本文選題：乳腺癌 + 循環(huán)腫瘤細(xì)胞��； 參考：《第三軍醫(yī)大學(xué)》2016年博士論文

【摘要】：侵襲轉(zhuǎn)移是惡性腫瘤重要的生物學(xué)特征,是導(dǎo)致癌癥復(fù)發(fā)和患者死亡的重要原因。乳腺癌是威脅全球女性健康的惡性腫瘤之一,早期即可發(fā)生遠(yuǎn)處轉(zhuǎn)移,循環(huán)腫瘤細(xì)胞被認(rèn)為是血行轉(zhuǎn)移的關(guān)鍵步驟,它對指導(dǎo)臨床制定治療方案、監(jiān)測治療效果、提示乳腺癌的復(fù)發(fā)或轉(zhuǎn)移、以及評估患者預(yù)后情況都有重要意義。循環(huán)腫瘤細(xì)胞的研究正在深入,愈來愈多的目光集中到臨床應(yīng)用方面,而對于各種治療能否降低循環(huán)腫瘤細(xì)胞仍有爭議。因此,我們開展一項meta分析,整理了已經(jīng)發(fā)表的在治療前后檢測循環(huán)腫瘤細(xì)胞的研究論文,并評估現(xiàn)有的抗腫瘤治療對循環(huán)腫瘤細(xì)胞的影響。結(jié)論是肯定的,但要將其應(yīng)用于臨床實踐還需更多更深入的研究。至今,化療仍然是乳腺癌治療的基本手段之一,一線藥物紫杉類、蒽環(huán)類和抗代謝類等化療藥物的使用,盡管可以在很大程度上改善患者預(yù)后,但其毒副反應(yīng)也不容忽視。隨著傳統(tǒng)中藥開發(fā)新藥治療癌癥成為新的研究方向。越來越多的報道證實槐耳清膏具有抗腫瘤作用,是有效的乳腺癌臨床輔助治療藥物。然而,槐耳清膏的抗腫瘤作用機(jī)制尚不完全明了,尤其對循環(huán)腫瘤細(xì)胞的形成的影響尚不清楚。有研究表明上皮細(xì)胞間質(zhì)化(EMT)與循環(huán)腫瘤細(xì)胞間存在密切的聯(lián)系,而且循環(huán)腫瘤細(xì)胞本身也會表達(dá)EMT的相關(guān)標(biāo)志物。因此我們提出假設(shè):槐耳清膏可能調(diào)節(jié)EMT影響循環(huán)腫瘤細(xì)胞的形成,從而降低乳腺癌的轉(zhuǎn)移風(fēng)險。由于商品化的儀器,比如Cellsearch?更側(cè)重于臨床,主要用于預(yù)后監(jiān)測等方面,不能夠分離活細(xì)胞進(jìn)行后續(xù)實驗�；诖�,我們建立適合本科室檢測乳腺癌循環(huán)腫瘤細(xì)胞的方法對32例臨床樣本進(jìn)行檢測應(yīng)用,然后在小鼠乳腺癌原位移植瘤模型上探討槐耳清膏抑制乳腺癌循環(huán)腫瘤細(xì)胞產(chǎn)生的作用與機(jī)制。其主要結(jié)果和結(jié)論如下:1.循環(huán)腫瘤細(xì)胞反映抗腫瘤治療效果的meta分析。(1)通過隨機(jī)效應(yīng)模型分析治療前后循環(huán)腫瘤細(xì)胞的陽性率,總體分析顯示:與治療前相比,治療后循環(huán)腫瘤細(xì)胞的陽性率顯著下降(RR=0.68,95%CI:0.61 to 0.76,P0.00001;I2=73%,P0.00001)。(2)亞組分析顯示不同治療手段對循環(huán)腫瘤細(xì)胞的陽性率的影響不盡相同。新輔助化療、化療和聯(lián)合治療后循環(huán)腫瘤細(xì)胞陽性率顯著下降:新輔助化療(RR=0.65,95%CI:0.52 to 0.81,P=0.0001;I2=32%,P=0.16),化療(RR=0.81,95%CI:0.69 to 0.95,P=0.009;I2=72%,P0.0001)和聯(lián)合治療(RR=0.64,95%CI:0.54 to 0.75,P0.0001;I2=67%,P0.0001),而手術(shù)亞組治療后循環(huán)腫瘤細(xì)胞陽性率未顯著降低(RR=1.40,95%CI:0.56 to 3.50,P=0.47;I2=45%,P=0.16)。(3)亞組分析顯示乳腺癌不同分子分型對循環(huán)腫瘤細(xì)胞陽性率有影響:與治療前相比,HER2陽性患者和HER2陰性患者的循環(huán)腫瘤細(xì)胞陽性率顯著下降:HER2陽性患者(RR=0.68,95%CI:0.57 to 0.82,P0.0001;I2=0%,P=0.59)和HER2陰性患者(RR=0.52,95%CI:0.31 to 0.86,P=0.01;I2=66%,P=0.01),但是三陰性患者的循環(huán)腫瘤細(xì)胞陽性率沒有變化(RR=0.38,95%CI:0.06 to 2.33,P=0.29;I2=72%,P=0.06)。(4)循環(huán)腫瘤細(xì)胞狀態(tài)與患者預(yù)后間關(guān)系的亞組分析顯示:與治療后循環(huán)腫瘤細(xì)胞上升或者持平的患者相比,循環(huán)腫瘤細(xì)胞下降的患者有更長的總生存期(均值差=11.61月,95%CI:8.63 to 14.59,P0.00001;I2=69%,P=0.07);其疾病進(jìn)展概率更低(OR=0.54,95%CI:0.33 to 0.89,P=0.01;I2=45%,P=0.05),無進(jìn)展生存期更長(均值差=5.07月,95%CI:2.70 to 7.44,P0.0001;I2=96%,P0.00001)。2.乳腺癌循環(huán)腫瘤細(xì)胞檢測方法的建立及在臨床樣本中的初步應(yīng)用(1)通過組合密度梯度離心、免疫磁珠分離和流式細(xì)胞儀檢測技術(shù),建立起乳腺癌外周血循環(huán)腫瘤細(xì)胞的分離方法。免疫熒光用于鑒定分離的循環(huán)腫瘤細(xì)胞。結(jié)果表明所建立的分離方法能有效地從乳腺癌患者外周血分離循環(huán)腫瘤細(xì)胞,鑒定結(jié)果顯示,乳腺癌循環(huán)腫瘤細(xì)胞是Epcam陽性、CK18陽性、CD45陰性的有核細(xì)胞,其細(xì)胞直徑較大,核漿比例較高,符合目前對循環(huán)腫瘤細(xì)胞的定義。雖然該測定方法以人工操作為主,但較商品化的儀器Cellsearch?等能夠提供更多信息,有利于對循環(huán)腫瘤細(xì)胞進(jìn)行更深入的基礎(chǔ)和臨床研究。(2)對32例乳腺癌患者外周血進(jìn)行了循環(huán)腫瘤細(xì)胞檢測,27例能檢出循環(huán)腫瘤細(xì)胞(≥1 CTC/7.5m L),占比為84.4%,而作為對照組的纖維腺瘤患者、健康自愿者中的血液均為陰性。