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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.

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Related in: MedlinePlus

Expression of E1a and Hsp70 mediated by oncolytic adenoviruses(A) Tumor xenografts were fixed in 10% neutralized formalin for 6 h to prepare the paraffin-embedded sections. SP immunohistochemical staining was performed to locate the expressions of indicated proteins; original magnification: ×200. (B) For each slice, the percentages of positive cells were counted within 5 medium-power magnification fields of view (20× objective lens) under microscope. The results were determined by scoring the stained cell ratio and the staining intensity; ***P<0.001. (C) Mouse blood was collected to prepare sera. The expression of Hsp70 protein was detected using an ELISA; ***P<0.001.
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Figure 4: Expression of E1a and Hsp70 mediated by oncolytic adenoviruses(A) Tumor xenografts were fixed in 10% neutralized formalin for 6 h to prepare the paraffin-embedded sections. SP immunohistochemical staining was performed to locate the expressions of indicated proteins; original magnification: ×200. (B) For each slice, the percentages of positive cells were counted within 5 medium-power magnification fields of view (20× objective lens) under microscope. The results were determined by scoring the stained cell ratio and the staining intensity; ***P<0.001. (C) Mouse blood was collected to prepare sera. The expression of Hsp70 protein was detected using an ELISA; ***P<0.001.

Mentions: Immunohistochemical staining was performed to observe the localization of the expressions of the adenovirus capsid protein Hexon and the therapeutic gene Hsp70. The results showed that, after treatment with oncolytic adenovirus, the expressions of Hexon and Hsp70 in the AdSurp-Hsp70+CIK and AdSurp-Hsp70 groups, as well as the expression of Hexon in the AdSurp-EGFP group, were confined within the cancer cells (Fig.4A-B), indicating that oncolytic adenoviruses can target the Survivin-positive HCC cells and replicate in tumor cells with specific expression of the therapeutic gene Hsp70.


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)

Expression of E1a and Hsp70 mediated by oncolytic adenoviruses(A) Tumor xenografts were fixed in 10% neutralized formalin for 6 h to prepare the paraffin-embedded sections. SP immunohistochemical staining was performed to locate the expressions of indicated proteins; original magnification: ×200. (B) For each slice, the percentages of positive cells were counted within 5 medium-power magnification fields of view (20× objective lens) under microscope. The results were determined by scoring the stained cell ratio and the staining intensity; ***P<0.001. (C) Mouse blood was collected to prepare sera. The expression of Hsp70 protein was detected using an ELISA; ***P<0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Expression of E1a and Hsp70 mediated by oncolytic adenoviruses(A) Tumor xenografts were fixed in 10% neutralized formalin for 6 h to prepare the paraffin-embedded sections. SP immunohistochemical staining was performed to locate the expressions of indicated proteins; original magnification: ×200. (B) For each slice, the percentages of positive cells were counted within 5 medium-power magnification fields of view (20× objective lens) under microscope. The results were determined by scoring the stained cell ratio and the staining intensity; ***P<0.001. (C) Mouse blood was collected to prepare sera. The expression of Hsp70 protein was detected using an ELISA; ***P<0.001.
Mentions: Immunohistochemical staining was performed to observe the localization of the expressions of the adenovirus capsid protein Hexon and the therapeutic gene Hsp70. The results showed that, after treatment with oncolytic adenovirus, the expressions of Hexon and Hsp70 in the AdSurp-Hsp70+CIK and AdSurp-Hsp70 groups, as well as the expression of Hexon in the AdSurp-EGFP group, were confined within the cancer cells (Fig.4A-B), indicating that oncolytic adenoviruses can target the Survivin-positive HCC cells and replicate in tumor cells with specific expression of the therapeutic gene Hsp70.

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