Limits...
Oncolytic targeting of androgen-sensitive prostate tumor by the respiratory syncytial virus (RSV): consequences of deficient interferon-dependent antiviral defense.

Echchgadda I, Chang TH, Sabbah A, Bakri I, Ikeno Y, Hubbard GB, Chatterjee B, Bose S - BMC Cancer (2011)

Bottom Line: LNCaP cells failed to activate the type-I interferon (IFNα/β)-induced transcription factor STAT-1, which is required for antiviral gene expression, although these cells could produce IFN in response to RSV infection.We demonstrated that RSV is potentially a useful therapeutic tool in the treatment of androgen-sensitive and androgen-independent prostate cancer.Moreover, impaired IFN-mediated antiviral response is the likely cause of higher viral burden and resulting oncolysis of androgen-sensitive prostate cancer cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MC-7758, San Antonio, TX 78229, USA.

ABSTRACT

Background: Oncolytic virotherapy for cancer treatment utilizes viruses for selective infection and death of cancer cells without any adverse effect on normal cells. We previously reported that the human respiratory syncytial virus (RSV) is a novel oncolytic virus against androgen-independent PC-3 human prostate cancer cells. The present study extends the result to androgen-dependent prostate cancer, and explores the underlying mechanism that triggers RSV-induced oncolysis of prostate cancer cells.

Methods: The oncolytic effect of RSV on androgen-sensitive LNCaP human prostate cancer cells and on androgen-independent RM1 murine prostate cancer cells was studied in vitro in culture and in vivo in a xenograft or allograft tumor model. In vitro, cell viability, infectivity and apoptosis were monitored by MTT assay, viral plaque assay and annexin V staining, respectively. In vivo studies involved virus administration to prostate tumors grown in immune compromised nude mice and in syngeneic immune competent C57BL/6J mice. Anti-tumorogenic oncolytic activity was monitored by measuring tumor volume, imaging bioluminescent tumors in live animals and performing histopathological analysis and TUNEL assay with tumors

Results: We show that RSV imposes a potent oncolytic effect on LNCaP prostate cancer cells. RSV infectivity was markedly higher in LNCaP cells compared to the non-tumorigenic RWPE-1 human prostate cells. The enhanced viral burden led to LNCaP cell apoptosis and growth inhibition of LNCaP xenograft tumors in nude mice. A functional host immune response did not interfere with RSV-induced oncolysis, since growth of xenograft tumors in syngeneic C57BL/6J mice from murine RM1 cells was inhibited upon RSV administration. LNCaP cells failed to activate the type-I interferon (IFNα/β)-induced transcription factor STAT-1, which is required for antiviral gene expression, although these cells could produce IFN in response to RSV infection. The essential role of IFN in restricting infection was further borne out by our finding that neutralizing IFN activity resulted in enhanced RSV infection in non-tumorigenic RWPE-1 prostate cells.

Conclusions: We demonstrated that RSV is potentially a useful therapeutic tool in the treatment of androgen-sensitive and androgen-independent prostate cancer. Moreover, impaired IFN-mediated antiviral response is the likely cause of higher viral burden and resulting oncolysis of androgen-sensitive prostate cancer cells.

Show MeSH

Related in: MedlinePlus

Histopathology of LNCaP xenograft prostate tumors. (a) Photograph of tumor (at 20× magnification), injected with medium shows an irregular expansible growth and compression (marked as C) of adjacent normal tissue, revascularization (marked as NV) and vascular metastasis (marked as M). (b) 100× magnification of the upper square in panel-a (solid-line boundary for the demarcated box), showing prominent vascular metastasis (M). (c) 400× magnification of the lower dashed square (demarcated by the broken-line boundary) in panel-a, showing a typical mitotic figure (see arrow). (d) Photograph (at 20X) of RSV-injected tumor. Tumor size is markedly reduced and complete necrosis of the neoplastic cells with minimal fibrovascular encapsulation and pyogranulamatous inflammation is evident. Marked necrosis at the center of the tumor is readily apparent. (e) 100× magnification and (f) 400× magnification of the solid-line square in panel-d, highlighting minimal fibrovascular encapsulation, FV (panel-e) and complete tumor necrosis, TN (panel-f). NT: normal tissue. ND: non-tumor debris.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3038980&req=5