在32例患者中,10例轉(zhuǎn)移患者的循環(huán)腫瘤細(xì)胞陽性且≥5 CTCs/7.5mL檢出率為80%,而無轉(zhuǎn)移患者的陽性且≥5 CTCs/7.5mL檢出率僅為22.7%,P=0.002。Ki67陽性患者的循環(huán)腫瘤細(xì)胞陽性且≥5 CTCs/7.5m L檢出率50%,高于Ki67陰性患者的循環(huán)腫瘤細(xì)胞陽性且≥5 CTCs/7.5mL檢出率(12.5%),P=0.061。上述結(jié)果顯示,我們建立的循環(huán)腫瘤細(xì)胞檢測方法穩(wěn)定性和可靠性好,能夠較好的反映乳腺癌的進(jìn)展。3.槐耳清膏抑制乳腺癌移植瘤的EMT表型,繼而抑制其循環(huán)腫瘤細(xì)胞產(chǎn)生的作用和機(jī)制(1)構(gòu)建帶綠色熒光的GFP-4T1細(xì)胞系,然后建立BALB/c小鼠乳腺癌原位移植瘤模型,再通過流式細(xì)胞儀檢測外周血中綠色熒光細(xì)胞的數(shù)量而反映乳腺癌循環(huán)腫瘤細(xì)胞狀態(tài)。通常在建模第12天即可從外周血中檢測到綠色熒光細(xì)胞,表明模型建立成功。(2)建模第二周末開始藥物干預(yù),通過流式細(xì)胞儀動態(tài)監(jiān)測血液中GFP-4T1細(xì)胞變化,每周1次,共4次,以反映乳腺癌荷瘤小鼠外周血循環(huán)腫瘤細(xì)胞的狀態(tài)。第一周各組間循環(huán)腫瘤細(xì)胞未見顯著差異。而在第2、3和4周,槐耳清膏給藥組(50mg和100mg)檢出的循環(huán)腫瘤細(xì)胞數(shù)量顯著少于對照組(P值均小于0.01),而多西他賽組則無顯著差異。這些結(jié)果表明槐耳清膏較多西他賽能更有效地抑制循環(huán)腫瘤細(xì)胞的形成。(3)槐耳清膏能減少轉(zhuǎn)移灶的形成,在對照組中有22處轉(zhuǎn)移灶,而槐耳清膏100mg組只有13處,P0.05;而多西他賽組與對照組無顯著差異,P0.05。通過調(diào)控移植瘤EMT表型,繼而減少循環(huán)腫瘤細(xì)胞的產(chǎn)生,P0.05。(4)槐耳清膏處理后,顯著增高E-cadherin表達(dá)而降低N-cadherin表達(dá),與降低循環(huán)腫瘤細(xì)胞數(shù)量及減少轉(zhuǎn)移灶形成相一致,提示槐耳清膏能通過調(diào)控移植瘤的EMT表型降低循環(huán)腫瘤細(xì)胞的產(chǎn)生進(jìn)而減少轉(zhuǎn)移的發(fā)生。(5)相較于對照組,槐耳清膏和多西他賽處理均能有效抑制腫瘤細(xì)胞的生長(P值均小于0.05)�；倍甯嗄軌蛱岣咝∈蟮纳媛是覍w重與白細(xì)胞無明顯影響,而多西他賽則相反。綜上所述,循環(huán)腫瘤細(xì)胞可以作為監(jiān)測乳腺癌治療效果、乳腺癌患者預(yù)后的指標(biāo),同時也能夠輔助臨床醫(yī)生為病人定制個體化診療的決策�；倍甯嗤ㄟ^調(diào)控乳腺癌的EMT表型從而抑制循環(huán)腫瘤細(xì)胞的生成,最終減少乳腺癌的轉(zhuǎn)移幾率。
[Abstract]:Invasion and metastasis is an important biological characteristic of malignant tumor, which is an important cause of cancer recurrence and patient death. Breast cancer is one of the malignant tumors that threaten the health of women in the world. Distant metastasis can occur in the early stage. Circulating tumor cells are considered to be the key steps of blood transfer. The therapeutic effects, which suggest the recurrence or metastasis of breast cancer, and the assessment of the prognosis of the patients are of great significance. The research on circulating tumor cells is going deep and more and more attention is focused on the clinical application, and it is still controversial whether various treatments can reduce circulating tumor cells. Therefore, we have carried out a meta analysis. Published research papers on circulating tumor cells before and after treatment, and assess the impact of existing antitumor therapies on circulating tumor cells. Conclusion is affirmative, but more in-depth studies are needed to apply it to clinical practice. To date, chemotherapy is still one of the basic methods for the treatment of breast cancer, first line medicine yew, anthracene ring The use of chemotherapeutic drugs such as class and antimetabolic drugs, although it can improve the prognosis of patients to a great extent, can not be ignored. With the development of new drugs in the development of new drugs