Abstract
Tumor growth and metastasis depend on angiogenesis. Thus, inhibiting tumor angiogenesis has become promising cancer therapeutic strategy in recent years. Tumstatin is a more powerful angiogenesis inhibitor than endostatin. Anti-angiogenic active fragment encoding amino acids 45–132 (Tum-5) of tumstatin was subcloned into four different inducible expression vectors and successfully solubly expressed in Escherichia coli BL21 (DE3) in this study. Subsequently, an anaerobic inducible expression vector was constructed under Vitreoscilla hemoglobin gene promoter Pvhb in E. coli Nissle 1917 (EcN). The secretory expression of Tum-5 in the engineered bacterium was determined in vitro and in vivo by Western blot or immunochemistry. The anti-tumor effect detection demonstrated that EcN could specifically colonize the tumor, and B16 melanoma tumor growth was remarkably restrained by EcN (Tum-5) in mice bearing B16 melanoma tumor. Abundant infiltrating inflammatory cells were observed in tumor areas of the EcN-treated group through hematoxylin and eosin staining, with a relatively reduced expression of endothelial marker platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) by immunofluorescence in tumor sections of EcN (Tum-5)-treated mice. No significant morphological differences were observed in the liver, kidney and spleen between EcN-treated mice and the control group, indicating that EcN was cleared by the immune system and did not cause systemic toxicity in mice. These findings demonstrated that the gene delivery of Tum-5 to solid tumors could be an effective strategy for cancer therapy.
Highlights
The use of bacteria for cancer treatment has a long history [1,2,3]
The anti-tumor effect detection demonstrated that E. coli Nissle 1917 (EcN) could colonize the tumor, and B16 melanoma tumor growth was remarkably restrained by EcN (Tum5) in mice bearing B16 melanoma tumor
These findings demonstrated that the gene delivery of Tum-5 to solid tumors could be an effective strategy for cancer therapy
Summary
The use of bacteria for cancer treatment has a long history [1,2,3]. The detailed mechanisms of their clinical effects are still unknown, but previous studies clearly showed that some bacteria could play important roles in treating some diseases, especially cancer. Bacteria were used in cancer therapy by combining with chemotherapeutic drugs [38, 39] or delivering anti-tumor agents such as interfering RNAs [40, 42] prodrug activating enzymes [30] and cytokines [41, 43] into tumor tissues. Intestinal probiotics EcN have been licensed as a pharmaceutical in several countries for the treatment of diseases, such as diarrhea and colitis ulcerosa, affecting the digestive tract [16, 26].
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