Abstract Metastatic relapse of carcinoma patients is mainly due to clinically occult micrometastases present at primary diagnosis, but undetectable even by high-resolution imaging technologies. Frequently, traditional prognostic factors are insufficient to predict metastasis and treatment decisions are mainly based on statistical risk parameters. Highly sensitive and specific cytometric and molecular methods enable now the detection of disseminated tumor cells (DTC) in bone marrow (BM) and circulating tumor cells (CTC) in peripheral blood of breast carcinoma patients. The presence of DTC has independent prognostic impact for patients with primary breast cancer with regard to metastatic relapse and overall survival(1) and DTC may even contribute to local relapse (2). Interestingly, bone marrow seems to be a common homing organ for cells derived from various epithelial tumors including breast, prostate, lung and colon cancer (3); (4)). This surprising finding is consistent with recent results obtained in mouse models (5),, supporting the hypothesis that BM might be an important reservoir for metastatic cells from where they can re-circulate into various organs and may be even back to the primary site (6); (7); (8). DTC may have adapted to the special environmental conditions in the BM and may survive in so called “bone marrow niches” over decades. This hypothesis has important clinical implications for the design of future clinical trials with drugs that are able to specifically block the interaction between tumor cells and the bone marrow microenvironement (e.g., bisphosphonate or antibodies to RANK ligand). However, a significant fraction of DTC remain over years in a “dormant” stage, and little is known about the conditions required for the persistence of dormancy or the escape from the dormant phase into the active phase of metastasis formation (9). Transition from a dormant into a dynamic phase may be caused by genetic changes within the disseminated tumor cells (i.e. acquisition of growth factor receptor Her-2/neu amplification (10); (11) but also by the influence of the surrounding bone marrow microenvironment. Furthermore, BM has a particular capability to host stem cells, which may also contribute to keep DTC in a stem cell-like state. This assumption is also supported by the fact that most DTC in BM and blood are in a nonproliferating state and survive systemic chemotherapy (12); (13). Moreover, most DTC in breast cancer patients showed a breast stem cell phenotype (CD44+/CD24- or MUC1-/CK19+) (14); (15). Moreover, epidermal growth factor (EGF) and fibroblast growth factor-2 (FGF-2) - two known stem cell factors - were relevant for the in vitro growth of DTC obtained from BM of cancer patients (16). Nevertheless, strong direct evidence that some of the few DTC or CTC detected in the BM or blood samples have cancer stem cell properties is still missing. Future studies including xenotransplantation of DTC/CTC into immunodeficient mice need to demonstrate that these cells are the actual founder cells of overt metastasis. BM analyses are not well accepted by the medical community for the clinical management patients in breast cancer and other solid tumors. Therefore, most current research efforts are directed to evaluate the clinical utility of CTC detection (17). Because of the high variability of results obtained by different cytometric and molecular approaches, standardization of current technologies is urgently required (18); (19). While the prognostic significance of CTC could be demonstrated for metastatic breast cancer patients (20), studies on the impact of CTC in primary breast cancer patients are still ongoing but the intermediate results are so far promising (21). Moreover, encouraging results on monitoring CTC during primary systemic or adjuvant chemotherapy in breast cancer patients were obtained in recent studies. Further characterization of CTC is pivotal to understand the biology of tumor cell dissemination (22). The molecular characterization of CTC with special emphasis on potential cancer stem cell features and therapeutically relevant targets such as HER2 (23) might improve individual risk assessment and stratification of patients for targeted therapies. This characterization will contribute to more “tailored” and personalized anti-metastatic therapies. At present, the success or failure of anti-cancer therapies is only assessed retrospectively by the absence or presence of overt metastases during the postoperative follow up period. Real-time monitoring of peripheral blood (i.e., during and after systemic adjuvant therapy) for CTC might provide unique information for the clinical management of the individual cancer patient and allow an early change in therapy years before the appearance of overt metastases signals incurability (24). Future clinical trials will show whether the assessment and monitoring of therapeutic targets (e.g., EGF-R, HER2 or VEGF) on CTC (and probably DTC) might become an important diagnostic tool for cancer patients undergoing targeted therapies and may provide new insights into the selection of tumor cells under biological therapies. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):CN02-01.
Search from 250 M+ research papersSearch from 250 M+ research papers
Jul 1, 2018
Klaus Pantel 
Open Access