Project description:Oncolytic viral therapy represents an alternative therapeutic strategy for the treatment of cancer. This therapy relies on efficient replication of virus in tumor cells in vivo with minimal or no replication in normal tissues. We recently described GLV-1h68 as a modified Vaccinia Virus (VACV) construct with exclusive in vivo tropism for tumor cells in experimental animal models. Moreover, we had previously observed a cell line-specific relationship between the ability of GLV-1h68 to replicate in vitro during the first 20 hours following infection and the in vivo ability to colonize and eliminate the corresponding tumor implant. Thus, we surveyed the in vitro permissivity to GLV-1h68 replication of the NCI-60 panel of cell lines, extensively characterized and used for the assessment of novel therapeutic modalities. All cell lines were cultured and infected in identical conditions. Pre-infection transcriptional profiling was obtained to search for correlates of permissivity to viral infection. Selected cell lines were also tested for permissivity to another VACV and a vesicular stomatitis virus (VSV) strain. We observed that permissivity to VACV infection during the first 20 hours is quite heterogeneous among cell lines but highly reproducible within each cell line. The tissue of origin of each cell line does not influence permissivity to infection with the exception of B cell derivation. Permissivity correlates between two VACV constructs and between them and VSV suggesting a common permissive phenotype. No clear transcriptional pattern predictive of permissivity to infection could be identified though weak associations were observed that suggest a multifactorial control of viral replication. This study adds to the current characterization of the NCI-60 panel to guide the design and interpretation of experimental models testing oncolytic therapies. Seventy-four microarray samples were obtained from 8 renal cancer cell lines (786-0, A498, ACHN, CAKI-I, RXF-393, SN12C, TK-10, UO-31); 12 melanoma cell lines (888-MEL, 1858-MEL, 1936-MEL, 397, A375-MEL, LOX IMVI, M14, SK-MEL-2, SK-MEL-5, SK-MEL-28, UACC 62, UACC 257 ); 11 lung cancer cell lines (A549 p7, A549 p107, EKVX, HOP-62, HOP-92, NCI-H23, NCI-H226, NCI-H322M, NCI-H460, NCI-H522, NCI-H1299); 13 colon cancer cell lines (HCT-15, HCT-116, HT-29 p155, HT-29 p9, KM-12, SW-620, Colo 205, HCC 2998, NCI-ADR-RES, OVCAR 3 p7, OVCAR 3 p42, OVCAR 5, SK-OV-3); 3 ovarian cancer cell lines (OVCAR 4, OVCAR 8, IGROV); 1 cervical cancer cell line (Siha); 6 brain cancer cell lines (SNB 19, SF 295, SF 298, SNB 75, U251, SF 539); 7 breast cancer cell lines (BT-549, GI101A, HS-578T, MCF 7, MDA-MB-231 p41, MDA-MB-435, MDA-MB-231 p6); 7 hematopoietic cancer cell lines (CCFR-CEM, HL-60, K-562, MOLT-4, RPMI 8226, SR, T-47D); 3 prostatic cancer cell lines (Du-145, PC 3 p7, PC 3 p35); 1 hepatic cancer cell lines (Huh 7.5.1); and 2 pancreatic cancer cell lines (MIA PACA 2, Panc 1). Two technical repeats were performed (cell lines Siha and SNB-19). Reference T-RNA was obtained from 6 normal donor PBMCs.

Project description:BackgroundRecent data suggest that cancer stem cells (CSCs) play an important role in cancer, as these cells possess enhanced tumor-forming capabilities and are responsible for relapses after apparently curative therapies have been undertaken. Hence, novel cancer therapies will be needed to test for both tumor regression and CSC targeting. The use of oncolytic vaccinia virus (VACV) represents an attractive anti-tumor approach and is currently under evaluation in clinical trials. The purpose of this study was to demonstrate whether VACV does kill CSCs that are resistant to irradiation and chemotherapy.MethodsCancer stem-like cells were identified and separated from the human breast cancer cell line GI-101A by virtue of increased aldehyde dehydrogenase 1 (ALDH1) activity as assessed by the ALDEFLUOR assay and cancer stem cell-like features such as chemo-resistance, irradiation-resistance and tumor-initiating were confirmed in cell culture and in animal models. VACV treatments were applied to both ALDEFLUOR-positive cells in cell culture and in xenograft tumors derived from these cells. Moreover, we identified and isolated CD44(+)CD24(+)ESA(+) cells from GI-101A upon an epithelial-mesenchymal transition (EMT). These cells were similarly characterized both in cell culture and in animal models.ResultsWe demonstrated for the first time that the oncolytic VACV GLV-1h68 strain replicated more efficiently in cells with higher ALDH1 activity that possessed stem cell-like features than in cells with lower ALDH1 activity. GLV-1h68 selectively colonized and eventually eradicated xenograft tumors originating from cells with higher ALDH1 activity. Furthermore, GLV-1h68 also showed preferential replication in CD44(+)CD24(+)ESA(+) cells derived from GI-101A upon an EMT induction as well as in xenograft tumors originating from these cells that were more tumorigenic than CD44(+)CD24(-)ESA(+) cells.ConclusionsTaken together, our findings indicate that GLV-1h68 efficiently replicates and kills cancer stem-like cells. Thus, GLV-1h68 may become a promising agent for eradicating both primary and metastatic tumors, especially tumors harboring cancer stem-like cells that are resistant to chemo and/or radiotherapy and may be responsible for recurrence of tumors.

