缺氧在卵巢癌血管生成拟态形成中的作用研究
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摘要
卵巢癌是女性生殖器官三大恶性肿瘤之一,死亡率居妇科恶性肿瘤首位,预后差。血管生成拟态(vasculogenic mimicry, VM)是大多数高度恶性肿瘤组织内普遍存在的一种功能性微循环形式,指具有可塑性的肿瘤细胞在没有内皮细胞参与的情况下,通过基质重塑和自身变形形成的微循环管道。血管生成拟态的存在也使传统的肿瘤抗血管治疗难以彻底阻断肿瘤血供,无法有效改善患者的生存率。VM是是肿瘤可塑性的一种表现,目前关于其诱导肿瘤细胞可塑性出现的分子机制仍不清楚。缺氧是肿瘤血管生成的主要诱导因素,且缺氧微环境普遍存在于快速增殖的实性肿瘤内,因而我们考虑缺氧也极可能是诱导肿瘤细胞可塑性,形成VM的重要因素之一。
目的
本研究旨在探讨缺氧微环境在肿瘤血管生成拟态形成中的作用,及缺氧促进肿瘤细胞形成VM的可能的分子机制。探究缺氧微环境下肿瘤细胞形成VM的分子机制有助于完善和发展VM理论；这对丰富肿瘤血管生成理论的研究具有重要意义,同时对临床抗肿瘤治疗提供了靶点。
方法
1)首先对前期实验中收集的来自天津医科大学附属肿瘤医院71例经手术切除且随访资料完整的卵巢癌临床标本进行HIF-1α、EMT表征蛋白E-cadherin、 vimentin及EMT调控蛋白Twist1、Snail、Slug及血管内皮相关蛋白VE-cadherin、FLT-1、FLK-1的免疫组织化学染色。重点观察HIF-1α与E-cadherin、vimentin及VM在同一例卵巢癌标本的连续性组织切片上的表达定位之间的关系。
2)构建体外三维培养模型,观察是否缺氧微环境促进了VM的形成。细胞功能学实验方法探究缺氧与肿瘤细胞的迁移、侵袭和三维管道化形成能力之间的关系。
3)应用RT-PCR、Western Blot、免疫荧光实验从蛋白和：mRNA水平检测E-cadherin, vimentin在缺氧与常氧环境下的表达情况,探究是否缺氧诱导肿瘤细胞发生了EMT,从而促进VM的形成。
4) Western Blot检测VM形成关键蛋白VE-cadherin在常氧环境和缺氧环境下表达的差异。
5)明胶酶谱法分析缺氧对基质金属蛋白酶MMP-2和MMP-9活性的影响。
结果
1)HIF-1α蛋白与血管生成拟态的形成有关71例卵巢癌中HIF-1α的阳性表达率为39.44%(28/71)。VM阳性组HIF-1α的阳性表达率为61.11%(11/18)；VM阴性组HIF-1α的阳性表达率为32.08%(17/53)。 HIF-1α在VM阴性组和VM阳性组阳性表达率的差别具有统计学意义。HIF-1α蛋白定位于卵巢癌细胞的胞核内,呈棕黄色颗粒。HIF-1α阳性细胞簇在肿瘤浸润边缘、坏死区及新生血管的周围最为密集。
2)体外三维培养证实缺氧促进了卵巢癌细胞血管生成拟态的形成,并增强了卵巢癌细胞的侵袭和迁移能力。
Matrigel三维培养模型上发现与常氧组相比,缺氧组卵巢癌细胞形成VM的时间较早,结构较复杂。OVCAR3主要形成管状型血管生成拟态,SKOV3主要形成基质型血管生成拟态。Transwell小室体外侵袭实验发现给予CoCl2缺氧处理24小时后,与常氧组相比,缺氧组穿膜细胞数增多,统计结果显示差别具有统计学意义。迁移实验发现给予CoCl2缺氧处理24小时后,与常氧组相比,缺氧组迁移细胞数较多,差别具有统计学意义。缺氧处理48小时后卵巢癌SKOV3和OVCAR3细胞MMP-2活性比常氧状态高,进一步证明缺氧情况下卵巢癌的侵袭性增强。
3)缺氧诱导EMT发生,是血管生成拟态形成的内在机制
在同一例标本的连续性组织切片上分析VM阳性组与阴性组中HIF-1α与E-cadherin, vimentin的表达定位之间的关系,发现在61%(11/18)VM阳性组HIF-1α高表达时,vimentin也同时高表达,而E-cadherin低表达。而VM阴性组不存在这种对应关系,即在VM阴性组HIF-1α高表达时,没发现这种对应关系的存在。且Twist、Slug蛋白在VM阴性组和VM阳性组阳性表达率间的差别具有统计学意义,VM阳性组表达较高。表明缺氧、EMT及VM三者间存在密切关系。
体外实验证实SKOV3、OVCAR3细胞在CoCl2缺氧48小时细胞均出现明显EMT样形态变化,转变成纤维母细胞样形态,出现多角伪足,细胞之间的粘附性降低,细胞核呈现团块状或固缩状结构。
细胞免疫荧光、Westernblot及RT-PCR检测常氧环境下和缺氧环境下细胞的蛋白和mRNA表达证实缺氧环境下卵巢癌细胞SKOV3、OVCAR3中vimentin蛋白及1nRNA水平均上调表达,E-cadherin表达显著下调。以上结果进一步证实缺氧微环境下卵巢癌细胞通过发生EMT样可塑性转变,促进了血管生成拟态的形成。
4)VM形成的关键蛋白VE-cadherin在缺氧微环境下表达升高在人卵巢癌石蜡标本上初步证实具有VM的卵巢癌高表达VE-cadherin蛋白,且体外Westernblot检测发现在缺氧微环境下,人卵巢癌细胞上调VM形成关键蛋白VE-cadherin的表达。
结论
1)缺氧诱导因子HIF-1α与血管生成拟态有关,促进了卵巢癌细胞血管生成拟态的形成。
2)缺氧可诱导EMT发生,是血管生成拟态形成的内在机制之一。
3)缺氧增强了卵巢癌细胞的侵袭和迁移性。
4)缺氧促进了VM形成的关键蛋白VE-cadherin表达上调。
Epithelia ovarian cancer has the highest mortality rate of all gynecological malignancies, which reflects the fact that most patients are diagnosed with advanced cancer. Vasculogenic mimicry describes the ability of aggressive cancer cells to form vasculogenic-like networks in vitro in the absence of endothelial cells or fibroblasts, concomitant with their expressions of vascular cell-associated molecules. Vasculogenic mimicry has now been shown to occur in many different aggressive cancers including ovarian cancers.
