本文選題：黑色素瘤 + 平足蛋白��； 參考：《吉林大學(xué)》2015年博士論文

【摘要】：腫瘤轉(zhuǎn)移是大多數(shù)惡性腫瘤患者死亡的主要原因之一，但腫瘤轉(zhuǎn)移的具體發(fā)生機(jī)制目前仍未完全明確。黑色素瘤是一種高度惡性、轉(zhuǎn)移率高的腫瘤。黑色素瘤多發(fā)生于皮膚，大部分腫瘤在早期即可發(fā)生血行轉(zhuǎn)移，肺轉(zhuǎn)移是黑色素瘤最常見(jiàn)的血行轉(zhuǎn)移部位。目前臨床對(duì)于惡性黑色素瘤患者的治療以手術(shù)聯(lián)合放、化療為主，但對(duì)于已發(fā)生轉(zhuǎn)移的腫瘤患者仍然沒(méi)有更好的治療方法。腫瘤轉(zhuǎn)移發(fā)生時(shí)，腫瘤細(xì)胞從原發(fā)部位病灶分離，通過(guò)降解周圍組織細(xì)胞外基質(zhì)而遷移并侵入血管和淋巴管，隨循環(huán)到達(dá)遠(yuǎn)處臟器并在局部形成腫瘤轉(zhuǎn)移灶。在腫瘤細(xì)胞轉(zhuǎn)移過(guò)程中，受到體內(nèi)多種因素的調(diào)節(jié)。腫瘤細(xì)胞誘導(dǎo)的血小板聚集（TCIPA）在腫瘤轉(zhuǎn)移中起重要作用。血行轉(zhuǎn)移發(fā)生時(shí)，由原發(fā)病灶進(jìn)入到血液循環(huán)內(nèi)的腫瘤細(xì)胞與血小板粘附聚集，激活血小板，形成血小板與腫瘤細(xì)胞聚集團(tuán)塊，使腫瘤細(xì)胞逃避宿主免疫系統(tǒng)捕獲，同時(shí)活化的血小板釋放各種生長(zhǎng)因子和促血管生成因子，促進(jìn)腫瘤細(xì)胞向新的轉(zhuǎn)移部位遷移。 平足蛋白（Podoplanin, PDPN）是一種I型唾液酸跨膜糖蛋白，由具有高度糖基化的胞外結(jié)構(gòu)域，跨膜部分和短胞質(zhì)尾區(qū)組成。PDPN選擇性表達(dá)于淋巴內(nèi)皮細(xì)胞，作為淋巴內(nèi)皮細(xì)胞標(biāo)志物已被廣泛應(yīng)用。除此之外，，PDPN還具有調(diào)節(jié)血管淋巴管的發(fā)育，調(diào)節(jié)細(xì)胞運(yùn)動(dòng)，促進(jìn)腫瘤發(fā)生和轉(zhuǎn)移的多種功能。在多種腫瘤細(xì)胞上可檢測(cè)到PDPN的表達(dá)，包括小鼠及人黑色素瘤細(xì)胞上也可檢測(cè)到PDPN的表達(dá)。有研究表明表達(dá)于某些腫瘤細(xì)胞表面上的PDPN通過(guò)促進(jìn)腫瘤細(xì)胞侵襲和擴(kuò)散促進(jìn)腫瘤的發(fā)生及轉(zhuǎn)移，但其具體作用機(jī)制尚不清楚。C型凝集素樣受體2（CLEC-2）屬于II型跨膜蛋白，表達(dá)于血小板表面，是PDPN的內(nèi)源性受體。CLEC-2可通過(guò)與PDPN的相互作用誘導(dǎo)血小板激活、聚集。之前有研究表明，PDPN與CLEC-2相互作用誘導(dǎo)的血小板激活，是胚胎期血管淋巴管發(fā)育的重要影響因素。近年來(lái)，對(duì)于PDPN與CLEC-2相互作用誘導(dǎo)的血小板活化在免疫、腫瘤及感染等方面作用的研究越來(lái)越引起人們的重視。 在本研究中，我們篩選分離PDPN表達(dá)水平不同的小鼠黑色素瘤細(xì)胞，建立CLEC-2基因缺陷小鼠模型并獲得CLEC-2基因缺陷血小板。建立實(shí)驗(yàn)性小鼠黑色素瘤肺轉(zhuǎn)移動(dòng)物模型，通過(guò)進(jìn)行體外和體內(nèi)實(shí)驗(yàn)研究，探討PDPN和CLEC-2在小鼠黑素瘤血行肺轉(zhuǎn)移過(guò)程中對(duì)血小板激活的作用，以及二者間的相互作用對(duì)小鼠黑色素瘤肺轉(zhuǎn)移的影響。并進(jìn)一步研究Syk酪氨酸激酶信號(hào)傳導(dǎo)通路在PDPN和CLEC-2激活血小板過(guò)程中及對(duì)小鼠黑色素瘤肺轉(zhuǎn)移的作用。 1.流式細(xì)胞術(shù)分離小鼠黑色素瘤B16-F0PDPN+細(xì)胞及PDPN-細(xì)胞，建立骨髓移植CLEC-2基因缺陷小鼠模型。 