Fibronectin suppression in head and neck cancers, inflammatory tissues and the molecular mechanisms potentially involved.

Epithelial cellular fibronectin is frequently repressed after malignant transformation in a variety of cancers. This change has been associated with a loss of contact inhibition. To determine if these findings are unique to malignant processes and to identify mechanisms responsible for fibronectin suppression, we investigated fibronectin expression patterns in 46 head and neck carcinomas, 16 samples of adenoid tissue, and 10 benign mucosal biopsies. We report fibronectin suppression in 78% of the head and neck cancer samples, occurring most prominently within tumor cells, as opposed to the adjacent stroma which exhibited abundant fibronectin. Interestingly, fibronectin was also strongly repressed in chronically inflamed adenoid samples. We showed that fibronectin suppression is mediated by different mechanisms in both benign as well as malignant scenarios: In adenoids, macrophages and T-cells were visualized throughout epithelium that has lost its tight cellular array, allowing leukocyte passage. We have shown that tumor necrosis factor-alpha secreted by macrophages is capable of inducing epithelial derangement via activator protein-1 and nuclear factor-kappaB mediated fibronectin suppression. In head and neck carcinomas, we identified human papilloma virus early protein-2 as a fibronectin transcription inhibitor. We conclude that epithelial fibronectin suppression may not be a hallmark of malignancy, because it can concur with benign processes that involve leukocyte migration. Furthermore, our data suggest that the pattern of fibronectin suppression within the tumor structure largely depends on the cancer cell-stroma relation, which could explain previous conflicting reports on its repression or overexpression along with malignant transformation. In addition, our data support an involvement of human papilloma virus as a mechanism of carcinogenesis mediated via a loss of fibronectin gene expression.