30tumor cell lines and two other immortalized primary cell lines. The total RNA was extracted using Trizol, and real-time RT-PCR was utilized to measure the mRNA levels of Sema4C. Histopathology based on EnvisionTM two-step method was conducted to detect Sema4C expression in150breast tumor samples and10hypertrophy breast samples in a semi-quantification way. The Sema4C specific shRNA lentiviral particles were used to infect MDA-MB-231cells followed by selection of cells expressing vector RFP, and the shRNA-transduced MDA-MB-231cells were studied for their proliferation using MTT assay in vitro and growth in nude mice in vivo. The alterations in cell cycle reflected by PI staining after depletion of Sema4C was also studied using flow cytometry. A transwell assay was utilized to study the endothelial cell and the macrophage cell migration after stimulated by tumor cell culture supernatant. Supernatants from the two cell lines were selected by the antibody-CHIP for absorption of cytokines (RayBiotech) that can promote vasculargenesis.
Results
1) Sema4C is expressed in the27tumor cell lines. In tumor cells the expression of Sema4C is higher than that in the immortalized cells. In cancer cells generated from origin of epithelial cells, Sema4C is associated with a high invasiveness.2) Histopathology results reveals that Sema4C levels are higher in breast cancers than those in normal tissues and benign lesions.3) Quantitative RT-PCR and Western blot analysis reveals that the depletion of Sema4C in transduced cells is stable and efficient. Depletion of Sema4C by specific shRNA leads to suppression in tumor expansion, low density of tumor vessels, less macrophage infiltration and few metastasis.4) MTT assay reveals that depletion of Sema4C results in inhibition of MDA-MB-231growth. The alterations in cell morphology after depletion of Sema4C are characterized by enlarged cell sizes, giant nucleus, reduced cytoplasm and vacuoles in the cytoplasm. PI staining shows that depletion of Sema4C results in blockage in G2/M transition, although double staining of Annexin V and PI did not show significant apoptosis. In addition, β-galactosidase staining reveals that depletion of Sema4C results in cell senescence.5) The macrophage generated by GM-CSF and IL-4stimulation of the isolated peripheral blood mononuclear cells were studied for the transwell assay. Cell culture supernatant from MDA-MB-231cells depleted of Sema4C can not induce as much cell migration in HUVECs and macrophages as those of normal MDA-MB-231cells.6) The secretion of Angiogenin and CSF-1in supernatant of MDA-MB-231cells after depletion of Sema4C attenuates to low levels as compared with control cells. The detection process is based on the RayBiotech cytokine analysis CHIP.
Conclusion
Sema4C expression is substantially high in tumor cell lines, especially in breast cancer cells, of which the level is in parallel with the potential of metastasis; in tumor samples, the expression level of Sema4C is also higher than that in normal and benign tissues. Our findings suggest that Sema4C regulates breast cancer cell proliferation through modulating the secretion of Angiogenin and CSF-1, which can in turn influence breast cancer development, vascularization, macrophage recruitment and metastasis.
In summary, Sema4C is associated with tumor vessel density, which can prevent breast tumor from aging, and which can promote the secretion of Angiogenin and CSF-1in the microenvironment of tumor foci. These effect imposed on tumor development is conducive to tumor vasculargenesis and metastasis through vessels. Sema4C will be a therapeutic target of antitumor drugs in future.
