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Optical detection and virotherapy of live metastatic tumor cells in body fluids with vaccinia strains.

Wang H, Chen NG, Minev BR, Zimmermann M, Aguilar RJ, Zhang Q, Sturm JB, Fend F, Yu YA, Cappello J, Lauer UM, Szalay AA - PLoS ONE (2013)

Bottom Line: Metastatic tumor cells in body fluids are important targets for treatment, and critical surrogate markers for evaluating cancer prognosis and therapeutic response.Importantly, a single intra-peritoneal delivery of VACV resulted in a dramatic decline in the number of tumor cells in the ascitic fluid from a patient with gastric cancer.Taken together, these results suggest VACV to be a useful tool for quantitative detection of live tumor cells in liquid biopsies as well as a potentially effective treatment for reducing or eliminating live tumor cells in body fluids of patients with metastatic disease.

View Article: PubMed Central - PubMed

Affiliation: Genelux Corporation, San Diego Science Center, San Diego, California, United States of America.

ABSTRACT
Metastatic tumor cells in body fluids are important targets for treatment, and critical surrogate markers for evaluating cancer prognosis and therapeutic response. Here we report, for the first time, that live metastatic tumor cells in blood samples from mice bearing human tumor xenografts and in blood and cerebrospinal fluid samples from patients with cancer were successfully detected using a tumor cell-specific recombinant vaccinia virus (VACV). In contrast to the FDA-approved CellSearch system, VACV detects circulating tumor cells (CTCs) in a cancer biomarker-independent manner, thus, free of any bias related to the use of antibodies, and can be potentially a universal system for detection of live CTCs of any tumor type, not limited to CTCs of epithelial origin. Furthermore, we demonstrate for the first time that VACV was effective in preventing and reducing circulating tumor cells in mice bearing human tumor xenografts. Importantly, a single intra-peritoneal delivery of VACV resulted in a dramatic decline in the number of tumor cells in the ascitic fluid from a patient with gastric cancer. Taken together, these results suggest VACV to be a useful tool for quantitative detection of live tumor cells in liquid biopsies as well as a potentially effective treatment for reducing or eliminating live tumor cells in body fluids of patients with metastatic disease.

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Detection and identification of live human CTCs in blood samples.(A) VACV GLV-1h254 detected live CTCs in mice bearing human PC-3 prostate cancer xenografts. Infected CTCs were CK+ (B) or EpCAM+ (C). Live CTCs were also detected by GLV-1h254 in mice bearing human A549 non-small lung cancer xenografts (D). (E) The live CTCs in the patient BC1 were identified as TurboFP635+/EpCAM+ or CK+/CD45−/DAPI+ cells. (F) The live CTCs detected in the patient BC5 were confirmed to express EpCAM, PR, or HER2/neu markers. (G) The live CTCs in the patient BC7 were confirmed as TurboFP635+/CK+/DAPI+ cells. (H) The live CTCs in the patient CC1 with metastatic colorectal cancer were identified as TurboFP635+/EpCAM+ or CK+/CD45−/DAPI+ cells. (I) The live CTCs in the metastatic lung cancer patient LC1 were confirmed as TurboFP635+/EpCAM+/DAPI+ cells. (J) The VACV detected live CTCs in the metastatic melanoma patient MM1 were shown to express melanoma tumor markers Melan-A or microphthalmia-associated transcription factor.
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pone-0071105-g001: Detection and identification of live human CTCs in blood samples.(A) VACV GLV-1h254 detected live CTCs in mice bearing human PC-3 prostate cancer xenografts. Infected CTCs were CK+ (B) or EpCAM+ (C). Live CTCs were also detected by GLV-1h254 in mice bearing human A549 non-small lung cancer xenografts (D). (E) The live CTCs in the patient BC1 were identified as TurboFP635+/EpCAM+ or CK+/CD45−/DAPI+ cells. (F) The live CTCs detected in the patient BC5 were confirmed to express EpCAM, PR, or HER2/neu markers. (G) The live CTCs in the patient BC7 were confirmed as TurboFP635+/CK+/DAPI+ cells. (H) The live CTCs in the patient CC1 with metastatic colorectal cancer were identified as TurboFP635+/EpCAM+ or CK+/CD45−/DAPI+ cells. (I) The live CTCs in the metastatic lung cancer patient LC1 were confirmed as TurboFP635+/EpCAM+/DAPI+ cells. (J) The VACV detected live CTCs in the metastatic melanoma patient MM1 were shown to express melanoma tumor markers Melan-A or microphthalmia-associated transcription factor.

Mentions: The mouse xenograft model of human prostate cancer was generated by implanting 5×106 PC-3 tumor cells into the right hind leg of nude mice. 100 µL of whole blood samples were taken from these mice by cardiac puncture for CTC analysis using the VACV-cytospin assay. Infection of blood samples with GLV-1h254 ex vivo revealed microscopically that infected cells were much larger than surrounding CD45+ immune cells, displayed bright TurboFP635 fluorescent signal, contained nuclei, and were CD45− (Figure 1A). These infected cells were also CK+ (Figure 1B) or EpCAM+ (Figure 1C), indicating that the infected cells were of epithelial origin, as expected for PC-3-derived CTCs. In another experiment, CTCs were also detected and identified as TurboFP635+/CD45−/DAPI+ cells in mice bearing late-stage human A549 non-small cell lung cancer xenografts (Figure 1D).


