Abstract
Angiogenesis is considered one of the hallmarks of cancer and plays a critical role in the development of tumor. Fibroblast growth factor 2 (FGF-2) is a member of the FGF family and participates in excessive cancer cell proliferation and tumor angiogenesis. Thus, targeting FGF-2 was considered to be a promising anti-tumor strategy. A disulfide-stabilized diabody (ds-Diabody) against FGF-2 was produced in Pichia pastoris (GS115) by fermentation and the anti-tumor activity was analyzed. The novel 10-L fed batch fermentation with newly designed media was established, and the maximum production of the ds-Diabody against FGF-2 reached 210.4 mg/L. The ds-Diabody against FGF-2 was purified by Ni2+ affinity chromatography and DEAE anion exchange chromatography. The recombinant ds-Diabody against FGF-2 could effectively inhibit proliferation, migration, and invasion of melanoma and glioma tumor cells stimulated by FGF-2. Furthermore, xenograft tumor model assays showed that the ds-Diabody against FGF-2 had potent antitumor activity in nude mice by inhibiting tumor growth and angiogenesis. The tumor growth inhibition rate of melanoma and glioma was about 70 and 45%, respectively. The tumor angiogenesis inhibition rate of melanoma and glioma was about 64 and 51%, respectively. The results revealed that the recombinant ds-Diabody against FGF-2 may be a promising anti-tumor drug for cancer therapy.
Highlights
Malignant tumor has become the second leading cause of death worldwide, and there were about 9.6 million cancer-related deaths in the year before last [1]
We mainly reported the production of ds-Diabody against Fibroblast growth factor 2 (FGF-2) by high density fermentation in recombinant Pichia pastoris and its effects on tumor angiogenesis and tumor growth in vitro and in vivo
The recombinant Pichia pastoris GS115-pPICZaA-ds-Diabody was constructed in our previous study (Figure 1A) [17]
Summary
Malignant tumor has become the second leading cause of death worldwide, and there were about 9.6 million cancer-related deaths in the year before last [1]. FGF-2 integrates the extracellular domain of fibroblast growth factor receptor (FGFR) and heparan sulfate proteoglycans (HSPG) to induce the autophosphorylation of FGFR intracellular tyrosine kinase domain and lead to the activation of complex signal transduction pathways [11, 12]. They participate in the development of tumors as oncogenes by inducing mitogenic and survival signals, promoting tumor cell invasion and metastasis, promoting epithelial–mesenchymal transition, promoting angiogenesis, and participating in tumor recurrence and drug resistance [13]. Targeting FGF-2 for inhibition of tumor growth and angiogenesis was considered to be a promising therapeutic strategy
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