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• W2896071503 abstract "The development of gastric cancer is frequently related to the overexpression of wild-type p21 proteins, but it is rarely related to mutated Ras proteins. We previously constructed a broad-spectrum anti-p21-Ras single-chain variable fragment antibody (scFv), which was carried by the oncolytic adenovirus KGHV500. Here we explored the antitumor effects of this recombinant oncolytic adenovirus carried by cytokine-induced killer (CIK) cells on human gastric SGC7901 cells that overexpress wild-type Ras. The MTT assay, scratch test, Transwell assay, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay were performed in vitro to investigate the proliferation, migration, invasiveness, and cell apoptosis rate, respectively, of the human gastric cell line SGC7901 treated with KGHV500 adenovirus. Then, the tumor-targeting ability and systemic safety of KGHV500 adenovirus delivered by CIK cells were explored in vivo. We found that KGHV500 adenovirus could significantly inhibit proliferation, migration, and invasiveness and promote cell apoptosis in SGC7901 cells in vitro. In vivo studies showed that CIK cells could successfully deliver KGHV500 adenovirus to the tumor site; the two vectors synergistically killed tumor cells, and the treatment was relatively safe for normal tissues. In conclusion, this therapeutic strategy of recombinant adenovirus KGHV500 delivered by CIK cells offers a positive prospect for the targeted therapy of Ras-related cancers. The development of gastric cancer is frequently related to the overexpression of wild-type p21 proteins, but it is rarely related to mutated Ras proteins. We previously constructed a broad-spectrum anti-p21-Ras single-chain variable fragment antibody (scFv), which was carried by the oncolytic adenovirus KGHV500. Here we explored the antitumor effects of this recombinant oncolytic adenovirus carried by cytokine-induced killer (CIK) cells on human gastric SGC7901 cells that overexpress wild-type Ras. The MTT assay, scratch test, Transwell assay, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay were performed in vitro to investigate the proliferation, migration, invasiveness, and cell apoptosis rate, respectively, of the human gastric cell line SGC7901 treated with KGHV500 adenovirus. Then, the tumor-targeting ability and systemic safety of KGHV500 adenovirus delivered by CIK cells were explored in vivo. We found that KGHV500 adenovirus could significantly inhibit proliferation, migration, and invasiveness and promote cell apoptosis in SGC7901 cells in vitro. In vivo studies showed that CIK cells could successfully deliver KGHV500 adenovirus to the tumor site; the two vectors synergistically killed tumor cells, and the treatment was relatively safe for normal tissues. In conclusion, this therapeutic strategy of recombinant adenovirus KGHV500 delivered by CIK cells offers a positive prospect for the targeted therapy of Ras-related cancers. Gastric cancer is the fourth most common cancer worldwide and the second leading cause of cancer-related mortality in humans.1Ang T.L. Fock K.M. Clinical epidemiology of gastric cancer.Singapore Med. J. 2014; 55: 621-628Crossref PubMed Scopus (247) Google Scholar Current therapies for gastric cancer are traditional surgical treatment and chemotherapy. Studies showed that adjuvant chemotherapy produced a 6% increase in the 5-year overall survival of resectable gastric cancer patients.2Park S.C. Chun H.J. Chemotherapy for advanced gastric cancer: review and update of current practices.Gut Liver. 