Optical detection and virotherapy of live metastatic tumor cells in body fluids with vaccinia strains.

Wang H, Chen NG, Minev BR, Zimmermann M, Aguilar RJ, Zhang Q, Sturm JB, Fend F, Yu YA, Cappello J, Lauer UM, Szalay AA - PLoS ONE (2013)

Detection and identification of live human CTCs in blood samples.(A) VACV GLV-1h254 detected live CTCs in mice bearing human PC-3 prostate cancer xenografts. Infected CTCs were CK+ (B) or EpCAM+ (C). Live CTCs were also detected by GLV-1h254 in mice bearing human A549 non-small lung cancer xenografts (D). (E) The live CTCs in the patient BC1 were identified as TurboFP635+/EpCAM+ or CK+/CD45−/DAPI+ cells. (F) The live CTCs detected in the patient BC5 were confirmed to express EpCAM, PR, or HER2/neu markers. (G) The live CTCs in the patient BC7 were confirmed as TurboFP635+/CK+/DAPI+ cells. (H) The live CTCs in the patient CC1 with metastatic colorectal cancer were identified as TurboFP635+/EpCAM+ or CK+/CD45−/DAPI+ cells. (I) The live CTCs in the metastatic lung cancer patient LC1 were confirmed as TurboFP635+/EpCAM+/DAPI+ cells. (J) The VACV detected live CTCs in the metastatic melanoma patient MM1 were shown to express melanoma tumor markers Melan-A or microphthalmia-associated transcription factor.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3760980&req=5

pone-0071105-g001: Detection and identification of live human CTCs in blood samples.(A) VACV GLV-1h254 detected live CTCs in mice bearing human PC-3 prostate cancer xenografts. Infected CTCs were CK+ (B) or EpCAM+ (C). Live CTCs were also detected by GLV-1h254 in mice bearing human A549 non-small lung cancer xenografts (D). (E) The live CTCs in the patient BC1 were identified as TurboFP635+/EpCAM+ or CK+/CD45−/DAPI+ cells. (F) The live CTCs detected in the patient BC5 were confirmed to express EpCAM, PR, or HER2/neu markers. (G) The live CTCs in the patient BC7 were confirmed as TurboFP635+/CK+/DAPI+ cells. (H) The live CTCs in the patient CC1 with metastatic colorectal cancer were identified as TurboFP635+/EpCAM+ or CK+/CD45−/DAPI+ cells. (I) The live CTCs in the metastatic lung cancer patient LC1 were confirmed as TurboFP635+/EpCAM+/DAPI+ cells. (J) The VACV detected live CTCs in the metastatic melanoma patient MM1 were shown to express melanoma tumor markers Melan-A or microphthalmia-associated transcription factor.
Mentions: The mouse xenograft model of human prostate cancer was generated by implanting 5×106 PC-3 tumor cells into the right hind leg of nude mice. 100 µL of whole blood samples were taken from these mice by cardiac puncture for CTC analysis using the VACV-cytospin assay. Infection of blood samples with GLV-1h254 ex vivo revealed microscopically that infected cells were much larger than surrounding CD45+ immune cells, displayed bright TurboFP635 fluorescent signal, contained nuclei, and were CD45− (Figure 1A). These infected cells were also CK+ (Figure 1B) or EpCAM+ (Figure 1C), indicating that the infected cells were of epithelial origin, as expected for PC-3-derived CTCs. In another experiment, CTCs were also detected and identified as TurboFP635+/CD45−/DAPI+ cells in mice bearing late-stage human A549 non-small cell lung cancer xenografts (Figure 1D).

Bottom Line: Metastatic tumor cells in body fluids are important targets for treatment, and critical surrogate markers for evaluating cancer prognosis and therapeutic response.Importantly, a single intra-peritoneal delivery of VACV resulted in a dramatic decline in the number of tumor cells in the ascitic fluid from a patient with gastric cancer.Taken together, these results suggest VACV to be a useful tool for quantitative detection of live tumor cells in liquid biopsies as well as a potentially effective treatment for reducing or eliminating live tumor cells in body fluids of patients with metastatic disease.

View Article: PubMed Central - PubMed

Affiliation: Genelux Corporation, San Diego Science Center, San Diego, California, United States of America.

ABSTRACT
Metastatic tumor cells in body fluids are important targets for treatment, and critical surrogate markers for evaluating cancer prognosis and therapeutic response. Here we report, for the first time, that live metastatic tumor cells in blood samples from mice bearing human tumor xenografts and in blood and cerebrospinal fluid samples from patients with cancer were successfully detected using a tumor cell-specific recombinant vaccinia virus (VACV). In contrast to the FDA-approved CellSearch system, VACV detects circulating tumor cells (CTCs) in a cancer biomarker-independent manner, thus, free of any bias related to the use of antibodies, and can be potentially a universal system for detection of live CTCs of any tumor type, not limited to CTCs of epithelial origin. Furthermore, we demonstrate for the first time that VACV was effective in preventing and reducing circulating tumor cells in mice bearing human tumor xenografts. Importantly, a single intra-peritoneal delivery of VACV resulted in a dramatic decline in the number of tumor cells in the ascitic fluid from a patient with gastric cancer. Taken together, these results suggest VACV to be a useful tool for quantitative detection of live tumor cells in liquid biopsies as well as a potentially effective treatment for reducing or eliminating live tumor cells in body fluids of patients with metastatic disease.

Show MeSH
Related in: MedlinePlus