| Esophageal cancer is one of the most common diseases in the digestive system with early metastasis, high mortality and poor prognosis. Curative treatment consists of surgical resection assisted by adjunctive therapy, such as chemotherapy and/or radiotherapy, but there is still a high rate of recurrence, leading to a five-year survival of only 25%. It has been shown that gene therapy can play a role as an adjuvant treatment modality for esophageal cancer. Gene therapy is now a mature discipline, which has the potential to treat or even cure several diseases. In light of the several hundred clinical trials conducted thus far, it is apparent that viral delivery methods currently represent the most appealing option for efficient gene delivery both ex vivo and in vivo. Oncolytic viruses are replicating microorganisms that have been selected or engineered to grow inside tumor cells. Arming oncolytic viruses with anti-cancer genes has been a major focus in cancer virotherapy, and exploited transgenes include tumor suppressor, pro-apoptotic, anti-angiogenic, "suicide," RNA interference and immunomodulatory genes.Newcastle disease virus (NDV) is an enveloped paramyxovirus with a single-stranded, negative-sense RNA genome. This virus has been used for the treatment of cancer patients based on its efficient replication in cancer cells, specific killing of cancer cells and its limited toxicity to normal cells. NDV expresses two surface proteins, hemagglutinin-neuraminidase (HN) and the fusion protein. The HN protein is a 74-kDa membrane glycoprotein, which is known to boost innate immunity in anti-tumor therapy. This molecule not only allows the attachment of the virus to the receptors of host cells rich in sialic acids as well as the release of viruses from the cells, but it also possesses neuraminidase activity, which can hydrolyze the sialic acid on those receptors. Additionally, the HN protein plays an important role in inducing protective immunity against virus infection and is therefore susceptible to immune pressure, which generates antigenic variation. Furthermore, HN can also induce IFN-α and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in human peripheral blood mononuclearcells (PBMC) and is involved in activation of apoptotic pathways. All of these characteristics support HN as a promising candidate for anti-tumor therapy.Here, we combined the tumor-specific apoptosis-inducing gene encoding HN and a cancer-specific human telomerase reverse transcriptase promoter (hTERT) with a RAP A.Ⅰ adenovirus vector to construct a novel dual-specific anti-tumor oncolytic adenovirus Ad-hTERT-Ela-HN, as well as the control recombinant adenoviruses Ad-mock, Ad-CMV-Ela, Ad-hTERT-E1a, Ad-CMV-HN, Ad-hTERT-HN and Ad-CMV-E1a-HN. Human telomerase reverse transcriptase, a catalytic subunit of the telomerase enzyme, has been identified as an ideal tumor-associated antigen. With its broad expression in more than 85% of all cancers despite little or no expression in normal somatic cells, hTERT has been investigated as a potentially highly specific molecular target for therapeutic interventions in various types of cancers. Therefore, hTERT has been used for tumor-specific expression of transgenes.We found that Ad-hTERT-E1a-HN could selectively target and kill tumor cells by inducing apoptosis in human esophageal cancer EC-109 cells in vitro. Furthermore, to determine whether Ad-hTERT-E1a-HN can cause tumor regression in BALB/c nude mice bearing EC-109 cells as xenografts, we also examined the effects of intratumoral and intravenous injections of Ad-hTERT-E1a-HN. The results indicated that Ad-hTERT-Ela-HN represents a potentially promising anti-tumor agent in developing new therapeutic strategies for the treatment of esophageal cancers and may have clinical value toward other neoplastic diseases. |
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