經(jīng)抗PDPN抗體染色，流式細(xì)胞術(shù)篩選分離并培養(yǎng)B16-F0細(xì)胞，經(jīng)流式細(xì)胞學(xué)及免疫印跡法檢測(cè)證實(shí)PDPN+細(xì)胞及PDPN-細(xì)胞中PDPN表達(dá)情況。體外培養(yǎng)結(jié)果顯示兩種細(xì)胞體外生長(zhǎng)增殖無(wú)差異。建立骨髓移植CLEC-2基因缺陷小鼠，并取外周血經(jīng)流式細(xì)胞學(xué)檢測(cè)證實(shí)小鼠體內(nèi)CLEC-2基因清除率。 2. PDPN與CLEC-2在體外通過(guò)激活血小板促進(jìn)腫瘤細(xì)胞與血小板的聚集。 在體外將B16-F0PDPN+細(xì)胞及PDPN-細(xì)胞分別與野生型血小板及CLEC-2基因缺陷血小板相混合，通過(guò)流式細(xì)胞學(xué)檢測(cè)、Western blot檢測(cè)、IF及ICC法比較各組血小板與腫瘤細(xì)胞聚集情況。結(jié)果顯示PDPN+細(xì)胞與野生型血小板混和組血小板與腫瘤細(xì)胞聚集明顯高于其他組，并在鏡下觀察到明顯的血小板與腫瘤細(xì)胞聚集團(tuán)塊。 3. PDPN與CLEC-2相互作用誘導(dǎo)體內(nèi)血小板激活，通過(guò)血小板與腫瘤細(xì)胞聚集作用促進(jìn)肺組織對(duì)腫瘤細(xì)胞的捕獲。 將以不同熒光染色劑染色的PDPN+細(xì)胞及PDPN-細(xì)胞等量混和后，經(jīng)尾靜脈注射給野生型小鼠建立實(shí)驗(yàn)性小鼠黑色素瘤肺轉(zhuǎn)移模型。注射后30min，2h及6h處死小鼠并取小鼠肺組織，免疫熒光顯微鏡下觀察到在野生型小鼠肺組織內(nèi)被捕獲的PDPN+腫瘤細(xì)胞數(shù)量明顯高于PDPN-細(xì)胞。比較注射給野生型小鼠及CLEC-2基因缺陷小鼠30min后肺組織內(nèi)腫瘤細(xì)胞被捕獲情況，PDPN+在野生型小鼠肺組織內(nèi)數(shù)量明顯高于其他三組。將PDPN+細(xì)胞及PDPN-細(xì)胞分別注射給野生型小鼠，比較注射前后小鼠體內(nèi)血小板水平的變化，注射PDPN+組小鼠體內(nèi)血小板下降較PDPN-組明顯。結(jié)果表明PDPN與CLEC-2相互作用誘導(dǎo)小鼠體內(nèi)血小板激活，并引起體內(nèi)血小板與腫瘤細(xì)胞的聚集。 4. PDPN與CLEC-2相互作用促進(jìn)小鼠黑色素瘤肺轉(zhuǎn)移的發(fā)生。 比較PDPN+細(xì)胞、PDPN-細(xì)胞分別注射給野生型小鼠及CLEC-2缺陷小鼠體內(nèi)引起小鼠黑色素瘤肺轉(zhuǎn)移發(fā)生的情況。結(jié)果顯示PDPN+腫瘤細(xì)胞在野生型小鼠體內(nèi)肺轉(zhuǎn)移率明顯高于其他組。肺組織HE染色結(jié)果分析表明PDPN+細(xì)胞在野生型小鼠肺組織轉(zhuǎn)移結(jié)節(jié)數(shù)量及轉(zhuǎn)移結(jié)節(jié)面積均明顯高于其他組。 5. Syk信號(hào)通路在PDPN與CLEC-2介導(dǎo)的血小板聚集及腫瘤轉(zhuǎn)移過(guò)程中起著重要作用。 用Syk酪氨酸激酶抑制劑R406在體內(nèi)外干預(yù)血小板與腫瘤細(xì)胞介導(dǎo)的血小板激活及聚集。Western blot結(jié)果顯示PDPN+細(xì)胞與野生型血小板作用激活Syk磷酸化，促進(jìn)血小板的聚集作用。流式細(xì)胞術(shù)及免疫熒光染色分析結(jié)果表明R406在一定程度上阻斷了體外PDPN+腫瘤細(xì)胞與血小板的聚集。體內(nèi)實(shí)驗(yàn)同樣顯示R406部分抑制了小鼠黑色素瘤的肺轉(zhuǎn)移。 6. PDPN與CLEC-2的相互作用不影響小鼠黑色素瘤皮下腫瘤的生長(zhǎng) 將PDPN+細(xì)胞及PDPN-細(xì)胞分別注射給野生型小鼠皮下，建立小鼠黑色素瘤皮下移植腫瘤模型，結(jié)果顯示PDPN+腫瘤及PDPN-腫瘤體內(nèi)生長(zhǎng)無(wú)明顯差異。