Herpes Simplex Virus (HSV)-Mediated ICAM-1 Gene Transfer Abrogates Tumorigenicity and Induces Anti-Tumor Immunity

D’Angelica, Michael I.; Tung, Cindy; Allen, Peter J.; Halterman, Marc W.; Delman, Keith A.; Delohery, Thomas; Klimstra, David S.; Brownlee, Michael; Federoff, Howard J.; Fong, Yuman

doi:10.1007/bf03402073

Cited by 21 publications

(13 citation statements)

References 45 publications

(59 reference statements)

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“…The indications of reduction of tumor progression associated with ICAM-1 overexpression in ovarian cancer, shown in the present study by using ATFs in vitro, is in line with results obtained upon transfecting ICAM-1 cDNA into various cancer cells: overexpression of the gene was associated with decreased tumorigenicity in vivo. [30][31][32][33][34][35] In fact, some studies show lower proliferation rates upon transfection of cancer cells (other than ovarian) with ICAM-1 cDNA and implantation into animal models. 32,33,35 The reduced growth in vivo has been ascribed to increased activation of immune response by the cells upon ICAM-1 expression.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of endogenous ICAM‐1 reduces ovarian cancer cell growth in the absence of immune cells

Groote

Kazemier

Huisman

et al. 2013

Intl Journal of Cancer

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Ovarian cancer is a difficult-to-treat cancer with a 5-year survival rate of only~45%, due to late diagnosis and therapy resistance. In need of new therapeutic approaches, induction of intercellular adhesion molecule (ICAM)-1 expression might be of interest, since the expression of ICAM-1 is lower in ovarian cancer cells compared with healthy ovarian cells and correlated with decreased tumorigenicity. Whereas ICAM-1 expression on tumor cells is of importance for attracting immune cells, ICAM-1 might also induce tumorigenicity and chemoresistance. In ovarian cancer, such a role of ICAM-1 is unclear. Here, we investigated whether ICAM-1 has a cell-biological role by bidirectional modulation of ICAM-1 expression using ICAM-targeting artificial transcription factors. For a panel of ovarian cancer cells, tumor growth and cisplatin sensitivity were evaluated. Induction of ICAM-1 expression (ranging from 3-to 228-fold on mRNA level and 1.7-to 108-fold on protein level) resulted in indications of decreased ovarian cancer cell growth and reduced cisplatin sensitivity. Repression ranged from 48 to 94% on mRNA level and 47 to 91% on protein level. This study shows that, next to its established immunogenic role, ICAM-1 affects cell biological behavior of ovarian cancer cells and, importantly, that reexpression by artificial transcription factors represents a powerful approach for functional validation of genes epigenetically silenced in cancer, such as ICAM-1.

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Section: Discussionmentioning

confidence: 99%

Upregulation of endogenous ICAM‐1 reduces ovarian cancer cell growth in the absence of immune cells

Groote

Kazemier

Huisman

et al. 2013

Intl Journal of Cancer

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“…[12][13][14] Production of cytokines in proximity to putative tumor antigens has been shown experimentally to result in antitumor immunity that prevents subsequent development of cancer. 12,[14][15][16][17][18][19][20][21][22] Recent animal studies from this laboratory have shown that neoadjuvant treatment of established, solitary liver tumors with modified, replication incompetent herpes simplex virus (HSV) encoding the interleukin-12 (IL-12) gene resulted in high levels of gene expression within the tumor and significantly reduced the incidence of tumor recurrence after resection. 23 However, this study showed no significant response of the parent tumor, which remains a major limitation of this treatment strategy.…”

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confidence: 99%

Neoadjuvant treatment of hepatic malignancy: an oncolytic herpes simplex virus expressing IL-12 effectively treats the parent tumor and protects against recurrence-after resection

et al. 2003

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The objective of the study was to evaluate the utility of NV1042, a replication competent, oncolytic herpes simplex virus (HSV) containing the interleukin-12 (IL-12) gene, as primary treatment for hepatic tumors and to further assess its ability to reduce tumor recurrence following resection. Resection is the most effective therapy for hepatic malignancies, but is not possible in the majority of the patients. Furthermore, recurrence is common after resection, most often in the remnant liver and likely because of microscopic residual disease in the setting of postoperative host cellular immune dysfunction. We hypothesize that, unlike other gene transfer approaches, direct injection of liver tumors with replication competent, oncolytic HSV expressing IL-12 will not only provide effective control of the parent tumor, but will also elicit an immune response directed at residual tumor cells, thus decreasing the risk of cancer recurrence after resection. Solitary Morris hepatomas, established in Buffalo rat livers, were injected directly with 10 7 particles of NV1042, NV1023, an oncolytic HSV identical to NV1042 but without the IL-12 gene, or with saline. Following tumor injection, the parent tumors were resected and measured and the animals were challenged with an intraportal injection of 10 5 tumor cells, recreating the clinical scenario of residual microscopic cancer. In vitro cytotoxicity against Morris hepatoma cells was similar for both viruses at a multiplicity of infection of 1 (MOI, ratio of viral particles to target cells), with 490% tumor cell kill by day 6. NV1042 induced high-level expression of IL-12 in vitro, peaking after 4 days in culture. Furthermore, a single intratumoral injection of NV1042, but not NV1023, induced marked IL-12 and interferon-g (IFN-g) expression. Both viruses induced a significant local immune response as evidenced by an increase in the number of intratumoral CD4(+) and CD8(+) lymphocytes, although the peak of CD8(+) infiltration was later with NV1042 compared with NV1023. NV1042 and NV1023 reduced parent tumor volume by 74% (Po.003) and 52% (Po.03), respectively, compared to control animals. Treatment of established tumors with NV1042, but not with NV1023, significantly reduced the number of hepatic tumors after resection of the parent tumor and rechallenge (16.8711 (median ¼ 4) vs. 65.9715 (median ¼ 66) in control animals, Po.025). In conclusion, oncolytic HSV therapy combined with local immune stimulation with IL-12 offers effective control of parent hepatic tumors and also protects against microscopic residual disease after resection. The ease of use of this combined modality approach, which appears to be superior to either approach alone, suggests that it may have clinical relevance, both as primary treatment for patients with unresectable tumors and also as a neoadjuvant strategy for reducing recurrence after resection.

