癌症患者血清p53抗体检测和肿瘤微环境压力对血管生成因子表达调控
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摘要
本论文包括两个部分：第一部分主要研究内容为癌症患者血清p53抗体检测；第二部分研究内容为肿瘤微环境压力对血管生成因子ANG、VEGF和bFGF的表达调控。两个课题均为本人在博士期间所从事研究方向，二者在二级学科上均属于细胞生物学范畴。所不同的是，第一部分属于肿瘤免疫学内容，而第二部分属于肿瘤细胞生物学内容，两方面在具体研究内容上并无直接联系，因此分部进行阐述。
是作说明。
第一部分癌症患者血清p53抗体检测
由于肿瘤在发生之初并没有特别的症状表现，导致很多癌症患者在被确诊罹患癌症的时候，已经处于晚期并丧失了治愈的机会。事实上，有很多方法可以改变目前肿瘤预防和诊疗所处的尴尬局面，以达到“早发现，早治疗”的目的。肿瘤标志物的检测正是这样的一种方法。
血清p53抗体（s-p53Ab）是被证明与p53基因突变和p53蛋白积累密切相关，是一种具有潜在应用价值的肿瘤特异性血清标准物。监测s-p53Ab的表达规律可能从一个侧面反映肿瘤发生、发展和恶化的情况以及肿瘤对某些抗癌药物的耐药性。目前，检测s-p53Ab的最常用的方法是酶联免疫吸附法（ELISA），但是传统ELISA方法检出率有待提高，而且所采用的抗原多是原核表达纯化后的重组型p53蛋白，其结构与人体内天然蛋白的结构存在差异，这可能导致在检测的时候出现漏检或假阴性的现象。此外，蛋白制备和纯化工艺复杂，成本较高。
噬菌体展示技术能在噬菌体的表面展示特定蛋白质或多肽。这种展示的多肽能很好的模拟天然蛋白表位构象，具有灵敏度高，抗原性强等特点。而且无需经过特殊纯化工艺，制备成本极低。
在本实验中，我们创新性地将以重组型蛋白为抗原建立的p53-ELISA和以杂合噬菌体为抗原的phage-ELISA联合起来，既发挥了p53-ELISA的抗原多表位、灵敏度高的特点，又融合了phage-ELISA抗原单表位、特异性高的特点。我们用p53-ELISA和phage-ELISA联合检测了829名包括肺癌、乳腺癌、结肠癌、胃癌、食管癌、肝癌和卵巢癌的癌症患者s-p53Ab表达情况。结果显示，在各类癌症患者中，s-p53Ab阳性率最高的是卵巢癌，最低的是肝癌。p53-ELISA的检出率为25.6%(212例)，phage-ELISA的检出率为19.9%(165例)，而p53-phage-ELISA的联合检出率达到35.9%(298例)；s-p53Ab水平与癌症患者淋巴结转移和肿瘤分期等诸多临床病理参数有关。此外，我们发现非小细胞肺癌患
者随着化疗结束后症状的缓解，s-p53Ab的表达在整体上有降低的趋势，s-p53Ab
阳性患者所占比例显著降低，而那些化疗前s-p53Ab高表达的患者存在对化疗药物的耐药性，治疗效果较差。
我们的研究表明，传统的ELISA方法和噬菌体展示ELISA方法具有很好的互补性，二者联合起来能够达到更好的检测效果。对s-p53Ab的监测或许能够
为癌症患者临床诊断和治疗提供更好的线索。
第二部分肿瘤微环境压力对血管生成因子ANG、VEGF和bFGF表达调控的初步探讨
无论是还创伤修复还是肿瘤发生过程，微环境的改变通常是诱发血管产生的最原始的因素和动力，因为受到微环境变化影响的组织或细胞会应激性地产生与这种改变相抗衡的刺激信号，以弥补对自身造成的损害或朝着利于自身发展的方向前进。
肿瘤细胞所处的内环境非常复杂。缺氧、细胞密度过大和营养成分的短缺是诸多微环境压力中最突出的三种。肿瘤要保证持续增殖并向远处转移，必须要靠诱导新生血管的发生来增加氧气含量，维持足够的养分。
ANG，VEGF和bFGF是非常重要的血管生成因子，除了在调控细胞增殖和血管生成方面具有重要作用，彼此之间似乎也存在相互制约，协调工作的机制。但是这种制约和协调的机制目前尚不清楚，尤其是在缺氧、高密度和血清饥饿这样的条件刺激下的作用机制，更是未见报道。
针对以上研究中存在的空白，本实验引入了缺氧(Hypoxia)、高密度(Highdensity)和血清饥饿(Serum starvation)条件刺激，初步探讨了上三种血管生成因子在不利环境中表达情况。我们发现在缺氧和高密度培养下，人前列腺癌细胞PC-3（p53缺失型）的ANG和VEGF的表达显著升高，而bFGF的表达显著降低；单纯提高内源性ANG或VEGF的表达量并不能介导bFGF的低表达；在PC-3细胞中转染p53表达质粒，也不能引起缺氧条件下ANG、VEGF和bFGF三者的表达变化。
根据实验结果，我们预测在不良微环境中，血管生成因子之间及缺氧诱导因子(HIF)之间或许存在某种未知的反馈调节机制；此外，p53缺失型细胞血管生成因子的调控机制与其他细胞或许存在差异。我们希望这些初步的研究能为后续深入探索奠定前期工作基础，并为揭示血管生成因子在肿瘤发生和发展中的调控机制做出一些贡献。
Part one
Tumorigenesis is imperceptible initially. Many cancer patients have lost theiroptimal therapeutic time when they were diagnosed. Actually, certain approaches cansolve this promblem, such as the serological detection methods, which is hopefullyable to reveal the existence of tumor cells.