病理組織HE染色結(jié)果顯示兩種腫瘤在組織形態(tài)上無(wú)明顯差異。 綜上，本研究利用FACS篩選PDPN表達(dá)不同的小鼠黑色素瘤細(xì)胞，并建立骨髓移植CLEC-2基因缺陷小鼠，通過(guò)腫瘤細(xì)胞與血小板體外實(shí)驗(yàn)研究及建立實(shí)驗(yàn)性小鼠黑色素瘤肺轉(zhuǎn)移動(dòng)物模型研究，明確了小鼠黑色素瘤細(xì)胞表達(dá)的PDPN與血小板CLEC-2相互作用，在體、內(nèi)外均能夠誘導(dǎo)血小板的活化，二者在體內(nèi)誘導(dǎo)的血小板激活促進(jìn)小鼠黑色素瘤肺轉(zhuǎn)移的發(fā)生，其中血小板的活化是部分依賴于Syk酪氨酸激酶信號(hào)通路完成的。腫瘤細(xì)胞表達(dá)的PDPN及血小板CLEC-2有望成為預(yù)示黑色素瘤腫瘤轉(zhuǎn)移發(fā)生及抗腫瘤轉(zhuǎn)移治療的新靶點(diǎn)。
[Abstract]:Tumor metastasis is one of the main causes of death in most malignant tumor patients, but the specific mechanism of tumor metastasis is still not completely clear. Melanoma is a highly malignant, high metastatic tumor. Melanoma occurs mostly in the skin, most of the tumor can occur in the early stage of blood metastasis, and lung metastasis is the most common melanoma. There is no better treatment for patients with malignant melanoma, but there is still no better treatment for cancer patients who have metastasize. When the metastasis occurs, the tumor cells are separated from the primary site and transferred and invaded through the degradation of the peripheral tissue extracellular matrix. Blood vessels and lymphatic vessels reach distant viscera and form tumor metastases locally. During the metastasis of tumor cells, many factors are regulated in the body. Tumor cell induced platelet aggregation (TCIPA) plays an important role in tumor metastasis. Blood metastasis occurs when the primary focus is entered into the blood circulation. Cell adhesion and aggregation, activating platelets, forming platelets and aggregation of tumor cells, causing tumor cells to escape from the host immune system, and the activated platelets release various growth factors and angiogenesis factors to promote the migration of tumor cells to the new metastatic sites.