2013; 7: 385-393Crossref PubMed Scopus (53) Google Scholar, 3Paoletti X. Oba K. Burzykowski T. Michiels S. Ohashi Y. Pignon J.P. Rougier P. Sakamoto J. Sargent D. Sasako M. et al.GASTRIC (Global Advanced/Adjuvant Stomach Tumor Research International Collaboration) GroupBenefit of adjuvant chemotherapy for resectable gastric cancer: a meta-analysis.JAMA. 2010; 303: 1729-1737Crossref PubMed Scopus (684) Google Scholar However, chemotherapy is not effective in patients diagnosed at an advanced or unresectable stage. Molecularly targeted therapies provide opportunities for gastric cancer patients with poor prognosis. Trastuzumab is a currently approved targeting agent for the treatment of HER2-positive gastric cancers, and it increases the median overall survival of patients up to 13.8 months, compared with the 11.1-month improvement in overall survival produced by chemotherapy alone.4Bang Y.J. Van Cutsem E. Feyereislova A. Chung H.C. Shen L. Sawaki A. Lordick F. Ohtsu A. Omuro Y. Satoh T. et al.ToGA Trial InvestigatorsTrastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.Lancet. 2010; 376: 687-697Abstract Full Text Full Text PDF PubMed Scopus (5210) Google Scholar The rate of HER2 overexpression in gastric cancer is approximately 22%,5De Vita F. Giuliani F. Silvestris N. Catalano G. Ciardiello F. Orditura M. Human epidermal growth factor receptor 2 (HER2) in gastric cancer: a new therapeutic target.Cancer Treat. Rev. 2010; 36: S11-S15Abstract Full Text PDF PubMed Scopus (72) Google Scholar which indicates that only a few subsets of patients could receive benefits from trastuzumab. A large number of HER2-negative gastric cancer patients could not receive any benefit. As it is known that the development of gastric cancer is a complex and multistep process, gastric cancer treatment will not be a simple one-size-fits-all therapy. Therefore, searching for new attractive candidate targets and developing relevant therapy agents are urgent needs in gastric cancer therapy. Ras genes, classic proto-oncogenes, play an important role in cell growth and differentiation. Abnormally activated Ras proteins act as molecular switches in the processes of malignant transformation and tumorigenesis.6Milburn M.V. Tong L. deVos A.M. Brünger A. Yamaizumi Z. Nishimura S. Kim S.H. Molecular switch for signal transduction: structural differences between active and inactive forms of protooncogenic ras proteins.Science. 1990; 247: 939-945Crossref PubMed Scopus (846) Google Scholar Disappointingly, clinically effective anti-p21-Ras therapies have remained elusive until now, and Ras proteins have even been considered “undruggable.”7Young A. Lyons J. Miller A.L. Phan V.T. Alarcón I.R. McCormick F. Ras signaling and therapies.Adv. Cancer Res. 2009; 102: 1-17Crossref PubMed Scopus (182) Google Scholar, 8Papke B. Der C.J. Drugging RAS: Know the enemy.Science. 2017; 355: 1158-1163Crossref PubMed Scopus (234) Google Scholar, 9Cox A.D. Fesik S.W. Kimmelman A.C. Luo J. Der C.J. Drugging the undruggable RAS: Mission possible?.Nat. Rev. Drug Discov. 2014; 13: 828-851Crossref PubMed Scopus (1191) Google Scholar We developed an anti-p21-Ras single-chain variable fragment antibody (scFv) in previous studies, and we found that it could bind with all the wild-type and partially mutated H-Ras, K-Ras, and N-Ras proteins that exist in different human tumor cell lines and primary tumor tissues.10Yang J.L. Liu D.X. Zhen S.J. Zhou Y.G. Zhang D.J. Yang L.Y. Chen H.B. Feng Q. A novel anti-p21Ras scFv antibody reacting specifically with human tumour cell lines and primary tumour tissues.BMC Cancer. 2016; 16: 131Crossref PubMed Scopus (22) Google Scholar Then, this anti-p21-Ras scFv gene was cloned into adenovirus vectors, and the recombinant vectors showed obvious antitumor effects on several tumor cell lines in vivo and in vitro.11Yang J.L. Pan X.Y. Zhao W.X. Hu Q.C. Ding F. Feng Q. Li G.Y. Luo Y. The antitumor efficacy of a novel adenovirus-mediated anti-p21Ras single chain fragment variable antibody on human cancers in vitro and in vivo.Int. J. Oncol. 