Expression and regulation of the Coxsackie- and Adenovirus Receptor (CAR) in premalignant lesions and advanced neoplasms.

M Anders, MD a, C Christian a, RS Warren, MD b, A. Balmain, PhD a, MJ Bissell d, PhD, WM Korn, MD a,c

a Comprehensive Cancer Center, b Department of Surgery, c Division of Gastroenterology, University of California San Francisco, San Francisco, CA and d Lawrence Berkeley National Laboratory, Berkeley, CA, United States

The recently identified Coxsackie-and Adenovirus Receptor (CAR) represents the primary cellular site of adenovirus attachment during infection. As genetically modified adenoviruses are currently explored as agents for the treatment of premalignant lesions (e.g. oral leucoplakia) and advanced cancer, information about representation of CAR in these diseases and the molecular mechanisms of its regulation is needed. We examined CAR expression in human samples of DCIS and invasive breast cancer as well as in colorectal adenomas and cancer. These studies demonstrated frequent preservation of CAR expression in early lesions. In advanced neoplasms, CAR levels and expression patterns were highly variable and a subset of tumors showed significant reduction of CAR expression. To elucidate the molecular mechanisms regulating expression of CAR, we took advantage of a three-dimensional breast cancer model, cell line models of colorectal cancer, and a mouse skin cancer progression model. We found that in models of early malignant lesions, deregulation of CAR expression was associated with a disturbance of tissue integrity. In models of advanced cancer, we were able to demonstrate that the Raf-1/MAPK signal transduction pathway regulates CAR expression. Inhibition of this pathway restored cell-surface expression of CAR and enhanced cell killing by a replication-competent adenovirus. We conclude from these studies that premalignant lesions might be particularly susceptible to adenovirus-based therapies. Furthermore, major oncogenic pathways regulate CAR expression in advanced cancer. Based on this observation, we hypothesize that combination therapies with signal transduction inhibitors and genetically modified adenovirus could represent a new strategy for the treatment of cancer.

KEY WORDS: gene therapy, breast cancer, colorectal cancer, coxsackie- and adenovirus receptor, Raf-1.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Novel Therapies, Part 2.