The hypoxic microenvironment of tumors results in changes in metabolism, angiogenesis and survival of the cells that are orchestrated by HIF-1α, and depending on tissue specificity. Hypoxia contributes to the progression of a variety of cancers by activating adaptive transcriptional programs that promote cell survival, motility and tumor angiogenesis. Given that HIF-1α has been found to be a crucial inducer contributing to tumor EMT, it is of great interest to examine the role of HIF-1α in VM formation in ovarian cancers. Although the importance of hypoxia and subsequent hypoxia-inducible factor-1α (HIF-1α) activation in tumor angiogenesis is well known, their role in the regulation of vasculogenic mimicry is unclear.
Purpose:
The study aims to investigate the effect of hypoxia on VM formation in ovarian cancer and to explore possible mechanism involved. Exploring the growth-promoting mechanisms of the tumor microenvironment will enhance our understanding of cancer biology and may identify new therapeutic approaches.
Methods:
1) Through the Tumor Tissue Bank of Tianjin Cancer Hospital,71ovarian cancer patients with detailed pathologic and clinical information were selected. Expression of HIF-1α protein was studied by immunohistochemistry in71specimens of epithelial ovarian cancers. To explore the potential mechanism, we examined the expressions of E-cadherin, vimentin, Twistl, Slug, Snail and VE-cadherin, FLT-1, FLK-1, and studied E-cadherin, vimentin topological correlation with HIF-la in VM-positive human ovarian cancers.
2) A well-established model of Three-dimensional Matrigel culture in vitro was used to compare vasculogenic mimicry formation under hypoxia and normoxia using two ovarian cancer cell lines, SKOV3and OVCAR3. Transwell invasion assay and migration assay were performed to evaluate the effect of hypoxia on cell motility and invasion.
3) The expression levels of HIF-la and E-cadherin, vimentin following hypoxia and normoxia were assessed using quantitative PCR and western blot. Immunofluorescence microscopy staining was performed to confirm the effect of hypoxia on the protein expressions of E-cadherin and vimentin.
4) The expression levels of VE-cadherin following hypoxia and normoxia were assessed using western blot.
5) Zymography assays were performed to detect the effect of hypoxia on the activity of MMP-2and MMP-9.
