No abstract

In this article we report about the role that tumor structure and extracellular matrix (ECM) may play in immunotherapy and in gene therapy using adenoviruses. We performed studies in a rat model for colorectal cancer, CC531, and in specimens of human colorectal cancer. The tumors were composed of two compartments, tumor cell nests surrounded by stromal cells. ECM proteins were expressed in the stromal part, where the blood vessels were also located. Furthermore, in several tumors, the tumor cell nests were surrounded by basal membrane-like structures. Therefore, in vascular approaches to treat cancer, therapeutic agents on their route to tumor cells may be hampered by ECM to reach tumor cells. We found that immune cells were abundantly present in tumors from colorectal origin. These cells were, however, not found in direct contact with tumor cells, but mainly in the stromal part of the tumor. Adenoviruses, when intravascularly injected, did not reach tumor cells in the CC531 rat model. Tumor cells were only infected, and even then in limited numbers, in cases of intratumoral injection. We hypothesize that ECM in a tumor is a barrier both for immune cells and for adenoviruses to make direct contact with these tumor cells, and thus limits colorectal tumor therapy.

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The chicken anemia virus-derived Apoptin protein shows remarkable specificity; namely, it induces apoptosis in tumor cells, but not in normal diploid cells. We have exploited the Apoptin gene for use in cancer gene therapy. Here we demonstrate that adenovirus-mediated intratumoral transfer and expression of the Apoptin gene results in regression or complete remission of human hepatomas grown as xenografts in immune-deficient mice, and significantly increases their survival long term. Early after intratumoral injection, Apoptin could be detected in significant quantities by Western blot analyses and immunohistochemistry. Furthermore, cell death and disruption of the tumor integrity were apparent in the transduced regions. This experimental gene therapeutic strategy constitutes a unique example of specific antitumor activity using a virus-derived gene with broad-spectrum applicability.