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“…Transfection of the human ICAM-1 gene into various cancer cells lines using plasmid or viral vectors resulted in decreased tumorigenicity when injected into mouse or rat hosts (Burno et al, 1995;Wei et al, 1996;Uzendoski et al, 1997;D'Angelica et al, 1999;Kikuchi et al, 1999). Several lines of evidence demonstrate that this protection was due, at least in part, to activation of cellular immunity by ICAM-1 (Burno et al, 1996;Wei et al, 1996;Uzendoski et al, 1997;D'Angelica et al, 1999). Therefore, while more investigation is required to determine the significance of the reduced ICAM-1 expression levels in ovarian cancer, evidence from other models suggests that ICAM-1 gene transfer may be of value for the immunotherapy of ovarian cancer.…”

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confidence: 99%

Reduced expression of intercellular adhesion molecule-1 in ovarian adenocarcinomas

et al. 2001

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Summary Ovarian adenocarcinomas develop as the result of multiple genetic and epigenetic changes in the precursor ovarian surface epithelial (OSE) cells which result in a malignant phenotype. We investigated changes in gene expression in ovarian adenocarcinoma using a cDNA array containing 588 known human genes. We found that intercellular adhesion molecule-1 (ICAM-1) was expressed at lower levels in the ovarian tumour cell lines OAW42, PEO1 and JAM than in the immortalised human ovarian surface epithelial cell line HOSE 17.1. Further investigation revealed ICAM-1 was expressed in the surface epithelium of normal ovaries and both mRNA and protein expression levels were reduced in the majority of ovarian adenocarcinoma cell lines and primary tumours. ICAM-1 expression was increased in 8/8 cell lines treated with the de novo methyltransferase inhibitor 5-aza-2′-deoxycytidine, indicating that methylation of CpG islands may play a role in the down-regulation of its expression in primary tumours. There was a significant association between patients whose tumours expressed ICAM-1 and survival (P = 0. 1351-1358© 2001 Cancer Research Campaign doi: 10.1054/ bjoc.2001.2075, available online at http://www.idealibrary.com on http://www.bjcancer.com 1987), SKOV3 (Fogh and Trempe, 1975), COLO316 (Woods et al, 1979), CAOV3 (Wong et al, 1999), OVCAR-3 (Hamilton et al, 1983) and 27/87 (derived by T Hurst) -were all maintained in RPMI 1640 with 10% FCS. Cells were harvested for RNA isolation at about 80% confluence. The cell lines OAW 42, PEO1, PEO14, JAM, SKOV3 and COLO316 were derived from serous tumours, and 27/87 was from an endometrioid tumour. The histological types of the tumours from which the cell lines HEY, CAOV3 and OVCAR3 were derived are unknown.Primary cultures of human ovarian surface epithelial (OSE) cells were prepared according to the method of Kruk et al (1990). Epithelial cells were obtained by scraping contaminating stromal cells away from proliferating epithelial sheets and were cultured in 1:1 MCDB105: Medium 199 with Earles' salts, supplemented with 20 ng ml -1 epidermal growth factor, 400 ng ml -1 hydrocortisone and 15% fetal calf serum. Their distinctive cellular morphology was used to confirm that the cultures were epithelial cells. In one case, RNA was extracted directly from the peeled epithelial cells without culturing.Ovarian adenocarcinomas were obtained from 44 patients undergoing surgery. There were 35 serous, 6 endometrioid, one mucinous and 2 clear-cell tumours. There were 43 malignant tumours and the other was of low malignant potential (LMP). All patients were staged at laparotomy, in accordance with the recommendations of the International Federation of Gynaecology and Obstetrics (FIGO). Of the malignant tumours, one was FIGO stage 1, 4 stage 2, 33 stage 3 and 5 stage 4. There were two grade 1-2, 11 grade 2, 10 grade 2/3, 17 grade 3, one grade 3-4, and 2 that were not graded. Clinicopathological data for these tumours are summarised in Table 2. Constitutional DNA was available in all ca...

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Herpes Simplex Virus (HSV)-Mediated ICAM-1 Gene Transfer Abrogates Tumorigenicity and Induces Anti-Tumor Immunity

Cited by 21 publications

References 45 publications

Upregulation of endogenous ICAM‐1 reduces ovarian cancer cell growth in the absence of immune cells

Upregulation of endogenous ICAM‐1 reduces ovarian cancer cell growth in the absence of immune cells

Neoadjuvant treatment of hepatic malignancy: an oncolytic herpes simplex virus expressing IL-12 effectively treats the parent tumor and protects against recurrence-after resection

Reduced expression of intercellular adhesion molecule-1 in ovarian adenocarcinomas

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