Limits...
Targeted Hsp70 expression combined with CIK-activated immune reconstruction synergistically exerts antitumor efficacy in patient-derived hepatocellular carcinoma xenograft mouse models.

Hu H, Qiu Y, Guo M, Huang Y, Fang L, Peng Z, Ji W, Xu Y, Shen S, Yan Y, Huang X, Zheng J, Su C - Oncotarget (2015)

Bottom Line: The results demonstrated that, either the immune anti-tumor effect caused by CIK cell infusion or the oncolytic effect generated by oncolytic adenovirus replication was very limited.However, the synergistic tumor inhibitory effect was significantly enhanced after treatments with oncolytic adenovirus expressing Hsp70 combined with CIK cells.This strategy can synergistically activate multiple anti-tumor mechanisms and exert effective anti-tumor activities that have a significant inhibitory effect against the growth of HCC xenografts.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatobiliary Surgery, Fuzhou General Hospital of Nanjing Military Area, Fuzhou, China.

ABSTRACT
The patient-derived tumor xenograft (PDTX) models can reproduce a similar natural genetic background and similar biological behaviors to tumor cells in patients, which is conducive to the assessment of personalized cancer treatment. In this study, to verify the targeting and effectiveness of the therapeutic strategy using a Survivin promoter-regulated oncolytic adenovirus expressing Hsp70, the PDTX models of hepatocellular carcinoma (HCC) were established in nude mice and the cytokine-induced killer (CIK) cells were intravenously infused into mice to partially reconstruct the mouse immune function. The results demonstrated that, either the immune anti-tumor effect caused by CIK cell infusion or the oncolytic effect generated by oncolytic adenovirus replication was very limited. However, the synergistic tumor inhibitory effect was significantly enhanced after treatments with oncolytic adenovirus expressing Hsp70 combined with CIK cells. Oncolytic adenovirus mediated the specific expression of Hsp70 in cancer tissues allowed the CIK chemotaxis, and induce the infiltration of CD3+ T cells in tumor stroma, thereby exhibiting anti-tumor activity. The anti-tumor effect was more effective for the highly malignant tumor xenografts with highly Survivin expression. This strategy can synergistically activate multiple anti-tumor mechanisms and exert effective anti-tumor activities that have a significant inhibitory effect against the growth of HCC xenografts.

Show MeSH

Related in: MedlinePlus

Anti-tumor effect of Hsp70 expression mediated by oncolytic adenovirus in HCC xenograft nude mouse models(A) Fresh HCC tissues from 10 cases of clinical surgical specimens were cut to a depth of 2 mm in diameter and subcutaneously buried in the right axilla of eighty nude mice by a trocar puncture. Mice were assigned to 5 groups (AdSurp-Hsp70+CIK, AdSurp-Hsp70, CIK, AdSurp-EGFP, and the blank control group). After tumor xenografts were formed, mice in the AdSurp-Hsp70+CIK and CIK groups were infused with CIK cells through tail vein to a concentration of 107 cells/mouse. Subsequently, the corresponding viral treatment was given based on the grouping at a total of 1×109 pfu of adenoviruses. The blank control group was injected with the viral preservation solution instead of virus injection. Tumor size was measured regularly, and tumor volume was calculated to result in the tumor growth curves; **P<0.01, ***P<0.001. (B) Each experimental group was divided into a weakly positive Survivin subgroup and a strongly positive Survivin subgroup for further comparison of tumor volume. **P<0.01. (C) After 35 days of the first treatment, the observation was terminated. The tumors were collected and weighed; *P<0.05, **P<0.01, ***P<0.001. (D) Each experimental group was divided into a weakly positive Survivin subgroup and a strongly positive Survivin subgroup for further comparison of tumor weight; *P<0.05, **P<0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4359218&req=5

Figure 3: Anti-tumor effect of Hsp70 expression mediated by oncolytic adenovirus in HCC xenograft nude mouse models(A) Fresh HCC tissues from 10 cases of clinical surgical specimens were cut to a depth of 2 mm in diameter and subcutaneously buried in the right axilla of eighty nude mice by a trocar puncture. Mice were assigned to 5 groups (AdSurp-Hsp70+CIK, AdSurp-Hsp70, CIK, AdSurp-EGFP, and the blank control group). After tumor xenografts were formed, mice in the AdSurp-Hsp70+CIK and CIK groups were infused with CIK cells through tail vein to a concentration of 107 cells/mouse. Subsequently, the corresponding viral treatment was given based on the grouping at a total of 1×109 pfu of adenoviruses. The blank control group was injected with the viral preservation solution instead of virus injection. Tumor size was measured regularly, and tumor volume was calculated to result in the tumor growth curves; **P<0.01, ***P<0.001. (B) Each experimental group was divided into a weakly positive Survivin subgroup and a strongly positive Survivin subgroup for further comparison of tumor volume. **P<0.01. (C) After 35 days of the first treatment, the observation was terminated. The tumors were collected and weighed; *P<0.05, **P<0.01, ***P<0.001. (D) Each experimental group was divided into a weakly positive Survivin subgroup and a strongly positive Survivin subgroup for further comparison of tumor weight; *P<0.05, **P<0.01.