Project description:Oncolytic viral therapy represents an alternative therapeutic strategy for the treatment of cancer. This therapy relies on efficient replication of virus in tumor cells in vivo with minimal or no replication in normal tissues. We recently described GLV-1h68 as a modified Vaccinia Virus (VACV) construct with exclusive in vivo tropism for tumor cells in experimental animal models. Moreover, we had previously observed a cell line-specific relationship between the ability of GLV-1h68 to replicate in vitro during the first 20 hours following infection and the in vivo ability to colonize and eliminate the corresponding tumor implant. Thus, we surveyed the in vitro permissivity to GLV-1h68 replication of the NCI-60 panel of cell lines, extensively characterized and used for the assessment of novel therapeutic modalities. All cell lines were cultured and infected in identical conditions. Pre-infection transcriptional profiling was obtained to search for correlates of permissivity to viral infection. Selected cell lines were also tested for permissivity to another VACV and a vesicular stomatitis virus (VSV) strain. We observed that permissivity to VACV infection during the first 20 hours is quite heterogeneous among cell lines but highly reproducible within each cell line. The tissue of origin of each cell line does not influence permissivity to infection with the exception of B cell derivation. Permissivity correlates between two VACV constructs and between them and VSV suggesting a common permissive phenotype. No clear transcriptional pattern predictive of permissivity to infection could be identified though weak associations were observed that suggest a multifactorial control of viral replication. This study adds to the current characterization of the NCI-60 panel to guide the design and interpretation of experimental models testing oncolytic therapies. Seventy-four microarray samples were obtained from 8 renal cancer cell lines (786-0, A498, ACHN, CAKI-I, RXF-393, SN12C, TK-10, UO-31); 12 melanoma cell lines (888-MEL, 1858-MEL, 1936-MEL, 397, A375-MEL, LOX IMVI, M14, SK-MEL-2, SK-MEL-5, SK-MEL-28, UACC 62, UACC 257 ); 11 lung cancer cell lines (A549 p7, A549 p107, EKVX, HOP-62, HOP-92, NCI-H23, NCI-H226, NCI-H322M, NCI-H460, NCI-H522, NCI-H1299); 13 colon cancer cell lines (HCT-15, HCT-116, HT-29 p155, HT-29 p9, KM-12, SW-620, Colo 205, HCC 2998, NCI-ADR-RES, OVCAR 3 p7, OVCAR 3 p42, OVCAR 5, SK-OV-3); 3 ovarian cancer cell lines (OVCAR 4, OVCAR 8, IGROV); 1 cervical cancer cell line (Siha); 6 brain cancer cell lines (SNB 19, SF 295, SF 298, SNB 75, U251, SF 539); 7 breast cancer cell lines (BT-549, GI101A, HS-578T, MCF 7, MDA-MB-231 p41, MDA-MB-435, MDA-MB-231 p6); 7 hematopoietic cancer cell lines (CCFR-CEM, HL-60, K-562, MOLT-4, RPMI 8226, SR, T-47D); 3 prostatic cancer cell lines (Du-145, PC 3 p7, PC 3 p35); 1 hepatic cancer cell lines (Huh 7.5.1); and 2 pancreatic cancer cell lines (MIA PACA 2, Panc 1). Two technical repeats were performed (cell lines Siha and SNB-19). Reference T-RNA was obtained from 6 normal donor PBMCs.

Dataset Information

Efficient colonization and therapy of human hepatocellular carcinoma (HCC) using the oncolytic vaccinia virus strain GLV-1h68.

Publications

Efficient colonization and therapy of human hepatocellular carcinoma (HCC) using the oncolytic vaccinia virus strain GLV-1h68.

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