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Journal of Virology, January 2008, p. 999-1010, Vol. 82, No. 2
0022-538X/08/$08.00+0     doi:10.1128/JVI.01769-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Herpes Simplex Virus Type 1 Preferentially Targets Human Colon Carcinoma: Role of Extracellular Matrix{triangledown}

Dror Kolodkin-Gal,1 Gideon Zamir,2 Yair Edden,2 Eli Pikarsky,3 Alon Pikarsky,2 Hillel Haim,1 Yosef S. Haviv,4 and Amos Panet1*

Department of Virology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel,1 Department of Surgery, The Hebrew University, Hadassah Medical School, Jerusalem, Israel,2 Department of Pathology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel,3 Division of Nephrology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel4

Received 13 August 2007/ Accepted 8 October 2007

Viral therapy of cancer (viral oncolysis) is dependent on selective destruction of the tumor tissue compared with healthy tissues. Several factors, including receptor expression, extracellular components, and intracellular mechanisms, may influence viral oncolysis. In the present work, we studied the potential oncolytic activity of herpes simplex virus type 1 (HSV-1), using an organ culture system derived from colon carcinoma and healthy colon tissues of mouse and human origin. HSV-1 infected normal colons ex vivo at a very low efficiency, in contrast to high-efficiency infection of colon carcinoma tissue. In contrast, adenoviral and lentiviral vectors infected both tissues equally well. To investigate the mechanisms underlying the preferential affinity of HSV-1 for the carcinoma tissue, intracellular and extracellular factors were investigated. Two extracellular components, collagen and mucin molecules, were found to restrict HSV-1 infectivity in the healthy colon. The mucin layer of the healthy colon binds to HSV-1 and thereby blocks viral interaction with the epithelial cells of the tissue. In contrast, colon carcinomas express small amounts of collagen and mucin molecules and are thus permissive to HSV-1 infection. In agreement with the ex vivo system, HSV-1 injected into a mouse colon carcinoma in vivo significantly reduced the volume of the tumor. In conclusion, we describe a novel mechanism of viral selectivity for malignant tissues that is based on variance of the extracellular matrix between tumor and healthy tissues. These insights may facilitate new approaches to the application of HSV-1 as an oncolytic virus.

* Corresponding author. Mailing address: Department of Virology, Hadassah Medical School, The Hebrew University, Jerusalem 91120, Israel. Phone: 972-2-6758548. Fax: 972-2-6757234. E-mail: amospa{at}ekmd.huji.ac.il

{triangledown} Published ahead of print on 31 October 2007.

Journal of Virology, January 2008, p. 999-1010, Vol. 82, No. 2
0022-538X/08/$08.00+0     doi:10.1128/JVI.01769-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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