2016; 48: 1218-1228Crossref PubMed Scopus (11) Google Scholar To decrease the infection of normal cells, the adenovirus vectors were modified to be oncolytic viral vectors, where the endogenous E1a and E1b promoters of the adenovirus were replaced with the human telomerase reverse transcriptase (hTERT) and hypoxia response element (HRE) promoters, two tumor-specific promoters. This engineered adenovirus was called recombinant oncolytic adenovirus KGHV300, and it exhibited significant antitumor activity in several tumors in previous studies.12Pan X.Y. Liu X.J. Li J. Zhen S.J. Liu D.X. Feng Q. Zhao W.X. Luo Y. Zhang Y.L. Li H.W. Yang J.L. The antitumor efficacy of anti-p21Ras scFv mediated by the dual-promoter-regulated recombinant adenovirus KGHV300.Gene Ther. 2017; 24: 40-48Crossref PubMed Scopus (11) Google Scholar However, it could only be administered by intratumoral injection, because it can infect normal cells even though it cannot replicate in normal cells. To increase the tumor cell-targeting ability and systemic administration safety of the KGHV300 adenovirus, its cilia gene was modified so that it could bind to cytokine-induced killer (CIK) cells, and, thus, the new recombinant oncolytic adenovirus KGHV500 was constructed (unpublished data). It is well known that CIK cells have potent intratumoral homing ability in gene therapy,13Introna M. CIK as therapeutic agents against tumors.J. Autoimmun. 2017; 85: 32-44Crossref PubMed Scopus (42) Google Scholar and they are often used as effective pharmacological tools for cancer immunotherapy.14Gao X. Mi Y. Guo N. Xu H. Xu L. Gou X. Jin W. Cytokine-Induced Killer Cells As Pharmacological Tools for Cancer Immunotherapy.Front. Immunol. 2017; 8: 774Crossref PubMed Scopus (88) Google Scholar In this study, we presumed that CIK cells could be used as a targeted delivery vehicle for KGHV500 adenovirus in vivo, which could largely decrease the infection of normal cells. We investigated the effects of anti-p21-Ras scFv delivered by KGHV500 adenovirus and CIK cells on human gastric cancer SGC7901 tumor xenograft models. Furthermore, the effects of KGHV500 adenovirus on SGC7901 cell proliferation, migration, and invasiveness were observed, as well as its effects on cell apoptosis and related genes. SGC7901 cells that were viewed by microcopy exhibited the following significant atypia: larger cell size, larger and deeply dyed cell nucleus, and higher nucleoplasmic ratio (Figure 1A). Because KGHV500 and KGHV400 adenoviruses infected cells by binding to CD46 molecules, the receptor of adenovirus cilia protein, on the cell surface, we detected the expression of CD46 receptors on SGC7901 cells by immunohistochemistry, and we found that the percentage of positive cells was nearly 100% (Figure 1B). These results revealed that KGHV500 and KGHV400 adenoviruses could infect SGC7901 cells. The description of these adenoviruses and the differences between them are detailed in Figure S1. To further identify whether KGHV500 and KGHV400 adenoviruses infected SGC7901 cells, transmission electron microscopy was used to observe adenovirus particles in SGC7901 cells after infection for 24 hr. KGHV500 adenovirus particles (70–90 nm) were found in the cell nucleus and cytoplasm of the SGC7901 cells (Figures 1C and 1D), and KGHV400 adenovirus particles were also found in SGC7901 cells (Figures 1E and 1F). Furthermore, the highest infection efficiencies for KGHV500 and KGHV400 adenoviruses on SGC7901 cells were detected by 50% tissue culture infective dose (TCID50) assay. SGC7901 cells were treated with KGHV500 or KGHV400 adenovirus at an MOI