Expression of coxsackie and adenovirus receptor reduces the lung metastatic potential of murine tumor cells

Abstract

The coxsackie and adenovirus receptor (CAR) is involved in the epithelial cell tight junction, the downregulated expression of which is observed in different cancer types. In the present study, we examined CAR's role in tumor metastasis using a B16 melanoma and CT26 colon adenocarcinoma model of experimental metastasis. In lung metastasis, the colony number of B16 cells stably expressing CAR (B16CAR) was significantly lower than that of the control CAR-negative B16 cells. B16 and CT26 cells transiently expressing CAR, which were transduced with adenovirus (Ad) vector expressing CAR, also reduced lung metastasis, suggesting that CAR plays a role in the early stage of metastasis. CAR expression significantly decreased the accumulation of B16 cells in the lung after i.v. injection and the migration in vitro. CAR expression reduced expression of a v , a 4 , b 3 and b 1 integrin, which play important roles in attachment to cells or basement membrane. Thus, CAR expression likely acts as a metastatic suppressor. ' 2007 Wiley-Liss, Inc. Key words: coxsackie and adenovirus receptor; metastasis; adenovirus vector; integrinThe tumor cell metastasis represents the primary source of clinical morbidity and mortality in the large majority of solid tumors. A mechanistic understanding of metastasis will help in the development of better therapies and improve patient outcome. Metastasis consists of multiple steps with many factors. The loss of adhesion to cells and extracellular matrix allows malignant cell to leave their origin site, degrade the extracellular matrix, enter either the lymphatics or the bloodstream and finally metastasize.

Expression of coxsackievirus and adenovirus receptor in human lung cancer: Possible clinical significance

“…Similarly, when compared with normal prostate, CAR expression decreased in prostate carcinoma specimens of all Gleason scores [37] . Yamashita et al reported that CAR expression signifi cantly decreased the lung metastatic potential of B16 melanoma cells in lung after IV injection and in the migration in murine model [38] . Here, we systematically analyzed CAR expression in a large number of lung cancer specimens with RT-PCR, immunohistochemistry and Western blot analysis.…”

Tat conjugation of adenovirus vector broadens tropism and enhances transduction efficiency

“…For example, because many tumor cells, including melanoma, that are targets for gene therapy express no or little CAR, it is difficult to achieve sufficient gene expression and therapeutic effect (Okada et al, 2003b;Mathis et al, 2006). Reduced expression of CAR in advanced tumor stages is one of the major obstacles to the use of Adv for cancer gene therapy (Yamamoto et al, 1997;Li et al, 1999;Yamashita et al, 2007). To overcome these problems, we developed Tat-modified Adv with broadened tropism and enhanced transduction efficiency.…”

Systemic administration of a PEGylated adenovirus vector with a cancer-specific promoter is effective in a mouse model of metastasis

“…30 As many tumor cells that are targets for gene therapy, including melanoma cells, express no or little CAR, it is difficult to achieve sufficient gene expression for a therapeutic effect. [31][32][33] Importantly, PEG-Ad-TERT/ HSVtk induced significant therapeutic effects against metastatic B16BL6 and CT26.CL25 cells, which are CARnegative cells, 34 whereas PEG[20K/45%]-Ad showed significantly reduced CAR-dependent transgene expression in vitro compared with unmodified Adv, because the interaction of Adv and CAR was inhibited by the steric hindrance of PEG chains. 35 As the nonspecific endocytotic activity of tumor tissue is enhanced in general compared with that of normal tissue, we think that the accumulation and retention of PEG[20K/45%]-Ad in the tumor tissue induced its efficient uptake.…”