Podoplanin (PDPN) is a kind of I type sialic acid transmembrane glycoprotein, which has a highly glycosylated extracellular domain, transmembrane part and short cytoplasmic tail region of.PDPN selectively expressed in lymphatic endothelial cells. It has been widely used as a marker of lymphatic endothelial cells. In addition, PDPN also regulates the development of vascular lymphatic vessels. A variety of functions that regulate cell movement and promote the occurrence and metastasis of tumors. The expression of PDPN can be detected on a variety of tumor cells, including the expression of PDPN on mice and human melanoma cells. Studies have shown that PDPN expressed on the surface of certain tumor cells promotes the occurrence of tumor by promoting tumor cells invasion and diffusion. However, it is not clear that the.C type lectin like receptor 2 (CLEC-2) belongs to the II type transmembrane protein, which is expressed on the surface of the platelets. It is the endogenous receptor.CLEC-2 of PDPN, which can induce platelet activation and aggregation through the interaction with PDPN. Previous studies showed that the platelet activation induced by the interaction of PDPN and CLEC-2 is the embryo. In recent years, more and more attention has been paid to the role of platelet activation induced by the interaction of PDPN and CLEC-2 in immunization, tumor and infection.
In this study, we screened the mouse melanoma cells with different levels of PDPN expression, established a CLEC-2 gene deficient mouse model and obtained the CLEC-2 gene defective platelets. The experimental mice model of pulmonary metastasis of melanoma was established. In vitro and in vivo experiments were carried out to explore the blood line lung of PDPN and CLEC-2 in murine melanoma. The effect of platelet activation in the process of metastasis, and the effect of the interaction between the two groups on the lung metastasis of melanoma in mice, and the effect of Syk tyrosine kinase signal transduction pathway on the activation of platelets in PDPN and CLEC-2 and the pulmonary metastasis of melanoma in mice were further studied.
1. mouse melanoma B16-F0PDPN+ cells and PDPN- cells were isolated by flow cytometry, and CLEC-2 gene deficient mice model was established.
B16-F0 cells were isolated and cultured by flow cytometry by flow cytometry. The expression of PDPN in PDPN+ cells and PDPN- cells was confirmed by flow cytometry and immunoblotting. In vitro culture results showed that there was no difference in growth and proliferation of two kinds of cells in vitro. A bone marrow transplant CLEC-2 gene defect mouse was established and the peripheral blood flow cytometry was taken. Cytology test confirmed the clearance rate of CLEC-2 gene in mice.
2. PDPN and CLEC-2 promote platelet aggregation by activating platelets in vitro.
In vitro, B16-F0PDPN+ cells and PDPN- cells were mixed with wild type platelets and CLEC-2 gene defective platelets, respectively, by flow cytometry, Western blot detection, IF and ICC methods to compare the aggregation of platelets and tumor cells in each group. The results showed that the platelet and tumor cells in the mixed group of PDPN+ cells and wild type platelets were clustered with the tumor cells. The aggregation was obviously higher than that of other groups, and obvious aggregation of platelet and tumor cells was observed under microscope.
