Theocharous, Panteli; (2001) Novel approaches in the detection and characterisation of circulating and micrometastatic tumour cells in epithelial malignancies. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The detection of disseminated tumour cells has introduced a new opportunity to evaluate the diverse biological characteristics of the primary tumour that might favour the early dissemination of its cells, since conventional risk factors do not provide specific or sensitive enough information. An immunocytochemical (ICC) assay established during the study, was shown to be capable of detecting one cytokeratin-positive (CK+VE) cell in 2 x 10 mononuclear cells (MNCs), by attachment to microscope slides coated with Cell-Tak Cell and Tissue Adhesive. The clinical data indicate that 57% of samples examined from patients undergoing therapy for carcinoma of the breast (BrCa), showed detectable CK+VE cells in peripheral blood (PB) or bone marrow (BM) aspirate samples. The incidence of tumour cell contaminated PB samples was higher in patients with metastatic disease than patients without overt metastatic disease (p<0.0001). In contrast, all control samples consistently tested negative for circulating CK+VE cells. Detection of micrometastases may also help to determine prognosis and allow development of new therapeutic approaches. In a study of the impact of chemotherapy on the presence of tumour cells in the PB, 24/33 high-risk nonmetastatic BrCa patients had detectable tumour cells pre-chemotherapy (steady state). A reduction, but not complete eradication, in the number of circulating CK+VE cells was observed in all patients during subsequent courses of chemotherapy (p<0.0001). This demonstrates that chemotherapy is not effective in eliminating all PB/BM tumour cells even in chemo-responsive patients. In addition, the phenotype of these cells may determine whether overt metastases will develop. A highly sensitive assay combining tumour cell enrichment with immunolabelling and fluorescence in situ hybridization (FISH), was developed to characterise cytogenetically aberrant tumour cells in haematopoietic samples. Using DNA probes to the Her-2/neu (c-erbB-2) oncogene and chromosomes 7, 8, and 17 hybridized to metaphase chromosomes and immunolabelled interphase cells, oncogene overamplification and chromosomal alterations have been established. Additional studies have confirmed an association between the level of Her- 2lneu gene amplification, clinical status and response to chemotherapy. Genotypic analyses suggest that Her-2/neu overexpression may enhance metastatic potential possibly by promoting steps in the invasion and metastasis process and that "shed" Her-2/neu+VE/CK+VE PB tumour cells might "home" to the BM, resulting in aggressive tumour behaviour and a poor prognosis.

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