of 10, 25, 50, 100, or 200. Then 48 hr later, the infection efficiency was observed with an inverted fluorescence microscope. The results showed that the fluorescence signal was weak at MOIs of 10, 25, and 50, but the signal increased up to 80% at an MOI of 100, and the cells showed a weak cytopathic effect (CPE) phenomenon compared with cells treated with an MOI of 200, which showed a low fluorescent signal with an excessively strong CPE phenomenon. Therefore, the MOI of 100 yielded the best infection efficiency for both KGHV500 (Figure 1G) and KGHV400 (Figure 1H) adenoviruses. To investigate the effect of KGHV500 adenovirus on SGC7901 cell migration ability, a scratch test was conducted. The scratch wounds of the KGHV500 group showed slower healing than those of the KGHV400 group and PBS group 24 and 48 hr after scratching (Figure 2A). The percentages of cell migration in the KGHV500 group were 1.89% ± 0.29% at 24 hr and 8.67% ± 0.55% at 48 hr; in the KGHV400 group, the percentages of cell migration were 3.85% ± 0.19% at 24 hr and 18.20% ± 0.86% at 48 hr, and, in the PBS group, the percentages of cell migration were 8.25% ± 0.46% at 24 hr and 22.06% ± 1.13% at 48 hr (Figure 2B). There was a significant difference between the KGHV500 group and the other two groups (p < 0.01). This result indicated that recombinant oncolytic adenovirus KGHV500 could inhibit the migration ability of SGC7901 cells. Transwell chamber invasion test results showed that the number of KGHV500-infected SGC7901 cells that invaded into the lower layer was significantly reduced compared to the number that invaded in the KGHV400 and PBS groups (Figure 2C). The number of invasive cells in the KGHV500 group was 15.0 ± 2.94; however, in the KGHV400 group it was 72.0 ± 4.03, and in the PBS group it increased to 108.57 ± 8.19 (Figure 2D). The differences among the three groups were significant (p < 0.01). Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays were employed to detect the effects of KGHV500 adenovirus on the apoptosis of SGC7901 cells. The number of apoptotic cells in the KGHV500 group was distinctly increased, whereas the numbers of apoptotic cells in the KGHV400 adenovirus and PBS groups were lower (Figure 2E). The percentage of cells undergoing apoptosis was 68.36% ± 3.95% in the KGHV500 group, but it was 26.60% ± 2.92% in the KGHV400 group and 12.62% ± 2.77% in the PBS group (Figure 2F). There were significant differences among the above groups (p < 0.01), which indicated that the recombinant oncolytic adenovirus KGHV500 could promote the apoptosis of SGC7901 gastric cancer cells. An MTT assay was carried out to investigate whether the KGHV500 adenovirus could inhibit the proliferation of SGC7901 cells. The cell viability of KGHV500-infected SGC7901 cells decreased significantly compared to the cell viability in the KGHV400 group and PBS group. The absorbance values in the KGHV500 group at 1, 2, 3, 4, and 5 days were 1.37 ± 0.32, 0.36 ± 0.15, 0.14 ± 0.06, 0.08 ± 0.03, and 0.03 ± 0.01, respectively. However, in the KGHV400 group, the absorbance values were 1.41 ± 0.22, 1.08 ± 0.18, 0.75 ± 0.25, 0.33 ± 0.09, and 0.25 ± 0.13, respectively, and, in the PBS group, they were 1.39 ± 0.43, 1.32 ± 0.37, 1.19 ± 0.29, 1.05 ± 0.21, and 0.82 ± 0.15, respectively (Figure 2G). There were significant differences among the above groups (p < 0.05). This result indicated that the recombinant oncolytic adenovirus KGHV500 could obviously inhibit the proliferation of SGC7901 cells. Mononuclear cells were isolated from 20 mL peripheral blood collected from healthy volunteers, and then they were differentiated into CIK cells by the cytokines interferon (IFN)-γ, CD3, interleukin (IL)-1α, and IL-2. The initial CIK cells exhibited suspended