Disseminated Tumor Cells in Bone Marrow and Circulating Tumor Cells in Blood of Breast Cancer Patients: Current State of Detection and Characterization

Abstract

Despite the progress resulting from early detection and improved adjuvant therapy, the prognosis of breast cancer patients is still limited by the occurrence of distant metastases largely due to clinically occult micrometastases that remain undetected at primary diagnosis even by high-resolution imaging approaches. Recent research efforts have concentrated on the identification of additional parameters allowing individual risk assessment and stratification of patients for targeted therapies, since traditional prognostic factors are not sufficient to predict metastatic relapse and treatment decisions are still mainly based on statistical risk parameters. Highly sensitive and specific immunocytochemical and molecular assays now enable the detection and characterization of disseminated and circulating tumor cells (DTCs and CTCs, respectively) at the single cell level in bone marrow (BM) and peripheral blood, providing insights into the first crucial steps of the metastatic cascade. However, because of the still high variability of results in DTC/CTC detection, the necessity of standardized approaches will be discussed. A large number of studies showed that the presence of DTCs in BM has prognostic impact for primary breast cancer patients. DTCs are likely to escape from chemotherapy by maintaining a dormant nonproliferating state. There is also evidence for a stem cell-like phenotype of DTCs, probably contributing to the opportunity to escape from dormancy control and to start expansion to manifest metastases. Blood would also be an ideal source for the detection and monitoring of CTCs because of an easy noninvasive sampling procedure enabling repeated analyses. While prognostic significance of CTCs could be reliably demonstrated for metastatic breast cancer, studies to analyze the impact of CTCs in primary breast cancer patients and the potential to replace or supplement BM analysis are still ongoing. Furthermore, molecular characterization of CTCs might contribute to improving targeted and more individualized cancer therapies.

Mechanism of the Mesenchymal–Epithelial Transition and Its Relationship with Metastatic Tumor Formation

“…Studies have shown that CSCs are enriched in cancer cells disseminated in the circulation or sites of metastases. For example, breast cancer cells disseminated in the circulation and bone marrow were found to be enriched for the CD44high/CD24low antigen phenotype (109)(110)(111). Furthermore, it was found that chemokine receptors can express on CSCs and that CSCs can migrate along a gradient of the CXCR4 ligand CXCL12 (also known as SDF-1), originating from hematopoietic niches and many other tissue sites, thereby facilitating metastasis of CSCs to particular sites (112)(113)(114).…”

Human tissue-specific microenvironment: An essential requirement for mouse models of breast cancer

“…It is well known that circulating tumor cells (DTCs) in breast cancer patients are rarely detectable. There are usually only 10 breast cancer cells per one million bone marrow cells, and DTCs are not detectable in every patient, even in those who develop relapsing breast cancer (26,27). The bone-metastasis formation in the circulation-inoculation mouse model does not imply osteotropism of breast cancer cells.…”

Suppression of Early Hematogenous Dissemination of Human Breast Cancer Cells to Bone Marrow by Retinoic Acid–Induced 2

“…However, many patients relapse after chemotherapy, most likely due to the activation of dormant disseminated tumor cells (DTC), which are nonproliferating and resistant to conventional chemotherapy ( 1 ). Using sensitive immunocytochemical assays, it has been shown that bone marrow is a common homing organ for DTCs of different origins, including breast, lung, and colon carcinomas (2)(3)(4). Several studies, including a large-scale pooled analysis ( 5 ), have shown that the presence of even a single DTC in the bone marrow of patients with breast cancer is an independent prognostic factor ( 3 , 5 ).…”