Serum anti-p53antibody (s-p53Ab) is proved to correlate with the p53genemutation and the aberrant p53protein accumulation. It is considered a potentialvaluable tumor serological biomarker and a reflection of oncogenesis, tumordevelopment, tumor deterious as well as chemoresistance. To date, the commonmethod that uses in the detection of s-p53Ab is enzyme-linked immunosorbent assay(ELISA). However, the detection rate of the traditional ELISA is far beyondsatisfactory, owning to the different structure of the antigen using in such systemcompared to the natural p53protein in the body of human being, and the falsenegative exists. Besides, the cost of preparation and purification of this sort of proteinis high.
With phage displaying technology, certain kind of protein or peptide can bedisplayed on the surface of filamentous phage. Because peptide of this sort is able tomimick the structure of natural protein, it has high antigenicity. Moreover, thepurification of filamentous phage is quite easy and lowcost.
In current study, we creatively unified the p53-ELISA and phage-ELISA, whichused the recombined wild type p53and hybrid phage protein as antigens respectively,and constructed the p53-phage ELISA. Using this system, the s-p53Ab of829cancerpatients including lung, breast, colorectal, gastric, esophageal, liver and ovariancancer were detected. The result revealed that the highest positive s-p53Ab detectionrate was ovarian caner, while the lowest was liver cancer. The detection rate of s-p53Ab in p53-ELISA was25.6%(212samples), and that of phage-ELISA was19.9%(165samples), p53-phage ELISA was35.9%(298samples). Further more, we foundthat the level of s-p53Ab correlated with several clinicopathological parameters ofcancer patients. Specially, it is found that the s-p53Ab level decreased along with thealleviation of patients’ condition, and those who overexpressed s-p53Ab before therapy often showed chemoresistance.
To sum up, the p53-ELISA and phage-ELISA compensate each other well, and thep53-phage ELISA has an edge over any single detection system. The surveillance ofs-p53Ab may probably provide a good diagnostic and therapeutic scheme for cancer
patients.
Part two
Whichever during the wound repair or tumorigenesis, microenvironments change isthe main inducingfactor of angiogenesis, because the tissues or cells may generate thebacklash to these change in order to survive and develop in the harsh environment.The internal environment that tumor cells exist in is complex, and the hypoxia, highcell density and serum starvation are three common conditions. To keep proliferatingand metastasis, tumor needs more oxygen and nutrient which are supported by newblood vessels.
Angiogenin (ANG), vascular endothelial growth factor (VEGF) and basic fibroblastgrowth factor are three important angiogenesis. They not only regulate the cellproliferation and angiogenesis/vascularization, but also cooperate and interact witheach other. However, the mechanism of such cooperation and interaction, till now, isnot quite clear, especially in the microenvironment of hypoxia, high cell density andserum starvation, and little report was seen.
To fill this research gap, we superficially investigated the expression of thereangiogenesis mentioned above under the suppression of hypoxia, high cell density andserum starvation. We found that the human being prostate cell line PC-3(p53null)expressed higher level of ANG and VEGF, as well as lower level of bFGF by thestimulation of hypoxia and high cell density than normal did. The transfection ofpCI.neo-ANG or pCI.neo-VEGF could not induce the up-regulation of bFGF.Otherwise, the introduction of p53into PC-3cell could not inhibit the expression ofANG, VEGF or bFGF whatever in normoxia or hypoxia, although it was reportedplaying an important role in hypoxic stimulation.