growth and remained at the same cell size; 5 days later, the CIK cells gradually formed a cell colony, the cells appeared morphologically irregular, and the number of cells increased rapidly until peaking on the 14th day (Figures 3A–3C). The number of CIK cells increased from 0.5 × 107 to 1.0 × 108 after 14 days, approximately 20× amplification. The CIK cells were embedded into cell wax blocks and viewed by microscopy, which showed that cell sizes were uniform with larger nuclei and less cytoplasm (Figure 3D). Immunohistochemical staining showed that the CIK cell markers CD3 and CD56 were expressed on the cell membrane (Figures 3E and 3F), and the adenovirus receptor CD46 was also expressed on the surface of nearly all the cells (Figure 3G). When CIK cells were cocultured with KGHV500 and KGHV400 adenoviruses at an MOI of 100 for 48 hr, positive staining of the adenovirus hexon was observed on the CIK cell membrane (Figures 3H and 3I), which indicated that KGHV500 and KGHV400 adenoviruses successfully bound to CIK cells. The average tumor diameter reached 5 mm in BALB/c nude mice approximately 3 weeks after subcutaneous inoculation of SGC7901 cells. All the mice were weighed and randomly divided into the following five groups: CIK + KGHV500 group, CIK + KGHV400 group, CIK group, KGHV500 group, and PBS group. The above treatments were administered via tail vein injection. Because some of the mouse tumors grew rapidly and broke through the surface of the skin, presenting as ulceration and bleeding, 34 days after the above treatment, all of the mice were euthanized at that time point. The tumor-bearing nude mice of each group are shown in Figure S2. The tumor growth curves were plotted after giving the different treatments for 34 days (Figure 4A), and the tumor volume from smallest to largest was as follows: CIK + KGHV500 group, CIK + KGHV400 group, CIK group, KGHV500 group, and PBS group (Figure 4B). The comparison among all groups was statistically significant (p < 0.05). CIK cells carrying the recombinant oncolytic adenovirus KGHV500 had a significant inhibitory effect on tumor growth in vivo. All mouse organs, including the heart, liver, spleen, lungs, kidneys, stomach, pancreas, large intestine, small intestine, and brain, were observed under a microscope. Compared with the PBS group, no obvious abnormalities or lesions were found in the CIK + KGHV500 group (Figure 4C). The tumor tissue from the CIK + KGHV500 group showed less necrosis and pathological mitosis compared with that observed in the tumor tissue from the PBS group, indicating a relatively slower proliferation progress in the CIK + KGHV500 group. All the mouse weights in each group before and after treatment were compared, and none of the differences was statistically significant (p > 0.05) (Table S1), which indicated that the oncolytic adenovirus vector itself did not affect mouse growth. To investigate the presence of KGHV500 adenovirus in tumor tissue, we detected the expression of adenovirus hexon protein by immunohistochemistry. The expression of adenovirus hexon increased gradually in both the CIK + KGHV500 group and the KGHV500 group, and on day 7 it reached its highest level (Figure 4D). The percentages of adenovirus hexon-positive cells in tumor tissue in the CIK + KGHV500 group were 21.46% ± 3.52%, 32.45% ± 2.79%, 39.51% ± 4.05%, 82.36% ± 8.09%, and 86.95% ± 5.65% on days 1, 2, 3, 5, and 7 after administration, respectively. However, in the KGHV500 group, the percentages were 3.55% ± 1.08%, 19.27% ± 2.64%, 31.65% ± 4.65%, 34.20% ± 1.83%, and 45.19% ± 2.86%, respectively (Figure 4E). The percentages of adenovirus hexon-positive cells were significantly higher in the CIK + KGHV500 group than in the KGHV500 group (p < 0.05). Moreover, KGHV500 