3. the interaction between PDPN and CLEC-2 induces platelet activation in vivo, and promotes the acquisition of tumor cells by the aggregation of platelets and tumor cells.
After being mixed with PDPN+ cells and PDPN- cells stained with different fluorescent stains, an experimental mouse model of pulmonary metastasis was established by injecting the tail vein to the wild mice. After injection, 30min, 2h and 6h were killed in mice and the lung tissues were taken and the PDPN+ captured in the lung tissue of wild mice was observed under the immunofluorescence microscope. The number of tumor cells was significantly higher than that of PDPN- cells. The tumor cells in the lung tissues of the wild type and CLEC-2 gene deficient mice were compared. The number of PDPN+ in the lung tissues of the wild type mice was significantly higher than that of the other three groups. The PDPN+ and PDPN- cells were injected to the wild type mice respectively, and the mice were compared before and after the injection. The changes in the level of internal platelets in the PDPN+ group were significantly lower than that in the PDPN- group. The results showed that the interaction between PDPN and CLEC-2 induced the activation of platelets in the mice and the aggregation of platelets and tumor cells in the body.
4. the interaction of PDPN and CLEC-2 promotes the occurrence of pulmonary metastasis of melanoma in mice.
The results showed that the lung metastasis rate of the PDPN+ tumor cells in the wild type mice was significantly higher than that of the other groups in the wild type mice and the CLEC-2 deficient mice. The results of HE staining in the lung tissue showed that the PDPN+ cells were transferred to the lung tissue of the wild type mice in the lung tissue. The results of the HE staining of the lung tissue showed that the PDPN+ cells were transferred to the lung tissue of the wild type mice. The number of nodules and the area of metastatic nodules were significantly higher than those of other groups.
5. the Syk signaling pathway plays an important role in platelet aggregation and tumor metastasis mediated by PDPN and CLEC-2.
The effect of Syk tyrosine kinase inhibitor R406 on platelet activation and aggregation of platelets mediated by platelet and tumor cells in vitro and in vivo.Western blot results showed that the action of PDPN+ cells and wild type platelets activated Syk phosphorylation and promoted platelet aggregation. The results of flow cytometry and immunofluorescence staining showed that R406 was to a certain extent. The aggregation of PDPN+ tumor cells and platelets in vitro was blocked. In vivo experiments also showed that R406 partially inhibited the metastasis of melanoma in mice.
6. the interaction between PDPN and CLEC-2 does not affect the growth of melanoma subcutaneous tumor in mice.
PDPN+ cells and PDPN- cells were injected subcutaneously into the subcutaneous tissue of wild type mice. The tumor model of subcutaneous melanoma in mice was established. The results showed that there was no significant difference in the growth of PDPN+ tumor and PDPN- tumor. The pathological tissue HE staining showed that there was no significant difference in the tissue morphology between the two kinds of tumor.
To sum up, this study uses FACS to screen PDPN to express different murine melanoma cells, and to establish a mouse with CLEC-2 gene defect in bone marrow transplantation. Through the study of the tumor cells and platelets in vitro and the establishment of experimental model of experimental mouse melanoma lung metastasis, the PDPN and platelet CLEC-2 expressed in the melanoma cells of the rat are clearly defined. Interaction, both in vivo and in vivo, can induce platelet activation, and the activation of platelets induced by two in vivo promotes the occurrence of lung metastases in murine melanoma, in which the activation of platelets is partly dependent on the Syk tyrosine kinase signaling pathway. The PDPN and platelet CLEC-2 expressed by the tumor cells are expected to be a prediction of melanoma. Tumor metastasis and new target of anti-tumor metastasis therapy.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R739.5

【共引文獻(xiàn)】

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