For this, we set up a hypothesis that there possibly exists an unknown negativefeedback mechanism between the angiogenesis and hypoxia-inducing factor. Besides,the regulation function of p53in PC-3cell could be different from other cells. Wehope current superficial work would pave a way for further investigation.
是作说明。
第一部分癌症患者血清p53抗体检测
由于肿瘤在发生之初并没有特别的症状表现，导致很多癌症患者在被确诊罹患癌症的时候，已经处于晚期并丧失了治愈的机会。事实上，有很多方法可以改变目前肿瘤预防和诊疗所处的尴尬局面，以达到“早发现，早治疗”的目的。肿瘤标志物的检测正是这样的一种方法。
血清p53抗体（s-p53Ab）是被证明与p53基因突变和p53蛋白积累密切相关，是一种具有潜在应用价值的肿瘤特异性血清标准物。监测s-p53Ab的表达规律可能从一个侧面反映肿瘤发生、发展和恶化的情况以及肿瘤对某些抗癌药物的耐药性。目前，检测s-p53Ab的最常用的方法是酶联免疫吸附法（ELISA），但是传统ELISA方法检出率有待提高，而且所采用的抗原多是原核表达纯化后的重组型p53蛋白，其结构与人体内天然蛋白的结构存在差异，这可能导致在检测的时候出现漏检或假阴性的现象。此外，蛋白制备和纯化工艺复杂，成本较高。
噬菌体展示技术能在噬菌体的表面展示特定蛋白质或多肽。这种展示的多肽能很好的模拟天然蛋白表位构象，具有灵敏度高，抗原性强等特点。而且无需经过特殊纯化工艺，制备成本极低。
在本实验中，我们创新性地将以重组型蛋白为抗原建立的p53-ELISA和以杂合噬菌体为抗原的phage-ELISA联合起来，既发挥了p53-ELISA的抗原多表位、灵敏度高的特点，又融合了phage-ELISA抗原单表位、特异性高的特点。我们用p53-ELISA和phage-ELISA联合检测了829名包括肺癌、乳腺癌、结肠癌、胃癌、食管癌、肝癌和卵巢癌的癌症患者s-p53Ab表达情况。结果显示，在各类癌症患者中，s-p53Ab阳性率最高的是卵巢癌，最低的是肝癌。p53-ELISA的检出率为25.6%(212例)，phage-ELISA的检出率为19.9%(165例)，而p53-phage-ELISA的联合检出率达到35.9%(298例)；s-p53Ab水平与癌症患者淋巴结转移和肿瘤分期等诸多临床病理参数有关。此外，我们发现非小细胞肺癌患
者随着化疗结束后症状的缓解，s-p53Ab的表达在整体上有降低的趋势，s-p53Ab
阳性患者所占比例显著降低，而那些化疗前s-p53Ab高表达的患者存在对化疗药物的耐药性，治疗效果较差。
我们的研究表明，传统的ELISA方法和噬菌体展示ELISA方法具有很好的互补性，二者联合起来能够达到更好的检测效果。对s-p53Ab的监测或许能够
为癌症患者临床诊断和治疗提供更好的线索。
第二部分肿瘤微环境压力对血管生成因子ANG、VEGF和bFGF表达调控的初步探讨
无论是还创伤修复还是肿瘤发生过程，微环境的改变通常是诱发血管产生的最原始的因素和动力，因为受到微环境变化影响的组织或细胞会应激性地产生与这种改变相抗衡的刺激信号，以弥补对自身造成的损害或朝着利于自身发展的方向前进。
肿瘤细胞所处的内环境非常复杂。缺氧、细胞密度过大和营养成分的短缺是诸多微环境压力中最突出的三种。肿瘤要保证持续增殖并向远处转移，必须要靠诱导新生血管的发生来增加氧气含量，维持足够的养分。
ANG，VEGF和bFGF是非常重要的血管生成因子，除了在调控细胞增殖和血管生成方面具有重要作用，彼此之间似乎也存在相互制约，协调工作的机制。但是这种制约和协调的机制目前尚不清楚，尤其是在缺氧、高密度和血清饥饿这样的条件刺激下的作用机制，更是未见报道。
针对以上研究中存在的空白，本实验引入了缺氧(Hypoxia)、高密度(Highdensity)和血清饥饿(Serum starvation)条件刺激，初步探讨了上三种血管生成因子在不利环境中表达情况。我们发现在缺氧和高密度培养下，人前列腺癌细胞PC-3（p53缺失型）的ANG和VEGF的表达显著升高，而bFGF的表达显著降低；单纯提高内源性ANG或VEGF的表达量并不能介导bFGF的低表达；在PC-3细胞中转染p53表达质粒，也不能引起缺氧条件下ANG、VEGF和bFGF三者的表达变化。
根据实验结果，我们预测在不良微环境中，血管生成因子之间及缺氧诱导因子(HIF)之间或许存在某种未知的反馈调节机制；此外，p53缺失型细胞血管生成因子的调控机制与其他细胞或许存在差异。我们希望这些初步的研究能为后续深入探索奠定前期工作基础，并为揭示血管生成因子在肿瘤发生和发展中的调控机制做出一些贡献。
Part one
Tumorigenesis is imperceptible initially. Many cancer patients have lost theiroptimal therapeutic time when they were diagnosed. Actually, certain approaches cansolve this promblem, such as the serological detection methods, which is hopefullyable to reveal the existence of tumor cells.