adenovirus inhibits tumor cell growth through the expression of anti-p21-Ras scFv; thus, the expression of anti-p21-Ras scFv in tumor tissues was detected by immunohistochemistry. The FLAG tag of the anti-p21-Ras scFv was stained and detected by immunohistochemistry on days 1, 2, 3, 5, and 7 after administration. The expression of anti-p21-Ras scFv was also increased over time in both the CIK + KGHV500 group and the KGHV500 group, with the highest expression on day 7 (Figure 4F), which was in accordance with the expression of KGHV500 adenovirus hexon. The percentages of positive cells were 14.21% ± 1.67%, 28.04% ± 2.08%, 39.66% ± 4.57%, 82.57% ± 4.69%, and 83.25% ± 4.88% on days 1, 2, 3, 5, and 7, respectively, in the CIK + KGHV500 group; but, in the KGHV500 adenovirus group, the percentages were 3.08% ± 0.44%, 15.74% ± 3.88%, 21.67% ± 3.66%, 41.58% ± 4.3%, and 44.37% ± 3.25%, respectively (Figure 4G). The number of positive cells in the CIK + KGHV500 group was significantly higher than that in the KGHV500 group (p < 0.05). The distribution of KGHV500 adenovirus in all mouse organs was also detected by immunohistochemistry. Because of the existence of the blood-brain barrier, the adenovirus in both the CIK + KGHV500 group and the KGHV500 group could not penetrate and distribute into the brain. Adenovirus hexon in the CIK + KGHV500 group was not found in any of the organs except the spleen (Figure 5A). The distribution in the spleen was probably related to the lymphocyte-homing characteristics of CIK cells. In contrast, adenovirus hexon was found in all mouse organs in the KGHV500 adenovirus group (Figure 5A). Therefore, the above results indicated that CIK cells could carry KGHV500 adenovirus to the targeted tumor tissue, thereby largely decreasing the distribution of KGHV500 adenovirus into normal organs. In addition, the expression of anti-p21-Ras scFv in tumor tissue and all mouse organs was investigated by western blot, which found that anti-p21-Ras scFv was expressed only in the tumor and spleen in the CIK + KGHV500 group; but, in the KGHV500 group, it was expressed in all of the mouse organs except for the brain (Figure 5B). The expression of anti-p21-Ras scFv was in accordance with the distribution of adenovirus hexon, which revealed that the recombinant oncolytic adenovirus KGHV500 was delivered to tumor tissues by CIK cells and continuously expressed anti-p21-Ras scFv. Tumor cell apoptosis was detected by TUNEL assay. Compared with the PBS group, the number of apoptotic cells increased, from lowest to highest as follows: KGHV500 group, CIK group, CIK + KGHV400 group, and CIK + KGHV500 group (Figure 6A). The percentage of apoptotic cells in the CIK + KGHV500 group was 82.68% ± 6.37%, and it was 28.50% ± 5.06% in the CIK + KGHV400 group, 25.72% ± 5.12% in the CIK group, 16.35% ± 2.25% in the KGHV500 group, and 4.56% ± 1.0% in the PBS group (Figure 6B). The comparisons among all the groups were statistically significant (p < 0.01). The recombinant adenovirus KGHV500 carried by CIK cells enhanced the apoptosis of tumor cells in vivo. Furthermore, the expression of pro-apoptotic genes (caspase-3, caspase-7, and p53) and anti-apoptosis genes (Bcl-2 and survivin) was detected by qPCR in mouse tumor tissue. Compared to the gene expression in the other four groups, the expression of caspase-3, caspase-7, and p53 increased in the CIK + KGHV500 group, but the expression of Bcl-2 and survivin decreased (Figure 6C). Therefore, the KGHV500 adenovirus carried by CIK cells induced tumor cell apoptosis by upregulating the expression of pro-apoptotic genes and simultaneously downregulating the expression of anti-apoptotic genes. Ras oncogenes coding for p21 proteins are frequently involved in the carcinogenesis of various human tumors. For gastric cancer, the total K-Ras mutation frequency is approximately 6%,15Peng N. Zhao X. Comparison of K-ras mutations in lung, colorectal and gastric cancer.Oncol. Lett. 2014; 8: 561-565Crossref PubMed Scopus (10) Google Scholar but overexpression of wild-type p21 proteins seems to occur more frequently.16Kasper H.