Figure 7: Histopathology of LNCaP xenograft prostate tumors. (a) Photograph of tumor (at 20× magnification), injected with medium shows an irregular expansible growth and compression (marked as C) of adjacent normal tissue, revascularization (marked as NV) and vascular metastasis (marked as M). (b) 100× magnification of the upper square in panel-a (solid-line boundary for the demarcated box), showing prominent vascular metastasis (M). (c) 400× magnification of the lower dashed square (demarcated by the broken-line boundary) in panel-a, showing a typical mitotic figure (see arrow). (d) Photograph (at 20X) of RSV-injected tumor. Tumor size is markedly reduced and complete necrosis of the neoplastic cells with minimal fibrovascular encapsulation and pyogranulamatous inflammation is evident. Marked necrosis at the center of the tumor is readily apparent. (e) 100× magnification and (f) 400× magnification of the solid-line square in panel-d, highlighting minimal fibrovascular encapsulation, FV (panel-e) and complete tumor necrosis, TN (panel-f). NT: normal tissue. ND: non-tumor debris.

Mentions: After administering 7 injections of RSV or medium intra-tumorally (injected every other day), tumors were examined for pathological status. The most prominent change for RSV-injected tumors, compared to medium-injected tumors, was complete necrosis with no histologically discernable tumor cells (Figure 7). RSV infected tumors showed markedly reduced size containing a central necrotic core surrounded by a fibrous pyogranulamatous capsule. The normal inflammatory process led to significant healing, as revealed by replacement of the tumor mass by non-malignant tissue (compare Figure 7d with Figure 7a). Histological evaluations of RSV-injected versus medium-injected tumors (3 tumor specimens in each group) are presented in Table 1. Differences between the control and experimental group are easily discernable. Differences were most prominent in the degree of invasiveness, (4, 4 and 5 vs. 0, 0 and 0), mitotic figures per high power field (2, 11 and 22 vs. 0, 0 and 0), necrosis (2, 1 and 2 vs. 5, 5 and 5), compression of adjacent tissue (2, 1 and 2 vs. 0, 0 and 0), mineralization (0, 0 and 0) vs. 4, 3 and 3). Differences for several additional criteria (edema, congestion, hemorrhage, and hemosiderin deposition) were not significant.


Oncolytic targeting of androgen-sensitive prostate tumor by the respiratory syncytial virus (RSV): consequences of deficient interferon-dependent antiviral defense.

Echchgadda I, Chang TH, Sabbah A, Bakri I, Ikeno Y, Hubbard GB, Chatterjee B, Bose S - BMC Cancer (2011)

Histopathology of LNCaP xenograft prostate tumors. (a) Photograph of tumor (at 20× magnification), injected with medium shows an irregular expansible growth and compression (marked as C) of adjacent normal tissue, revascularization (marked as NV) and vascular metastasis (marked as M). (b) 100× magnification of the upper square in panel-a (solid-line boundary for the demarcated box), showing prominent vascular metastasis (M). (c) 400× magnification of the lower dashed square (demarcated by the broken-line boundary) in panel-a, showing a typical mitotic figure (see arrow). (d) Photograph (at 20X) of RSV-injected tumor. Tumor size is markedly reduced and complete necrosis of the neoplastic cells with minimal fibrovascular encapsulation and pyogranulamatous inflammation is evident. Marked necrosis at the center of the tumor is readily apparent. (e) 100× magnification and (f) 400× magnification of the solid-line square in panel-d, highlighting minimal fibrovascular encapsulation, FV (panel-e) and complete tumor necrosis, TN (panel-f). NT: normal tissue. ND: non-tumor debris.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3038980&req=5