Mentions: Through establishing a PDTX model using 10 cases of HCC surgical specimens, combined with the infusion of CIK cells to partially reconstruct the immune function in nude mice, the killing effect of oncolytic adenovirus-mediated Hsp70 expression on tumor xenografts was observed. After 7 days of viral therapy on the tumor xenografts with a total viral dose of 1×109 pfu, compared with the blank control group, the AdSurp-Hsp70+CIK treatment group showed a significant efficacy. After 14 days, the AdSurp-Hsp70 treatment group showed a certain effect. After 21 days, the CIK and AdSurp-EGFP groups also displayed a certain effect, but the efficacy of CIK treatment gradually disappeared thereafter. Comparison of the anti-tumor efficacy of different groups showed that the efficacy of the AdSurp-Hsp70+CIK treatment group was best, followed by the AdSurp-Hsp70 group. Additionally, the CIK group or AdSurp-EGFP group also exhibited some anti-tumor effect in the later stage (Fig. 3A). Each experimental group was divided into a weakly positive Survivin subgroup and a strongly positive Survivin subgroup for further comparisons, considering the blank control group, the growth of tumor xenografts from the strongly positive Survivin subgroup was slightly faster than that from the weakly positive Survivin subgroup, but this difference was not statistically significant. In the AdSurp-Hsp70+CIK, AdSurp-Hsp70 and AdSurp-EGFP treatment groups, the treatment efficacies for the tumor xenografts in the strongly positive Survivin subgroups were significantly better than those in the weakly positive Survivin subgroups, and the efficacy of the CIK group was not related to Survivin expression (Fig. 3B).


Targeted Hsp70 expression combined with CIK-activated immune reconstruction synergistically exerts antitumor efficacy in patient-derived hepatocellular carcinoma xenograft mouse models.

Hu H, Qiu Y, Guo M, Huang Y, Fang L, Peng Z, Ji W, Xu Y, Shen S, Yan Y, Huang X, Zheng J, Su C - Oncotarget (2015)

Anti-tumor effect of Hsp70 expression mediated by oncolytic adenovirus in HCC xenograft nude mouse models(A) Fresh HCC tissues from 10 cases of clinical surgical specimens were cut to a depth of 2 mm in diameter and subcutaneously buried in the right axilla of eighty nude mice by a trocar puncture. Mice were assigned to 5 groups (AdSurp-Hsp70+CIK, AdSurp-Hsp70, CIK, AdSurp-EGFP, and the blank control group). After tumor xenografts were formed, mice in the AdSurp-Hsp70+CIK and CIK groups were infused with CIK cells through tail vein to a concentration of 107 cells/mouse. Subsequently, the corresponding viral treatment was given based on the grouping at a total of 1×109 pfu of adenoviruses. The blank control group was injected with the viral preservation solution instead of virus injection. Tumor size was measured regularly, and tumor volume was calculated to result in the tumor growth curves; **P<0.01, ***P<0.001. (B) Each experimental group was divided into a weakly positive Survivin subgroup and a strongly positive Survivin subgroup for further comparison of tumor volume. **P<0.01. (C) After 35 days of the first treatment, the observation was terminated. The tumors were collected and weighed; *P<0.05, **P<0.01, ***P<0.001. (D) Each experimental group was divided into a weakly positive Survivin subgroup and a strongly positive Survivin subgroup for further comparison of tumor weight; *P<0.05, **P<0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4359218&req=5