-U. Schneider-Stock R. Mellin W. Roessner A. P21 protein expression and ras-oncogene mutations in gastric carcinoma: correlation with clinical data.Int. J. Oncol. 1998; 12: 69-74PubMed Google Scholar Studies have indicated that malignant transformation in gastric cancer is rarely associated with activation of Ras genes by point mutations, but it is frequently related to overexpression of wild-type p21 proteins.16Kasper H.-U. Schneider-Stock R. Mellin W. Roessner A. P21 protein expression and ras-oncogene mutations in gastric carcinoma: correlation with clinical data.Int. J. Oncol. 1998; 12: 69-74PubMed Google Scholar, 17Fujita K. Ohuchi N. Yao T. Okumura M. Fukushima Y. Kanakura Y. Kitamura Y. Fujita J. Frequent overexpression, but not activation by point mutation, of ras genes in primary human gastric cancers.Gastroenterology. 1987; 93: 1339-1345Abstract Full Text PDF PubMed Scopus (42) Google Scholar Similarly, our previous studies showed that the overexpression of wild-type p21-Ras proteins, in addition to Ras mutations, may play a prominent role in the development of colorectal cancer and breast cancer and could be a promising target for cancer therapies.18Bai S. Feng Q. Pan X.Y. Zou H. Chen H.B. Wang P. Zhou X.L. Hong Y.L. Song S.L. Yang J.L. Overexpression of wild-type p21Ras plays a prominent role in colorectal cancer.Int. J. Mol. Med. 2017; 39: 861-868Crossref PubMed Scopus (8) Google Scholar, 19Hong Y.L. Yang L.Y. Pan X.Y. Feng Q. Zou H. Song S.L. Wang L. Wang P. Bai S. Zhou X.L. Yang J.L. Mutation status of ras genes in breast cancers with overexpressed p21Ras protein.Int. J. Clin. Exp. Pathol. 2016; 9: 10422-10429Google Scholar Therefore, the role of wild-type Ras proteins in human cancers cannot be ignored; in other words, wild-type Ras is also an important therapeutic target in many cancers, including gastric cancer. In this study, the gastric cancer SGC7901 cell line was used because its three Ras genes are all wild-type, according to the literature.20Shi M. Shi H. Ji J. Cai Q. Chen X. Yu Y. Liu B. Zhu Z. Zhang J. Cetuximab inhibits gastric cancer growth in vivo, independent of KRAS status.Curr. Cancer Drug Targets. 2014; 14: 217-224Crossref PubMed Scopus (11) Google Scholar Therefore, we aimed to investigate the impacts of anti-p21-Ras scFv carried by the KGHV500 adenovirus on wild-type Ras proteins. The results showed that KGHV500 adenovirus could successfully infect SGC7901 cells and express anti-p21-Ras scFv. The proliferation, migration, and invasiveness of SGC7901 cells were also inhibited by the KGHV500 adenovirus. Moreover, the KGHV500 adenovirus could induce cell apoptosis in SGC7901 cells. The above evidence revealed that this oncolytic adenovirus vector mediated targeted gene therapy that was feasible and effective. Virus-based gene therapy is the most common and effective approach for cancer gene therapies.21Chira S. Jackson C.S. Oprea I. Ozturk F. Pepper M.S. Diaconu I. Braicu C. Raduly L.Z. Calin G.A. Berindan-Neagoe I. Progresses towards safe and efficient gene therapy vectors.Oncotarget. 