with traditional Chinese medicine, it has become a new research direction. More and more reports have confirmed that the ointment has anti tumor use and is an effective clinical adjuvant therapy for breast cancer. However, the anti-tumor mechanism of the cream is still not fully understood, especially the effect of the formation of circulating tumor cells. Studies have shown that there is a close relationship between EMT and circulating tumor cells, and the circulating tumor cells themselves also express EMT related markers. Therefore we propose that: It may regulate the formation of circulating tumor cells and reduce the risk of metastasis of breast cancer. As commercial instruments, such as Cellsearch, are more focused on clinical and mainly for prognosis monitoring, it is not possible to separate living cells for follow-up experiments. Based on this, we set up a suitable laboratory for the detection of breast cancer in the undergraduate room. The tumor cell method was used to detect 32 cases of clinical samples, and then the effect and mechanism of the inhibition of the circulating tumor cells in breast cancer were investigated in the mouse model of breast cancer in situ transplantation. The main results and conclusions were as follows: the meta analysis of the 1. circulating tumor cells reflecting the therapeutic effect of anti-tumor treatment. (1) through random Xiao Yingmo The positive rate of circulating tumor cells before and after treatment was analyzed. The overall analysis showed that the positive rate of circulating tumor cells decreased significantly after treatment (RR=0.68,95%CI:0.61 to 0.76, P0.00001; I2=73%, P0.00001). (2) subgroup analysis showed that the effect of different treatment methods on the positive rate of circulating tumor cells was different. The positive rate of circulating tumor cells decreased significantly after chemotherapy, chemotherapy and combined therapy: neoadjuvant chemotherapy (RR=0.65,95%CI:0.52 to 0.81, P=0.0001; I2=32%, P=0.16), chemotherapy (RR=0.81,95%CI:0.69 to 0.95, P=0.009; I2=72%, P0.0001), and combined therapy (RR=0.64,95%CI: 0.54 to 0.75), and surgery subgroup after treatment of circulating tumor The positive rate of cell was not significantly decreased (RR=1.40,95%CI:0.56 to 3.50, P=0.47; I2=45%, P=0.16). (3) the subgroup analysis showed that different molecular types of breast cancer had an influence on the positive rate of circulating tumor cells: compared with before treatment, the positive rate of circulating tumor cells in HER2 positive patients and HER2 negative patients decreased significantly: HER2 positive patients (RR=0.68,95%CI:0.5) 7 to 0.82, P0.0001; I2=0%, P=0.59) and HER2 negative patients (RR=0.52,95%CI:0.31 to 0.86, P=0.01; I2=66%, P=0.01), but there was no change in