乳腺癌是女性最常见的恶性肿瘤之一,据资料统计,发病率占全身各种恶性肿瘤的7%-10%,仅次于宫颈癌,但近年来有超过子宫颈癌的倾向,并呈逐年上升趋势。乳腺周围淋巴管网丰富,其主要转移途径为局部扩散、淋巴转移和血运转移。以往认为血运转移多发生在晚期,这一概念已被否定。研究发现有些早期乳腺癌已有血运转移。癌细胞可经淋巴途径进入静脉,也可直接侵入血循环而致远处转移。最常见的远处转移依次为肺、骨、肝。是否转移在很大程度上影响着患者术后的生存质量,因此,探讨乳腺癌通过血运转移的机制,寻找有效的分子治疗靶标,抑制乳腺癌通过血运转移,成为目前国内外分子肿瘤学研究热点。肿瘤的生长高度依赖于它的血管供应。然而,肿瘤生长需要的养分和氧气往往超过现有脉管系统为它供给的能力。因此,肿瘤的持续生长需要新的血管。这种实体肿瘤诱导的血管生成包括两个相辅相成的过程：发芽血管生成和血管新生。发芽血管生成是局部反应,涉及现有的血管。血管新生,是通过动员和募集骨髓来源细胞形成新的血管。实验室前期研究工作(激光捕获显微切割技术和生物芯片分析)获得乳腺癌组织与正常乳腺组织之间淋巴内皮细胞差异表达的基因Sema4C,并在多种癌组织和对应正常组织中检测Sema4C的表达。本研究旨在探讨Sema4C在多种体外肿瘤细胞系和体内乳腺癌组织中的表达情况,及其在肿瘤生长和肿瘤血管生成中的作用。基于Sema4C在乳腺癌组织中表达异于正常乳腺组织,从而影响乳腺癌微环境而促进肿瘤血管新生和肿瘤生长,促进肿瘤血运转移,因此,通过药物或者遗传手段控制Sema4C功能或其调节通路,将是一个振奋人心的抗乳腺癌生长和血运转移的分子治疗靶点。
方法
收集27株肿瘤细胞系及2株正常永生化细胞系,应用Trizol法抽提总mRNA,荧光实时定量PCR法检测Sema4C的表达；免疫组化EnvisionTM二步法及半定量分析方法检测乳腺癌150例,乳腺增生组织10例中Sema4C的表达,并进行相关临床病理因素分析；采用慢病毒基因干预技术,转染MDA-MB-231细胞,流式筛选后获得带有红色荧光(RFP)稳定封闭SEMA4C基因的细胞株和对照细胞株,检测这两株细胞在裸鼠体内的生长情况；应用MTT法检测两株细胞的生长情况；应用PI染色流式细胞术检测封闭SEMA4C后细胞周期的变化；收集两株细胞上清,应用Transwell体外运动实验检测肿瘤上清对血管内皮细胞和巨噬细胞的趋化；应用三维培养试验观察肿瘤细胞上清对血管内皮细胞形成管样结构能力的改变；将两株细胞上清经RayBiotech细胞因子抗体芯片筛选调控血管生成的细胞因子。
结果
1. Sema4C在29株细胞系中普遍表达,但在肿瘤细胞中的表达普遍高于正常永生化细胞；在上皮性来源的肿瘤细胞株中,侵袭转移能力强的细胞中Sema4C的表达高于侵袭转移能力弱的细胞。
2.免疫组化结果提示乳腺癌中Sema4C的表达高于正常乳腺和乳腺良性病变；并且与肿瘤血管密度高度相关。
3.实时定量PCR和Western blot结果显示,慢病毒转染的细胞株封闭SEMA4C基因的效果稳定,动物体内试验发现,封闭掉SEMA4C后的瘤体生长慢,体积小,瘤周和瘤内血管密度低,巨噬细胞减少,远处转移少。
4.MTT试验结果表明封闭SEMA4C后的MDA-MB-231细胞较对照生长速度明显减慢,光学显微镜下发下细胞形态发生变化,细胞变的肥大、核大、细胞质变少并有空泡形成；PI染色流式细胞术试验结果提示封闭SEMA4C后的细胞出现G2/M期细胞阻滞,Annexin V-FITC/PI-PE细胞凋亡染色结果无统计学差异,但β-半乳糖苷酶染色提示细胞发生衰老。
5.利用人淋巴细胞分离液分离外周血单核细胞,经GM-CSF和IL-4刺激后转化为巨噬细胞,Transwell体外实验提示封闭SEMA4C后的MDA-MB-231细胞上清趋化血管内皮细胞HUVEC和巨噬细胞能力减弱,三维培养试验证明封闭SEMA4C后的231细胞上清减弱了HUVEC的成管能力。
6.收集封闭SEMA4C后的MDA-MB-231细胞和对照MDA-MB-231上清经RayBiotech细胞因子抗体芯片分析发现,封闭SEMA4C后的MDA-MB-231细胞上清中的Angiogenin和CSF-1分泌减少,差异具有统计学意义。
结论
在细胞水平,Sema4C在肿瘤细胞系中表达普遍高于正常细胞系,特别是在乳腺癌中它的表达水平与肿瘤的转移潜能成正比；在组织水平,Sema4C在乳腺癌中的表达高于正常乳腺组织和乳腺良性病变,并且与肿瘤血管密度高度相关。
试验证实,Sema4C通过调控乳腺癌肿瘤细胞自身生长和肿瘤微环境中Angiogenin和CSF-1的表达来调控乳腺癌生长、血管生成、巨噬细胞募集和远处转移。
综上所述,首次发现Sema4C在乳腺癌组织中高表达与肿瘤血管密度高度相关,并且抵抗乳腺癌细胞衰老,促进乳腺癌微环境中Angiogenin和CSF-1分泌来促进肿瘤血管新生和血运转移。因此,Sema4C是一个振奋人心的抗乳腺癌生长和血运转移的分子靶点。
Background and Objective
Breast cancer is the most common malignant tumor in women. According to data about malignant tumor incidences, breast cancer consists of approximately7-10%of total tumor cases, ranking only beneath that of cervical cancer; however, there is an increasing tendency for breast cancer to surpass cervical cancer in the occurrence rate in recent years. The notion that metastasis of tumor cells via vessels has been revised, which is substituted with the finding that breast cancer cell can spread through vascular pathway at the early stage of the cancer development. At