Results:
1) VM present in Ovarian Cancer associated with HIF-la expression. VM was detected in18out of71Ovarian Cancer samples (25%). HIF-1α nuclear expression could be detected in11of the18(61%) samples in the VM-positive group and in17of the53(32%) samples in the VM-negative group. HIF-1α protein expression was significant between the VM-positive group and the VM-negative group. A Kaplan-Meier survival analysis revealed that the patients with expression of HIF-la had a shorter survival period than those without HIF-la expression.
2) Hypoxia facilitates invasiveness, migration, and VM formation of Ovarian Cancer cell
We observed the emergence of more pipe-like structures and cellular plasticity in hypoxic group than normoxic group. We only observed simpler and less pipe-like structures in normoxic group than hypoxic group. Two different types (the patterned matrix type and the tubular type) of VM were observed in vitro under hypoxia. SKOV3cell lines formed looping patterns rich in extracellular matrix in3D cultures containing Matrigel,OVCAR3cell lines formed networks of tubular or sinusoidal channels.
The invasive capacity of the ovarian cancer cells was significantly facilitated under hypoxia compared with that under normoxia in both SKOV3(P=0.000) and OVCAR3cells (P=0.000); an increase in cell migration was observed under hypoxic conditions SKOV3and OVCAR3cell lines compared with the control (P<0.05).
Zymography assays were performed to detect the effect of hypoxia on the activity of MMP-2and MMP-9.
3) Hypoxia leading to VM formation through inducing EMT
The HIF-la expression was topologically correlated with loss of E-cadherin expression and up-regulated the expression of vimentin in11of the18VM-positive patients (61%). EMT-associated molecular Twist and Slug had higher expressions in VM-positive ovarian cancer samples than those in VM-negative ovarian cancer samples.
In vitro experiments, we observed that ovarian cancer cell lines had morphological EMT-like changes (a more fibroblastoid morphology, a loss of cellular cohesiveness) after150μM CoCl2hypoxia for48hours. Messenger RNA (mRNA) and protein levels demonstrated induction of EMT after hypoxia, as shown by a shift in expression of epithelial markers (E-cadherin) to mesenchymal markers (vimentin).
4) Hypoxic could induce tumor cells highexpression of VE-cadherin, promote the formation of VM. VE-cadherin is exclusively expressed by highly aggressive tumor cells and is critical in tumor VM.VM-associated molecular VE-cadherin had higher expressions in VM-positive ovarian cancer samples than those in VM-negative ovarian cancer samples. In vitro experiments,VM-related characterizing protein VE-cadherin was detected to be highly expressed under hypoxia.
Conclusions:
1) VM was associated with HIF-la expression in ovarian cancer, hypoxia promoted VM formation.
2) Hypoxia inducing EMT was one of the mechanisms leading to VM formation.
3) Hypoxia facilitated invasiveness, migration of ovarian cancer cell.
4) Hypoxic could induce tumor cells highexpression of VE-cadherin, promote the formation of VM
目的
