The development of metastasis is a highly selective process favoring the survival of a minor subpopulation of metastatic cells. To produce metastases, tumor cells from this subpopulation must complete a sequence of interrelated steps. To produce clinically relevant distant metastases, the successful metastatic cell must therefore exhibit a complex phenotype that is regulated by transient or permanent changes at the gene level. Many malignant tumors, including pancreatic cancer, contain heterogeneous subpopulations of cells. This heterogeneity is exhibited in a wide range of genetic, biochemical, immunological, and biological characteristics such as growth rate, antigenic and immunogenic status, cell surface receptors and products, enzymes, karyotypes, cell morphologies, invasiveness, drug resistance, and metastatic potential. It is likely that specific tumor cells or colonies within the larger heterogeneous tumor specimen are the forerunners of distant metastases. The overall efficiency of the whole metastatic process itself is low. Although the absolute number of cancer cells required for metastasis in humans is unknown, a positive relationship between the number of circulating cancer cells and the subsequent development of metastases has been the subject of several experimental studies (Fisher, E.R. and Fisher, B. Experimental study of factors influencing development of hepatic metastases from circulating tumor cells. Acta Cytol. 9: 146-159, 1965. Fidler, I.J. The relationship of embolic homogeneity, number, size and viability to the incidence of experimental metastasis. Europ. J. Cancer 9: 223-227, 1973. Liotta, L.A., Kleinerman, J., Saidel, G. Quantitative relationships of intravascular tumor cells, tumor vessels and pulmonary metastasis. Cancer Res. 34: 977-1004, 1974. Weiss, L., Mayhew, E., Glaves, R.P. and Holmes, J.C. Metastatic inefficiency in mice bearing B16 melanomas. Br. J. Cancer 45: 44-53, 1982. Topal B, Aerts JL, Roskams T, Fieuws S, Van Pelt J, Vandekerckhove P, Penninckx F. Cancer cell dissemination during curative surgery for colorectal liver metastases. Eur J Surg Oncol 2005; 31: 506-511).