Figure 3: Anti-tumor effect of Hsp70 expression mediated by oncolytic adenovirus in HCC xenograft nude mouse models(A) Fresh HCC tissues from 10 cases of clinical surgical specimens were cut to a depth of 2 mm in diameter and subcutaneously buried in the right axilla of eighty nude mice by a trocar puncture. Mice were assigned to 5 groups (AdSurp-Hsp70+CIK, AdSurp-Hsp70, CIK, AdSurp-EGFP, and the blank control group). After tumor xenografts were formed, mice in the AdSurp-Hsp70+CIK and CIK groups were infused with CIK cells through tail vein to a concentration of 107 cells/mouse. Subsequently, the corresponding viral treatment was given based on the grouping at a total of 1×109 pfu of adenoviruses. The blank control group was injected with the viral preservation solution instead of virus injection. Tumor size was measured regularly, and tumor volume was calculated to result in the tumor growth curves; **P<0.01, ***P<0.001. (B) Each experimental group was divided into a weakly positive Survivin subgroup and a strongly positive Survivin subgroup for further comparison of tumor volume. **P<0.01. (C) After 35 days of the first treatment, the observation was terminated. The tumors were collected and weighed; *P<0.05, **P<0.01, ***P<0.001. (D) Each experimental group was divided into a weakly positive Survivin subgroup and a strongly positive Survivin subgroup for further comparison of tumor weight; *P<0.05, **P<0.01.
Mentions: Through establishing a PDTX model using 10 cases of HCC surgical specimens, combined with the infusion of CIK cells to partially reconstruct the immune function in nude mice, the killing effect of oncolytic adenovirus-mediated Hsp70 expression on tumor xenografts was observed. After 7 days of viral therapy on the tumor xenografts with a total viral dose of 1×109 pfu, compared with the blank control group, the AdSurp-Hsp70+CIK treatment group showed a significant efficacy. After 14 days, the AdSurp-Hsp70 treatment group showed a certain effect. After 21 days, the CIK and AdSurp-EGFP groups also displayed a certain effect, but the efficacy of CIK treatment gradually disappeared thereafter. Comparison of the anti-tumor efficacy of different groups showed that the efficacy of the AdSurp-Hsp70+CIK treatment group was best, followed by the AdSurp-Hsp70 group. Additionally, the CIK group or AdSurp-EGFP group also exhibited some anti-tumor effect in the later stage (Fig. 3A). Each experimental group was divided into a weakly positive Survivin subgroup and a strongly positive Survivin subgroup for further comparisons, considering the blank control group, the growth of tumor xenografts from the strongly positive Survivin subgroup was slightly faster than that from the weakly positive Survivin subgroup, but this difference was not statistically significant. In the AdSurp-Hsp70+CIK, AdSurp-Hsp70 and AdSurp-EGFP treatment groups, the treatment efficacies for the tumor xenografts in the strongly positive Survivin subgroups were significantly better than those in the weakly positive Survivin subgroups, and the efficacy of the CIK group was not related to Survivin expression (Fig. 3B).

Bottom Line: The results demonstrated that, either the immune anti-tumor effect caused by CIK cell infusion or the oncolytic effect generated by oncolytic adenovirus replication was very limited.However, the synergistic tumor inhibitory effect was significantly enhanced after treatments with oncolytic adenovirus expressing Hsp70 combined with CIK cells.This strategy can synergistically activate multiple anti-tumor mechanisms and exert effective anti-tumor activities that have a significant inhibitory effect against the growth of HCC xenografts.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatobiliary Surgery, Fuzhou General Hospital of Nanjing Military Area, Fuzhou, China.

ABSTRACT
The patient-derived tumor xenograft (PDTX) models can reproduce a similar natural genetic background and similar biological behaviors to tumor cells in patients, which is conducive to the assessment of personalized cancer treatment. In this study, to verify the targeting and effectiveness of the therapeutic strategy using a Survivin promoter-regulated oncolytic adenovirus expressing Hsp70, the PDTX models of hepatocellular carcinoma (HCC) were established in nude mice and the cytokine-induced killer (CIK) cells were intravenously infused into mice to partially reconstruct the mouse immune function. The results demonstrated that, either the immune anti-tumor effect caused by CIK cell infusion or the oncolytic effect generated by oncolytic adenovirus replication was very limited. However, the synergistic tumor inhibitory effect was significantly enhanced after treatments with oncolytic adenovirus expressing Hsp70 combined with CIK cells. Oncolytic adenovirus mediated the specific expression of Hsp70 in cancer tissues allowed the CIK chemotaxis, and induce the infiltration of CD3+ T cells in tumor stroma, thereby exhibiting anti-tumor activity. The anti-tumor effect was more effective for the highly malignant tumor xenografts with highly Survivin expression. This strategy can synergistically activate multiple anti-tumor mechanisms and exert effective anti-tumor activities that have a significant inhibitory effect against the growth of HCC xenografts.

Show MeSH
Related in: MedlinePlus