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Anti-angiogenic therapy inhibits liver cancer growth and metastasis, recurrence and Mechanism

Author: WangZuoLong
Tutor: WangLu
School: Fudan University
Course: Surgery
Keywords: Hepatocellular carcinoma IFN-α Hepatocyte growth factor Vascular endothelial growth factor Angiogenesis DLL4 VEGF Prognosis
CLC: R735.7
Type: Master's thesis
Year: 2010
Downloads: 85
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Abstract

Research purposes interferon-α (IFN-a) as a multi-purpose cytokines, not only for the treatment of chronic hepatitis, but also directly inhibit tumor cell proliferation and inhibition of tumor angiogenesis by in vivo tests and clinical randomized controlled study clearly alpha interferon have confirmed study the inhibition of tumor growth and delay the recurrence, inhibition of tumor angiogenesis, the study by the unique transfer animal model LCI-D20 alpha interferon highly metastatic liver cancer nude mouse model of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF) mRNA expression, further understanding of the mechanism of its anti-angiogenic effect. Materials and methods of application of green fluorescent protein transfection of highly metastatic hepatoma cell line HCC-LM3 establish high metastatic potential of human hepatocellular carcinoma in nude mice model LCI-D20 (n = 48), the day after planting respectively interferon-α 1.5 × subcutaneous injection of 104u/kg · d (treatment group, n = 24) or saline (control group, n = 24), respectively, 2w, 3w, 4w 5w after the treatment group and the control group in nude mice were sacrificed 6 each comparison size of liver tumors and intrahepatic metastasis, immunohistochemical detection of tumor microvessel density and angiogenesis the PCR microarray gene, real-time PCR validation. Intrahepatic tumor size of the results of the treatment group and the control group were 0.11 ± 0.03 cm3, 0.99 ± 0.37cm3 (P lt; 0.05); the intrahepatic metastasis rates were 33.3% (4/12), 83.3% (10/12) (P lt; 0.05); number of intrahepatic metastasis were 0.67 ± 0.31 vs 1.91 ± 0.43 (P lt; 0.05); intratumoral microvessel density (MVD) respectively 3.19 ± 0.52,4.85 ± 0.72 (P lt; 0.05 PCR microarray); generated through the blood vessels, we found 4w after alpha interferon treatment significantly inhibited tumor VEGF and HGF expression, RT-PCR results suggest that the treatment group and the control group the tumor VEGFmRNA expression (-ΔCT) were -8.16 ± 0.54 , -6.95 ± 0.86 (P lt; 0.05); HGFmRNA expression were -11.62 ± 0.63, -10.56 ± 0.48 (P lt; 0.05). Conclusion IFN-α inhibition of HGF and VEGF expression may be the role of anti-angiogenesis, inhibit the role of one of the mechanisms of tumor growth and metastasis. benign trend may be part of the beginning of alpha interferon treatment group action in the IFN-a inhibition of HGF, thereby reducing downstream of VEGF expression to inhibit angiogenesis, inhibit tumor growth, and to reduce the transition probability Objective To study the purpose of: liver cells cancer (Hepatocellular Carcinoma, HCC) is a common malignant solid tumors, approximately 600,000 cases worldwide, the annual number of new cases, and liver cancer fatal cases of all tumor-related deaths. With the development of anti-tumor angiogenesis therapy studies, VEGF targeted therapy is becoming an important means in the treatment of liver cancer, but its clinical usefulness is often accompanied by the inevitable acquired resistance. In recent years, more and more scholars began to focus on the interaction the DLL4/Notch signaling pathway of VEGF pathway and subsequent extensive research results suggest that the DLL4 targeted therapy may bring new strategies to anti-angiogenic therapy. In this study, analysis of DLL4 expression in HCC and adjacent normal liver tissue and its relationship with VEGF-A, CD31, and explore DLL4 prognostic value in patients with liver cancer after. Materials and methods to collect the period January 1999 - March Zhongshan Hospital, Liver Surgical Oncology underwent radical resection of HCC patients with tumors and noncancerous liver tissue specimens 105 cases produced tissue microarray. The pathological diagnosis in patients with HCC, did not receive any treatment before surgery. Detect tissue microarray by immunohistochemical methods (immunohistochemistry) of DLL4 and CD31 expression. Comparative paracancerous of DLL4 expression of cancer nests of DLL4 expression of the differences of the clinical and pathological features of of DLL4 patient age, gender, tumor diameter, capsule, microvascular tumor thrombus, tumor cell differentiation degree, and overall survival time (Overall Survival, OS) and patients with recurrence time (Time to Recurrence, TTR). Analysis chip DLL4 and vascular endothelial growth factor-A (Vascular Endothelial Growth Factor-A, VEGF-A) and CD31 correlation. . Results DLL4 positive staining mainly located in the the hepatoma cell cancer and adjacent normal liver cell envelope and cytoplasmic staining of the same degree of visible most of the vascular endothelial cells in cancer paraneoplastic tumor stromal cells as negative staining, cancer next DLL4 expression , there is no significant difference compared with the cancer nests. The cancer nests DLL4 low expression was associated with younger age (P = 0.049), tumor poorly differentiated Related (PP = 0.028), while the the DLL4 low cancerous liver tissues expression with large tumor volume (P = 0.037), tumor poorly differentiated ( P = 0.004) related. Low paracancerous the DLL4 expression of the patient's overall survival (OS) and disease-free survival time (DFS) were 25.3 and 23.2 months, high paracancerous DLL4 expression by univariate analysis found patients overall survival and disease-free survival time 107.0 and 87.7 months, comparing the two statistically significant difference (P = 0.002, P = 0.017); the DLL4 expression within the low cancer nests patients overall survival time to 45.2 months DLL4 expression in patients with high cancer nests 107.0 month, both compared to the statistically significant difference (P = 0.031), the DLL4 expression within the cancer nests and tumor-free survival time was no significant correlation. Multivariate analysis of the DLL4 expression prompt paraneoplastic OS (HR = 2.042; 95% CI, 1.130 to 3.688; P = 0.018) and DFS (HR = 1.979; 95% CI, 1.071 to 3.733; P = 0.030) were independent risk factors . Cancer nests DLL4 OS (HR = 2.029; 95% CI, 1.107 to 3.717; P = 0.022) but not an independent risk factor for DFS. In adjacent endothelial cells of the liver tissue and cancer nests can be found in the expression of CD31-positive, and the expression of DLL4 expression of the degree of the intensity of the corresponding tissue. Cancerous liver tissues of CD31 expression of DLL4 expression was negatively correlated (r = -0.229, P = 0.019), but in the tumor tissue, the correlation is not significant (r = -0.131, P = 0.073). In adjacent (r = 0.248, P = 0.011) and cancer nests (r = 0.154, P = 0.012), VEGF-A expression was positively correlated with DLL4 expression. Conclusions cancer paraneoplastic cancer nest low DLL4 expression is an independent risk factor for HCC patients' survival and tumor recurrence. The DLL4 expected clinical application to become independent prognostic indicators predict liver cancer patients. DLL4 may be a potential target as postoperative adjuvant treatment of HCC and require further mechanisms.

Anti-angiogenic therapy inhibits liver cancer growth and metastasis, recurrence and Mechanism

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