their entrance into vessels, tumor cell can subsequently translocate to lung, bone marrow, liver, etc. Since metastasis is a main determinant factor in the diagnosis of tumor patients, finding the efficient therapeutic target for inhibiting metastasis becomes the most interest task for researchers in this prominent field. Tumor growth is highly dependent on its vascular supply. However, tumor growth often exceeds the ability of the existing vasculature to supply it with nutrients and oxygen. Continued tumor growth therefore requires new blood vessels. This induction of angiogenesis by solid tumors encompasses two complementary processes:sprouting angiogenesis and neovascularization. Sprouting angiogenesis is a local response, involving existing blood vessels. Neovascularization, or vasculogenesis, is the de novo formation of new blood vessels through the mobilization and recruitment of bone marrow-derived cells (BMDCs). Our previous data, acquired from laser scanning microscopy and bio-CHIP analysis, showed that the Sema4C gene expression in breast cancer tissues differs from that in normal breast tissues. In this study, the author aimed to investigate the expression pattern of Sema4C in various tumor cell lines and breast cancer tissues, as well as its role in promoting tumor vasculargenesis. In view of the probable role of Sema4C in affecting the tumor vasculargenesis and tumor development, manipulation of a certain target for modulating the Sema4C function will be of considerable interest in the perspective of finding a therapeutic method.
Method
The author tested the Sema4C mRNA expression levels in as much as30tumor cell lines and two other immortalized primary cell lines. The total RNA was extracted using Trizol, and real-time RT-PCR was utilized to measure the mRNA levels of Sema4C. Histopathology based on EnvisionTM two-step method was conducted to detect Sema4C expression in150breast tumor samples and10hypertrophy breast samples in a semi-quantification way. The Sema4C specific shRNA lentiviral particles were used to infect MDA-MB-231cells followed by selection of cells expressing vector RFP, and the shRNA-transduced MDA-MB-231cells were studied for their proliferation using MTT assay in vitro and growth in nude mice in vivo. The alterations in cell cycle reflected by PI staining after depletion of Sema4C was also studied using flow cytometry. A transwell assay was utilized to study the endothelial cell and the macrophage cell migration after stimulated by tumor cell culture supernatant. Supernatants from the two cell lines were selected by the antibody-CHIP for absorption of cytokines (RayBiotech) that can promote vasculargenesis.
