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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

Identification of Survivin expression in HCC specimens(A) HCC specimens and paracancerous liver tissues collected from 10 patients with HCC were fixed in 10% formalin for 6 h to prepare the paraffin-embedded sections, and the expression of Survivin was detected by streptavidin-peroxidase (SP) immunohistochemistry; original magnification: ×200. (B) For each slice, the number of Survivin positive cells was 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, from 0 to 6 scores.
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Figure 2: Identification of Survivin expression in HCC specimens(A) HCC specimens and paracancerous liver tissues collected from 10 patients with HCC were fixed in 10% formalin for 6 h to prepare the paraffin-embedded sections, and the expression of Survivin was detected by streptavidin-peroxidase (SP) immunohistochemistry; original magnification: ×200. (B) For each slice, the number of Survivin positive cells was 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, from 0 to 6 scores.

Mentions: The HCC specimens and the paracancerous liver tissues were collected from 10 patients undergoing clinical operation, and Survivin expression was detected by immunohistochemistry (Fig. 2A). The expression of Survivin was positive in all 10 HCC specimens, among them 3 were weakly positive and 7 were strongly positive. Whereas, Survivin expression in the corresponding paracancerous liver tissues was significantly weakened, with negative expression in 6 cases and weakly positive expression in 4 cases (Fig. 2B).


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)

Identification of Survivin expression in HCC specimens(A) HCC specimens and paracancerous liver tissues collected from 10 patients with HCC were fixed in 10% formalin for 6 h to prepare the paraffin-embedded sections, and the expression of Survivin was detected by streptavidin-peroxidase (SP) immunohistochemistry; original magnification: ×200. (B) For each slice, the number of Survivin positive cells was 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, from 0 to 6 scores.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Identification of Survivin expression in HCC specimens(A) HCC specimens and paracancerous liver tissues collected from 10 patients with HCC were fixed in 10% formalin for 6 h to prepare the paraffin-embedded sections, and the expression of Survivin was detected by streptavidin-peroxidase (SP) immunohistochemistry; original magnification: ×200. (B) For each slice, the number of Survivin positive cells was 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, from 0 to 6 scores.
Mentions: The HCC specimens and the paracancerous liver tissues were collected from 10 patients undergoing clinical operation, and Survivin expression was detected by immunohistochemistry (Fig. 2A). The expression of Survivin was positive in all 10 HCC specimens, among them 3 were weakly positive and 7 were strongly positive. Whereas, Survivin expression in the corresponding paracancerous liver tissues was significantly weakened, with negative expression in 6 cases and weakly positive expression in 4 cases (Fig. 2B).

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