Serum anti-p53antibody (s-p53Ab) is proved to correlate with the p53genemutation and the aberrant p53protein accumulation. It is considered a potentialvaluable tumor serological biomarker and a reflection of oncogenesis, tumordevelopment, tumor deterious as well as chemoresistance. To date, the commonmethod that uses in the detection of s-p53Ab is enzyme-linked immunosorbent assay(ELISA). However, the detection rate of the traditional ELISA is far beyondsatisfactory, owning to the different structure of the antigen using in such systemcompared to the natural p53protein in the body of human being, and the falsenegative exists. Besides, the cost of preparation and purification of this sort of proteinis high.
With phage displaying technology, certain kind of protein or peptide can bedisplayed on the surface of filamentous phage. Because peptide of this sort is able tomimick the structure of natural protein, it has high antigenicity. Moreover, thepurification of filamentous phage is quite easy and lowcost.
In current study, we creatively unified the p53-ELISA and phage-ELISA, whichused the recombined wild type p53and hybrid phage protein as antigens respectively,and constructed the p53-phage ELISA. Using this system, the s-p53Ab of829cancerpatients including lung, breast, colorectal, gastric, esophageal, liver and ovariancancer were detected. The result revealed that the highest positive s-p53Ab detectionrate was ovarian caner, while the lowest was liver cancer. The detection rate of s-p53Ab in p53-ELISA was25.6%(212samples), and that of phage-ELISA was19.9%(165samples), p53-phage ELISA was35.9%(298samples). Further more, we foundthat the level of s-p53Ab correlated with several clinicopathological parameters ofcancer patients. Specially, it is found that the s-p53Ab level decreased along with thealleviation of patients’ condition, and those who overexpressed s-p53Ab before therapy often showed chemoresistance.
To sum up, the p53-ELISA and phage-ELISA compensate each other well, and thep53-phage ELISA has an edge over any single detection system. The surveillance ofs-p53Ab may probably provide a good diagnostic and therapeutic scheme for cancer
patients.
Part two
Whichever during the wound repair or tumorigenesis, microenvironments change isthe main inducingfactor of angiogenesis, because the tissues or cells may generate thebacklash to these change in order to survive and develop in the harsh environment.The internal environment that tumor cells exist in is complex, and the hypoxia, highcell density and serum starvation are three common conditions. To keep proliferatingand metastasis, tumor needs more oxygen and nutrient which are supported by newblood vessels.
Angiogenin (ANG), vascular endothelial growth factor (VEGF) and basic fibroblastgrowth factor are three important angiogenesis. They not only regulate the cellproliferation and angiogenesis/vascularization, but also cooperate and interact witheach other. However, the mechanism of such cooperation and interaction, till now, isnot quite clear, especially in the microenvironment of hypoxia, high cell density andserum starvation, and little report was seen.
To fill this research gap, we superficially investigated the expression of thereangiogenesis mentioned above under the suppression of hypoxia, high cell density andserum starvation. We found that the human being prostate cell line PC-3(p53null)expressed higher level of ANG and VEGF, as well as lower level of bFGF by thestimulation of hypoxia and high cell density than normal did. The transfection ofpCI.neo-ANG or pCI.neo-VEGF could not induce the up-regulation of bFGF.Otherwise, the introduction of p53into PC-3cell could not inhibit the expression ofANG, VEGF or bFGF whatever in normoxia or hypoxia, although it was reportedplaying an important role in hypoxic stimulation.
For this, we set up a hypothesis that there possibly exists an unknown negativefeedback mechanism between the angiogenesis and hypoxia-inducing factor. Besides,the regulation function of p53in PC-3cell could be different from other cells. Wehope current superficial work would pave a way for further investigation.
引文
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