2015; 6: 30675-30703Crossref PubMed Scopus (145) Google Scholar Its therapeutic efficacy has been widely recognized, resulting in the use of recombinant human p53 adenovirus (Gendicine)22Zhang W.W. Li L. Li D. Liu J. Li X. Li W. Xu X. Zhang M.J. Chandler L.A. Lin H. et al.The First Approved Gene Therapy Product for Cancer Ad-p53 (Gendicine): 12 Years in the Clinic.Hum. Gene Ther. 2018; 29: 160-179Crossref PubMed Scopus (152) Google Scholar, 23Li Y. Li B. Li C.J. Li L.J. Key points of basic theories and clinical practice in rAd-p53 ( Gendicine ™) gene therapy for solid malignant tumors.Expert Opin. Biol. Ther. 2015; 15: 437-454Crossref PubMed Scopus (37) Google Scholar and T-Vec (talimogene laherparepvec),24Fukuhara H. Ino Y. Todo T. Oncolytic virus therapy: A new era of cancer treatment at dawn.Cancer Sci. 2016; 107: 1373-1379Crossref PubMed Scopus (412) Google Scholar, 25Kaufman H.L. Kim D.W. DeRaffele G. Mitcham J. Coffin R.S. Kim-Schulze S. Local and distant immunity induced by intralesional vaccination with an oncolytic herpes virus encoding GM-CSF in patients with stage IIIc and IV melanoma.Ann. Surg. Oncol. 2010; 17: 718-730Crossref PubMed Scopus (403) Google Scholar which were approved for clinical cancer treatments in China and the United States, respectively. However, virus-based gene therapy still cannot be systemically administered through the venous injection route to treat deep tumors, such as gastric cancer, because of the inherent risks associated with the viral vector itself. The two main obstacles presently existing in virus-based gene therapies are target specificity and safety of systemic administration.26Howells A. Marelli G. Lemoine N.R. Wang Y. Oncolytic Viruses-Interaction of Virus and Tumor Cells in the Battle to Eliminate Cancer.Front. Oncol. 2017; 7: 195Crossref PubMed Scopus (89) Google Scholar To solve these problems, CIK cells were employed to carry the KGHV500 adenovirus to tumor tissue. CIK cells were first reported in 1991 by Schmidt-Wolf et al.,27Schmidt-Wolf I.G. Negrin R.S. Kiem H.P. Blume K.G. Weissman I.L. Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity.J. Exp. Med. 1991; 174: 139-149Crossref PubMed Scopus (557) Google Scholar who used them to kill human lymphoma cells. CIK cells are a heterogeneous population of effector CD3+ CD56+ natural killer T cells that are artificially differentiated in vitro from peripheral blood mononuclear cells and are commonly used for cancer immunotherapy, as they exhibit major histocompatibility complex (MHC)-unrestricted, safe, and effective antitumor activity.28Mata-Molanes J.J. Sureda González M. Valenzuela Jiménez B. Martínez Navarro E.M. Brugarolas Masllorens A. Cancer Immunotherapy with Cytokine-Induced Killer Cells.Target. Oncol. 2017; 12: 289-299Crossref PubMed Scopus (24) Google Scholar, 29Thorne S.H. Negrin R.S. Contag C.H. Synergistic antitumor effects of immune cell-viral biotherapy.Science. 2006; 311: 1780-1784Crossref PubMed Scopus (240) Google Scholar In 2006, Thorne et al.29Thorne S.H. Negrin R.S. Contag C.H. Synergistic antitumor effects of immune cell-viral biotherapy.Science. 2006; 311: 1780-1784Crossref PubMed Scopus (240) Google Scholar reported that CIK cells could be used to carry modified vaccinia virus to tumor tissue and synergistically kill tumor cells, which revealed the potential value of this combined therapy in cancer-targeted gene therapy. In this study, the specific distribution of KGHV500 adenovirus hexon in tumor tissues and the expression of anti-p21-Ras scFv in tumor cells revealed that CIK cells could successfully deliver the recombinant oncolytic adenovirus KGHV500 to the tumor site, which largely decreased t" @default.
• W2896071503 created "2018-10-26" @default.
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• W2896071503 date "2018-12-01" @default.
• W2896071503 modified "2023-09-27" @default.
• W2896071503 title "Recombinant Adenovirus KGHV500 and CIK Cells Codeliver Anti-p21-Ras scFv for the Treatment of Gastric Cancer with Wild-Type Ras Overexpression" @default.
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