本研究旨在探讨缺氧微环境在肿瘤血管生成拟态形成中的作用,及缺氧促进肿瘤细胞形成VM的可能的分子机制。探究缺氧微环境下肿瘤细胞形成VM的分子机制有助于完善和发展VM理论；这对丰富肿瘤血管生成理论的研究具有重要意义,同时对临床抗肿瘤治疗提供了靶点。
方法
1)首先对前期实验中收集的来自天津医科大学附属肿瘤医院71例经手术切除且随访资料完整的卵巢癌临床标本进行HIF-1α、EMT表征蛋白E-cadherin、 vimentin及EMT调控蛋白Twist1、Snail、Slug及血管内皮相关蛋白VE-cadherin、FLT-1、FLK-1的免疫组织化学染色。重点观察HIF-1α与E-cadherin、vimentin及VM在同一例卵巢癌标本的连续性组织切片上的表达定位之间的关系。
2)构建体外三维培养模型,观察是否缺氧微环境促进了VM的形成。细胞功能学实验方法探究缺氧与肿瘤细胞的迁移、侵袭和三维管道化形成能力之间的关系。
3)应用RT-PCR、Western Blot、免疫荧光实验从蛋白和：mRNA水平检测E-cadherin, vimentin在缺氧与常氧环境下的表达情况,探究是否缺氧诱导肿瘤细胞发生了EMT,从而促进VM的形成。
4) Western Blot检测VM形成关键蛋白VE-cadherin在常氧环境和缺氧环境下表达的差异。
5)明胶酶谱法分析缺氧对基质金属蛋白酶MMP-2和MMP-9活性的影响。
结果
1)HIF-1α蛋白与血管生成拟态的形成有关71例卵巢癌中HIF-1α的阳性表达率为39.44%(28/71)。VM阳性组HIF-1α的阳性表达率为61.11%(11/18)；VM阴性组HIF-1α的阳性表达率为32.08%(17/53)。 HIF-1α在VM阴性组和VM阳性组阳性表达率的差别具有统计学意义。HIF-1α蛋白定位于卵巢癌细胞的胞核内,呈棕黄色颗粒。HIF-1α阳性细胞簇在肿瘤浸润边缘、坏死区及新生血管的周围最为密集。
2)体外三维培养证实缺氧促进了卵巢癌细胞血管生成拟态的形成,并增强了卵巢癌细胞的侵袭和迁移能力。
Matrigel三维培养模型上发现与常氧组相比,缺氧组卵巢癌细胞形成VM的时间较早,结构较复杂。OVCAR3主要形成管状型血管生成拟态,SKOV3主要形成基质型血管生成拟态。Transwell小室体外侵袭实验发现给予CoCl2缺氧处理24小时后,与常氧组相比,缺氧组穿膜细胞数增多,统计结果显示差别具有统计学意义。迁移实验发现给予CoCl2缺氧处理24小时后,与常氧组相比,缺氧组迁移细胞数较多,差别具有统计学意义。缺氧处理48小时后卵巢癌SKOV3和OVCAR3细胞MMP-2活性比常氧状态高,进一步证明缺氧情况下卵巢癌的侵袭性增强。
3)缺氧诱导EMT发生,是血管生成拟态形成的内在机制
在同一例标本的连续性组织切片上分析VM阳性组与阴性组中HIF-1α与E-cadherin, vimentin的表达定位之间的关系,发现在61%(11/18)VM阳性组HIF-1α高表达时,vimentin也同时高表达,而E-cadherin低表达。而VM阴性组不存在这种对应关系,即在VM阴性组HIF-1α高表达时,没发现这种对应关系的存在。且Twist、Slug蛋白在VM阴性组和VM阳性组阳性表达率间的差别具有统计学意义,VM阳性组表达较高。表明缺氧、EMT及VM三者间存在密切关系。
体外实验证实SKOV3、OVCAR3细胞在CoCl2缺氧48小时细胞均出现明显EMT样形态变化,转变成纤维母细胞样形态,出现多角伪足,细胞之间的粘附性降低,细胞核呈现团块状或固缩状结构。
细胞免疫荧光、Westernblot及RT-PCR检测常氧环境下和缺氧环境下细胞的蛋白和mRNA表达证实缺氧环境下卵巢癌细胞SKOV3、OVCAR3中vimentin蛋白及1nRNA水平均上调表达,E-cadherin表达显著下调。以上结果进一步证实缺氧微环境下卵巢癌细胞通过发生EMT样可塑性转变,促进了血管生成拟态的形成。
4)VM形成的关键蛋白VE-cadherin在缺氧微环境下表达升高在人卵巢癌石蜡标本上初步证实具有VM的卵巢癌高表达VE-cadherin蛋白,且体外Westernblot检测发现在缺氧微环境下,人卵巢癌细胞上调VM形成关键蛋白VE-cadherin的表达。
结论
1)缺氧诱导因子HIF-1α与血管生成拟态有关,促进了卵巢癌细胞血管生成拟态的形成。
2)缺氧可诱导EMT发生,是血管生成拟态形成的内在机制之一。
3)缺氧增强了卵巢癌细胞的侵袭和迁移性。
4)缺氧促进了VM形成的关键蛋白VE-cadherin表达上调。
Epithelia ovarian cancer has the highest mortality rate of all gynecological malignancies, which reflects the fact that most patients are diagnosed with advanced cancer. Vasculogenic mimicry describes the ability of aggressive cancer cells to form vasculogenic-like networks in vitro in the absence of endothelial cells or fibroblasts, concomitant with their expressions of vascular cell-associated molecules. Vasculogenic mimicry has now been shown to occur in many different aggressive cancers including ovarian cancers.
The hypoxic microenvironment of tumors results in changes in metabolism, angiogenesis and survival of the cells that are orchestrated by HIF-1α, and depending on tissue specificity. Hypoxia contributes to the progression of a variety of cancers by activating adaptive transcriptional programs that promote cell survival, motility and tumor angiogenesis. Given that HIF-1α has been found to be a crucial inducer contributing to tumor EMT, it is of great interest to examine the role of HIF-1α in VM formation in ovarian cancers. Although the importance of hypoxia and subsequent hypoxia-inducible factor-1α (HIF-1α) activation in tumor angiogenesis is well known, their role in the regulation of vasculogenic mimicry is unclear.
