PLoS Medicine and the Pharmaceutical Industry

Using an immunoperoxidase procedure, we have examined the distribution of laminin and fibronectin in normal human large intestinal mucosa and in 50 cases of rectal adenocarcinoma for which extensive clinical follow up was available. In normal tissue, laminin staining was largely restricted to basement membranes, including that underlying the epithelial cells, whereas fibronectin was found in both basement membranes and surrounding connective tissue. In rectal carcinomas, basement membrane-like staining for laminin associated with tumour cells was found in only 27 out of the 50 cases studied. Statistical analysis showed that the presence of laminin-containing basement membranes was correlated with low histological grade (well-differentiated tumours), but not with stage (progression through the bowel wall and the development of lymph node metastases) and, in a highly significant way, with a reduced incidence of distant metastases and increased patient survival. Although fibronectin was found in tumour cell basement membranes where these were present, it was also found in the stroma of all 50 tumours. There was no apparent correlation between the presence of stromal fibronectin and grade, stage or development of metastases. Finally, attention is drawn to some of the technical difficulties in detecting basement membrane antigens in formalin-fixed tissue, the material most frequently available for retrospective study. Colorectal carcinoma remains one of the commonest causes of death from malignant disease in the Western world, despite intensive therapeutic efforts. One reason is that distant, blood-borne metastases form insidiously, perhaps even before a "curative" surgical procedure is undertaken. The stage of the disease at surgery, as defined by Dukes (1932) is useful in determining the prognosis, and it has further been shown by Talbot et al. (1980) that invasion of rectal veins is an important step in the pathogenesis of liver and other distant metastases. However, the tendency for tumours of epithelial origin to disseminate by malignant embolism is also thought to depend on the organisation of basement membrane within the primary growth (Salo et al., 1982). The attachment of epithelial cells to their underlying basement membrane may be mediated by adhesive glycoproteins such as fibronectin, laminin and type IV collagen (Kleinman et al., 1981) which are known to be present in basement membranes (Heathcote & Grant, 1981, Szarfman et al., 1982). Loss of these adhesive substances and disruption of basement membrane structure may therefore be an important factor in detachment of cells from the primary tumour, and the subsequent development of metastases. A …