Cancer: the role of extracellular disease

Invasive carcinoma originates from the epithelial cells lining the lumen of an organ. It is often preceded by metaplasia, dysplasia or carcinoma in situ. The purpose of this review is to suggest that this disease of the epithelium may be, in part, the result of underlying tissue-based disorganization. Human cancer is frequently associated with pre-existing tissue disease. For example, hepatocellular carcinoma usually occurs in patients with a macronodular cirrhotic liver. Most lung cancers arise among patients with chronic lung disease (bronchitis, emphysema, and chronic infection). Mechanical forces appear to play a major role in regulating normal and cancer cell growth. The loss of cell polarity by neoplastic cells, coupled to an otherwise normal growth rate is enough to explain the cancer star-shaped pattern. By changing the plane of cell division, tumor cells may escape physical constraints from surrounding cells and divide. Loss of cell polarity and the resulting cell proliferation appears to be a consequence of either tissue-based disorganization (chronic inflammation, fibrosis) or of direct carcinogenic insult. The multiple mutations frequently described in cancer may be, in part, secondary to physical stress and not primary events. Several animal and clinical trials have shown that tissue disruption (i.e. radiation-induced fibrosis or liver cirrhosis) can be successfully treated. It is possible that treatment targeted at tissue disruption would delay or reduce cancer incidence regardless of the precise biological mechanism of carcinogenesis.