Purpose:
The study aims to investigate the effect of hypoxia on VM formation in ovarian cancer and to explore possible mechanism involved. Exploring the growth-promoting mechanisms of the tumor microenvironment will enhance our understanding of cancer biology and may identify new therapeutic approaches.
Methods:
1) Through the Tumor Tissue Bank of Tianjin Cancer Hospital,71ovarian cancer patients with detailed pathologic and clinical information were selected. Expression of HIF-1α protein was studied by immunohistochemistry in71specimens of epithelial ovarian cancers. To explore the potential mechanism, we examined the expressions of E-cadherin, vimentin, Twistl, Slug, Snail and VE-cadherin, FLT-1, FLK-1, and studied E-cadherin, vimentin topological correlation with HIF-la in VM-positive human ovarian cancers.
2) A well-established model of Three-dimensional Matrigel culture in vitro was used to compare vasculogenic mimicry formation under hypoxia and normoxia using two ovarian cancer cell lines, SKOV3and OVCAR3. Transwell invasion assay and migration assay were performed to evaluate the effect of hypoxia on cell motility and invasion.
3) The expression levels of HIF-la and E-cadherin, vimentin following hypoxia and normoxia were assessed using quantitative PCR and western blot. Immunofluorescence microscopy staining was performed to confirm the effect of hypoxia on the protein expressions of E-cadherin and vimentin.
4) The expression levels of VE-cadherin following hypoxia and normoxia were assessed using western blot.
5) Zymography assays were performed to detect the effect of hypoxia on the activity of MMP-2and MMP-9.
Results:
1) VM present in Ovarian Cancer associated with HIF-la expression. VM was detected in18out of71Ovarian Cancer samples (25%). HIF-1α nuclear expression could be detected in11of the18(61%) samples in the VM-positive group and in17of the53(32%) samples in the VM-negative group. HIF-1α protein expression was significant between the VM-positive group and the VM-negative group. A Kaplan-Meier survival analysis revealed that the patients with expression of HIF-la had a shorter survival period than those without HIF-la expression.
2) Hypoxia facilitates invasiveness, migration, and VM formation of Ovarian Cancer cell
We observed the emergence of more pipe-like structures and cellular plasticity in hypoxic group than normoxic group. We only observed simpler and less pipe-like structures in normoxic group than hypoxic group. Two different types (the patterned matrix type and the tubular type) of VM were observed in vitro under hypoxia. SKOV3cell lines formed looping patterns rich in extracellular matrix in3D cultures containing Matrigel,OVCAR3cell lines formed networks of tubular or sinusoidal channels.
The invasive capacity of the ovarian cancer cells was significantly facilitated under hypoxia compared with that under normoxia in both SKOV3(P=0.000) and OVCAR3cells (P=0.000); an increase in cell migration was observed under hypoxic conditions SKOV3and OVCAR3cell lines compared with the control (P<0.05).
Zymography assays were performed to detect the effect of hypoxia on the activity of MMP-2and MMP-9.
3) Hypoxia leading to VM formation through inducing EMT
The HIF-la expression was topologically correlated with loss of E-cadherin expression and up-regulated the expression of vimentin in11of the18VM-positive patients (61%). EMT-associated molecular Twist and Slug had higher expressions in VM-positive ovarian cancer samples than those in VM-negative ovarian cancer samples.
In vitro experiments, we observed that ovarian cancer cell lines had morphological EMT-like changes (a more fibroblastoid morphology, a loss of cellular cohesiveness) after150μM CoCl2hypoxia for48hours. Messenger RNA (mRNA) and protein levels demonstrated induction of EMT after hypoxia, as shown by a shift in expression of epithelial markers (E-cadherin) to mesenchymal markers (vimentin).
4) Hypoxic could induce tumor cells highexpression of VE-cadherin, promote the formation of VM. VE-cadherin is exclusively expressed by highly aggressive tumor cells and is critical in tumor VM.VM-associated molecular VE-cadherin had higher expressions in VM-positive ovarian cancer samples than those in VM-negative ovarian cancer samples. In vitro experiments,VM-related characterizing protein VE-cadherin was detected to be highly expressed under hypoxia.
Conclusions:
1) VM was associated with HIF-la expression in ovarian cancer, hypoxia promoted VM formation.
2) Hypoxia inducing EMT was one of the mechanisms leading to VM formation.
3) Hypoxia facilitated invasiveness, migration of ovarian cancer cell.
4) Hypoxic could induce tumor cells highexpression of VE-cadherin, promote the formation of VM
引文
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