Characterisation of micrometastatic tumor cells

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Using monoclonal antibodies to epithelial cytokeratins (CK) or tumor-associated cell membrane glycoproteins, individual carcinoma cells can be detected on cytological preparations at frequencies of 10^-5 to 10^-6 (for review, see Pantel et al, JNCI, 1999). Our prospective clinical studies have shown that the presence of these immunostained cells in bone marrow and lymph nodes of patients without clinical or histopathological signs of metastases is prognostically relevant (Pantel et al, Lancet, 1996; Izbicki et al, N Engl J Med, 1997; Braun et al, N Engl J Med, 2000). In addition to immunocytochemistry, new molecular detection methods based on the amplification of a marker mRNA species by the polymerase chain reaction technique have been developed (Zippelius et al, JCO, 1997). The current assays may be used to improve tumor staging with potential consequences for adjuvant therapy. Another promising clinical application is monitoring the response of micrometastatic cells to adjuvant therapies (Braun et al, JCO, 2000), which, at present, can only be assessed retrospectively after an extended period of clinical follow-up. Moreover, the screening methods can be applied to detect tumor cells in the autologous transplant. The extremely low frequency of bone marrow tumor cells greatly hampers approaches to obtain more specific information on their biological properties. The tools established in our laboratory (eg, micrometastatic cell lines, single cell (RT)PCR, multiple labelling, and FISH) allow one to obtain further insights into the phenotype and genotype of therapy-sensitive and resistant micrometastases. The available data indicate that micrometastatic cells represent a selected population of cancer cells which, however, still express a considerable degree of heterogeneity with regard to chromosomal aberrations and phenotypic properties. Prominent characteristics of bone marrow tumor cells at the time of primary tumor diagnosis are the lack of both p53 mutations and proliferation-associated marker proteins and the frequent overexpression of the erbB2 oncogene (Pantel et al, JNCI, 1993; Putz et al, Cancer Res, 1999; Offner et al, PNAS, 1999). Identification of the molecular determinants of micrometastasis may help to design new strategies to detect and eliminate minimal residual cancer.