Thromboplastin release, but not content, correlates with spontaneous metastasis of cancer cells

No previous studies on the possible contribution of cancer-cell procoagulants to metastasis have fulfilled all the criteria for attaining biologically relevant and readily interpretable data (Grimstad et al., 1986), viz: (1) Spontaneous metastasis from primary tumors should be assessed in syngeneic animals; (2) cloned cell lines should be used to correlate cell properties, because heterogeneity within the cell lines employed is a source of serious error; (3) enough clones, derived from the same original tumor, should be used to identify only nonrandom correlations. Observing these criteria, we examined the procoagulant activities of 19 murine fibrosarcoma cell clones and 4 uncloned cell lines with high to moderate or low potential for lung metastases formation. The procoagulant activity found was exclusively of the thromboplastin (tissue factor, factor III) type. It occurred in all cell homogenates, but the quantities did not correlate with metastatic potential. In contrast, all highly to moderately metastatic cell clones and lines from 2 different fibrosarcomas shed thromboplastin activity into the culture medium, whereas no weakly metastatic cells did. Histological examination further supported these indications that release of thromboplastin from cancer cells can promote metastasis by initiating blood clotting and thereby facilitating arrest of the cancer cells in target organ vessels. Examination of a third fibrosarcoma showed that release of thromboplastin activity is not necessary for metastasis in all tumors.