13 - Metastatic Inefficiency and Tumor Dormancy

Summary

METASTASIS – THE CLINICAL PROBLEM

It is well recognized that metastases – not primary tumors – are responsible for most cancer deaths. Fortunately, however, the metastatic process is highly inefficient. Both clinically and in experimental models, large numbers of cancer cells may leave the primary tumor and be detected in the circulation or in distant organs, yet very few of these disseminated cancer cells go on to form overt, clinically relevant metastases. This was dramatically demonstrated clinically years ago, in a study of patients who received peritoneovenous shunts as palliative treatment for pain associated with malignant ascites. Large numbers of viable, clonogenic tumor cells were detected in the blood of these patients [1, 2]. However, these patients appeared to have no worse outcome, and at autopsy no evidence of increased macroscopic metastatic burden was identified [1, 2].

Consistent with these clinical findings are numerous reports from experimental animal models of metastasis. Large numbers of cancer cells may be detected in (or injected into) the circulation of experimental mice, and only a small fraction of these cells produce progressively growing metastases (early examples include [3–6]). For example, Fidler showed that when 50,000 B16F1 melanoma cells were injected intravenously via the tail vein, only 0.12 percent of the cells produced lung metastases, whereas the B16F11 cells – which had been selected for increased metastatic ability – had an increased metastatic efficiency of 0.74 percent [7].