Up-regulation of platelet-derived growth factor-A is responsible for the failure of re-initiated interferon alpha treatment in hepatocellular carcinoma

• Published in: BMC cancer Vol. 12; no. 1; p. 439
• Main Authors: Zhang, Ju-Bo, Sun, Hui-Chuan, Jia, Wei-Dong, Zhuang, Peng-Yuan, Qian, Yong-Bing, Zhu, Xiao-Dong, Kong, Ling-Qun, Wang, Lu, Wu, Wei-Zhong, Tang, Zhao-You
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 01.10.2012; BioMed Central; BMC
• Subjects: Analysis; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Benzamides - pharmacology; Biological response modifiers; Blotting, Western; Cancer; Care and treatment; Cell Line, Tumor; Drug therapy; Endothelium; Gene Expression Regulation, Neoplastic - drug effects; Health aspects; Hepatocellular carcinoma; Hepatoma; Humans; Imatinib Mesylate; Interferon alpha; Interferon-alpha - pharmacology; Interferon-α; Liver cancer; Liver Neoplasms, Experimental - blood supply; Liver Neoplasms, Experimental - drug therapy; Liver Neoplasms, Experimental - metabolism; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Microvessel density; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - prevention & control; Phosphorylation - drug effects; Physiological aspects; Piperazines - pharmacology; Platelet-derived growth factor; Platelet-Derived Growth Factor - genetics; Platelet-Derived Growth Factor - metabolism; Platelet-derived growth factor-A; Proteins; Pyrimidines - pharmacology; Receptors, Platelet-Derived Growth Factor - metabolism; Retreatment; Reverse Transcriptase Polymerase Chain Reaction; Studies; Treatment Failure; Tumor Burden - drug effects; Tumors; Up-Regulation - drug effects; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - blood; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Xenograft Model Antitumor Assays; China
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/1471-2407-12-439

Postoperative interferon-α(IFN-α) treatment delays hepatocellular carcinoma(HCC) recurrence and prolongs patient survival, and may thus be an effective form of adjuvant therapy. However, clinical observations found that HCC recurs in some patients within 8 months of IFN-α treatment being discontinued. We investigated whether HCC regrowth appears after IFN-α is discontinued, whether re-initiated IFN-α is effective, and the underlying mechanisms of IFN-α treatment. The human HCC nude mouse model LCI-D20 was used to study the effects of IFN-α treatment, discontinued IFN-α treatment, and re-initiated IFN-α treatment on tumor growth. Tumor weight, microvessel density(MVD), serum vascular endothelial growth factor (VEGF), and tumor cell apoptosis were analyzed. Angiogenesis-related factors were studied using cDNA microarray in different tumor samples and confirmed using reverse transcription-polymerase chain reaction(RT-PCR) and Western blotting assays. Finally, imatinib was added with re-initiated IFN-α treatment to improve efficacy. IFN-α (1.5 × 107 U/kg/day for 20 days) suppressed HCC growth by 60.3% and decreased MVD by 52.2% compared with the control. However, tumor regrowth occurred after IFN-α was discontinued, and re-initiated IFN-α treatment was not effective for inhibiting tumor growth or reducing MVD compared with a saline-treated group. cDNA microarray showed VEGF was down-regulated while platelet-derived growth factor-A (PDGF-A) was up-regulated when IFN-α treatment was re-initiated. These findings were further confirmed with RT-PCR and Western blotting assay. The combination of imatinib with re-initiated IFN-α reduced HCC weight by 30.7% and decreased MVD by 31.1% compared with IFN-α treatment only (P=0.003 and 0.015, respectively). Tumor regrowth occurred after IFN-α treatment was discontinued. Re-initiated IFN-α treatment was not effective and was associated with up-regulation of PDGF-A, while the VEGF remained suppressed. The combination of a PDGF-receptor inhibitor with IFN-α improved the effect of the re-initiated treatment.