Results
1) Sema4C is expressed in the27tumor cell lines. In tumor cells the expression of Sema4C is higher than that in the immortalized cells. In cancer cells generated from origin of epithelial cells, Sema4C is associated with a high invasiveness.2) Histopathology results reveals that Sema4C levels are higher in breast cancers than those in normal tissues and benign lesions.3) Quantitative RT-PCR and Western blot analysis reveals that the depletion of Sema4C in transduced cells is stable and efficient. Depletion of Sema4C by specific shRNA leads to suppression in tumor expansion, low density of tumor vessels, less macrophage infiltration and few metastasis.4) MTT assay reveals that depletion of Sema4C results in inhibition of MDA-MB-231growth. The alterations in cell morphology after depletion of Sema4C are characterized by enlarged cell sizes, giant nucleus, reduced cytoplasm and vacuoles in the cytoplasm. PI staining shows that depletion of Sema4C results in blockage in G2/M transition, although double staining of Annexin V and PI did not show significant apoptosis. In addition, β-galactosidase staining reveals that depletion of Sema4C results in cell senescence.5) The macrophage generated by GM-CSF and IL-4stimulation of the isolated peripheral blood mononuclear cells were studied for the transwell assay. Cell culture supernatant from MDA-MB-231cells depleted of Sema4C can not induce as much cell migration in HUVECs and macrophages as those of normal MDA-MB-231cells.6) The secretion of Angiogenin and CSF-1in supernatant of MDA-MB-231cells after depletion of Sema4C attenuates to low levels as compared with control cells. The detection process is based on the RayBiotech cytokine analysis CHIP.
Conclusion
Sema4C expression is substantially high in tumor cell lines, especially in breast cancer cells, of which the level is in parallel with the potential of metastasis; in tumor samples, the expression level of Sema4C is also higher than that in normal and benign tissues. Our findings suggest that Sema4C regulates breast cancer cell proliferation through modulating the secretion of Angiogenin and CSF-1, which can in turn influence breast cancer development, vascularization, macrophage recruitment and metastasis.
In summary, Sema4C is associated with tumor vessel density, which can prevent breast tumor from aging, and which can promote the secretion of Angiogenin and CSF-1in the microenvironment of tumor foci. These effect imposed on tumor development is conducive to tumor vasculargenesis and metastasis through vessels. Sema4C will be a therapeutic target of antitumor drugs in future.
引文
1. Comeau, M. R. et al. A poxvirus-encoded semaphoring induces cytokine production from monocytes and binds to a novel cellular semaphorin receptor, VESPR [J]. Immunity,1998,8:473-482
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13.黄绍艳Sema4C在卵巢上皮性癌中的表达及意义(天津医科大学).(2009).
14.叶双梅信号素分子4C在食管癌、胃癌和直肠癌中的表达及其意义。中华医学杂志,2012,92(28)。
15.陈颖Semaphorin4C在乳腺癌子宫内膜癌及前列腺癌中的表达及意义。中国肿瘤临床,2010,37(9)。
16.陈颖siRNA抑制Sema4C基因表达对人乳腺癌细胞恶性行为的影响。中国肿瘤临床,2010,37(16)。
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11.黄绍艳Sema4C在卵巢上皮性癌中的表达及意义(天津医科大学).(2009).
12.叶双梅信号素分子4C在食管癌、胃癌和直肠癌中的表达及其意义。中华医学杂志,2012,92(28)。
13.陈颖Semaphorin4C在乳腺癌子宫内膜癌及前列腺癌中的表达及意义。中国肿瘤临床,2010,37(9)。
14.陈颖siRNA抑制Sema4C基因表达对人乳腺癌细胞恶性行为的影响。中国肿瘤临床,2010,37(16)。
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10.陈颖siRNA抑制Sema4C基因表达对人乳腺癌细胞恶性行为的影响。中国肿瘤临床,2010,37(16)。
11.叶双梅信号素分子4C在食管癌、胃癌和直肠癌中的表达及其意义。中华医学杂志,2012,92(28)。
12.陈颖Semaphorin4C在乳腺癌子宫内膜癌及前列腺癌中的表达及意义。中国肿瘤临床,2010,37(9)。
13.黄绍艳Sema4C在卵巢上皮性癌中的表达及意.(2009).
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13.陈颖Semaphorin4C在乳腺癌子宫内膜癌及前列腺癌中的表达及意义。中国肿瘤临床,2010,37(9)。
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12.陈颖Semaphorin4C在乳腺癌子宫内膜癌及前列腺癌中的表达及意义。中国肿瘤临床,2010,37(9)。
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