Figure 7: Histopathology of LNCaP xenograft prostate tumors. (a) Photograph of tumor (at 20× magnification), injected with medium shows an irregular expansible growth and compression (marked as C) of adjacent normal tissue, revascularization (marked as NV) and vascular metastasis (marked as M). (b) 100× magnification of the upper square in panel-a (solid-line boundary for the demarcated box), showing prominent vascular metastasis (M). (c) 400× magnification of the lower dashed square (demarcated by the broken-line boundary) in panel-a, showing a typical mitotic figure (see arrow). (d) Photograph (at 20X) of RSV-injected tumor. Tumor size is markedly reduced and complete necrosis of the neoplastic cells with minimal fibrovascular encapsulation and pyogranulamatous inflammation is evident. Marked necrosis at the center of the tumor is readily apparent. (e) 100× magnification and (f) 400× magnification of the solid-line square in panel-d, highlighting minimal fibrovascular encapsulation, FV (panel-e) and complete tumor necrosis, TN (panel-f). NT: normal tissue. ND: non-tumor debris.
Mentions: After administering 7 injections of RSV or medium intra-tumorally (injected every other day), tumors were examined for pathological status. The most prominent change for RSV-injected tumors, compared to medium-injected tumors, was complete necrosis with no histologically discernable tumor cells (Figure 7). RSV infected tumors showed markedly reduced size containing a central necrotic core surrounded by a fibrous pyogranulamatous capsule. The normal inflammatory process led to significant healing, as revealed by replacement of the tumor mass by non-malignant tissue (compare Figure 7d with Figure 7a). Histological evaluations of RSV-injected versus medium-injected tumors (3 tumor specimens in each group) are presented in Table 1. Differences between the control and experimental group are easily discernable. Differences were most prominent in the degree of invasiveness, (4, 4 and 5 vs. 0, 0 and 0), mitotic figures per high power field (2, 11 and 22 vs. 0, 0 and 0), necrosis (2, 1 and 2 vs. 5, 5 and 5), compression of adjacent tissue (2, 1 and 2 vs. 0, 0 and 0), mineralization (0, 0 and 0) vs. 4, 3 and 3). Differences for several additional criteria (edema, congestion, hemorrhage, and hemosiderin deposition) were not significant.

Bottom Line: LNCaP cells failed to activate the type-I interferon (IFNα/β)-induced transcription factor STAT-1, which is required for antiviral gene expression, although these cells could produce IFN in response to RSV infection.We demonstrated that RSV is potentially a useful therapeutic tool in the treatment of androgen-sensitive and androgen-independent prostate cancer.Moreover, impaired IFN-mediated antiviral response is the likely cause of higher viral burden and resulting oncolysis of androgen-sensitive prostate cancer cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MC-7758, San Antonio, TX 78229, USA.

ABSTRACT

Background: Oncolytic virotherapy for cancer treatment utilizes viruses for selective infection and death of cancer cells without any adverse effect on normal cells. We previously reported that the human respiratory syncytial virus (RSV) is a novel oncolytic virus against androgen-independent PC-3 human prostate cancer cells. The present study extends the result to androgen-dependent prostate cancer, and explores the underlying mechanism that triggers RSV-induced oncolysis of prostate cancer cells.

Methods: The oncolytic effect of RSV on androgen-sensitive LNCaP human prostate cancer cells and on androgen-independent RM1 murine prostate cancer cells was studied in vitro in culture and in vivo in a xenograft or allograft tumor model. In vitro, cell viability, infectivity and apoptosis were monitored by MTT assay, viral plaque assay and annexin V staining, respectively. In vivo studies involved virus administration to prostate tumors grown in immune compromised nude mice and in syngeneic immune competent C57BL/6J mice. Anti-tumorogenic oncolytic activity was monitored by measuring tumor volume, imaging bioluminescent tumors in live animals and performing histopathological analysis and TUNEL assay with tumors

Results: We show that RSV imposes a potent oncolytic effect on LNCaP prostate cancer cells. RSV infectivity was markedly higher in LNCaP cells compared to the non-tumorigenic RWPE-1 human prostate cells. The enhanced viral burden led to LNCaP cell apoptosis and growth inhibition of LNCaP xenograft tumors in nude mice. A functional host immune response did not interfere with RSV-induced oncolysis, since growth of xenograft tumors in syngeneic C57BL/6J mice from murine RM1 cells was inhibited upon RSV administration. LNCaP cells failed to activate the type-I interferon (IFNα/β)-induced transcription factor STAT-1, which is required for antiviral gene expression, although these cells could produce IFN in response to RSV infection. The essential role of IFN in restricting infection was further borne out by our finding that neutralizing IFN activity resulted in enhanced RSV infection in non-tumorigenic RWPE-1 prostate cells.

Conclusions: We demonstrated that RSV is potentially a useful therapeutic tool in the treatment of androgen-sensitive and androgen-independent prostate cancer. Moreover, impaired IFN-mediated antiviral response is the likely cause of higher viral burden and resulting oncolysis of androgen-sensitive prostate cancer cells.

Show MeSH
Related in: MedlinePlus