the positive rate of circulating tumor cells in three negative patients (RR=0.38,95%CI:0.06 to 2.33). (4) a subgroup analysis of the relationship between the state of the circulating tumor cells and the prognosis of the patients showed that after treatment Patients with circulatory tumor cells rising or flat had longer total survival (=11.61 months, 95%CI:8.63 to 14.59, P0.00001; I2=69%, P=0.07) in patients with decreased circulating tumor cells; the progression of the disease was lower (OR=0.54,95%CI:0.33 to 0.89, P=0.01; I2=45%, P=0.05), and the progression - free survival period was longer (mean mean =5.07 months) 2.70 to 7.44, P0.0001, I2=96%, P0.00001) the establishment of a method for detecting circulating tumor cells in.2. breast cancer and its preliminary application in clinical samples (1) a separation method was established by combining density gradient centrifugation, immunomagnetic beads separation and flow cytometry, and the immunofluorescence was used to identify and isolate the tumor cells in the peripheral blood of breast cancer. The results show that the circulating tumor cells can be isolated from the peripheral blood of the breast cancer patients effectively. The results show that the circulating tumor cells of breast cancer are Epcam positive, CK18 positive and CD45 negative nucleated cells. The cell diameter is larger and the proportion of the nuclear plasma is high, which conforms to the current circulating tumor cells. Definition. Although this method is based on manual operation, but more information can be provided than commercial instrument Cellsearch? It is beneficial to further basic and clinical study of circulating tumor cells. (2) circulating tumor cell detection in peripheral blood of 32 patients with breast cancer and 27 cases of circulating tumor cells (> 1 CTC/7.5m) can be detected. L) was 84.4%, and the blood of the healthy volunteers was negative in the fibroadenoma patients of the control group. In the 32 patients, 10 cases of metastatic tumor cells were positive and the detection rate of 5 CTCs/7.5mL was 80%, while no metastases were positive and the rate of 5 CTCs/7.5mL was only 22.7%, and the circulating tumor in P=0.002.Ki67 positive patients The positive rate of cell positive and 5 CTCs/7.5m L was 50%, higher than the positive rate of circulating tumor cells in Ki67 negative patients and the positive rate of 5 CTCs/7.5mL (12.5%). The above results of P=0.061. showed that the method of circulating tumor cell detection established by us was stable and reliable, and the good progress in anti screening of breast cancer was to inhibit the migration of breast cancer. The EMT phenotype of the tumor, then inhibits the role and mechanism of its circulating tumor cells (1) to construct a GFP-4T1 cell line with green fluorescence, and then establish an in situ xenograft model of breast cancer in BALB/c mice, and then detect the number of green fluorescent cells in the peripheral blood by flow cytometry. Green fluorescent cells could be detected from the peripheral blood for Twelfth days, indicating that the model was established successfully. (2) the drug intervention was started at the end of the second week of modeling, and the changes of GFP-4T1 cells in the blood were monitored dynamically by flow cytometry. 1 times a week, a total of 4 times, in order to reflect the state of peripheral blood circulating tumor cells in the breast cancer bearing mice. There was no significant difference in tumor cells, but in the 2,3 and 4 weeks, the number of circulating tumor cells in the group (50mg and 100mg) was significantly less than that of the control group (P value was less than 0.01), but there was no significant difference in the docetaxel group. These results showed that Huaxi ointment was more effective than docetaxel in inhibiting the formation of circulating tumor cells. (3) Sophora japonica Ointment can reduce the formation of metastases, and there are 22 metastatic foci in the control group, while group 100mg only 13, P0.05, but there is no significant difference between the docetaxel group and the control group. P0.05. can reduce the production of circulating tumor cells by regulating the EMT phenotype of the transplanted tumor, and after the treatment of P0.05. (4), the E-cadherin expression is significantly increased. Low N-cadherin expression was consistent with reducing the number of circulating tumor cells and reducing the formation of metastatic foci. It was suggested that Hua ear ointment could reduce the occurrence of circulating tumor cells by regulating the EMT phenotype of the transplanted tumor and then reduce the occurrence of metastasis. (5) compared to the control group, the growth of the tumor cells could be effectively suppressed by the control group (P The value is less than 0.05). It can improve the survival rate of mice and have no obvious effect on the body weight and the white blood cells, while the docetaxel is the opposite. In summary, the circulating tumor cells can be used to monitor the therapeutic effect of breast cancer and the prognosis of the breast cancer patients, and can also assist the clinicians to make the decision making and individualized diagnosis and treatment for the patients. Conclusion: the black ear extract can inhibit the formation of circulating tumor cells by regulating the EMT phenotype of breast cancer, and ultimately reduce the metastatic probability of breast cancer.
【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R737.9

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