Recent advances in the detection of bone marrow micrometastases: A promising area for research or just another false hope? A review of the literature

Abstract

The presence of early disseminated tumor cells (DTC), otherwise termed micrometastases or minimal residual disease, in the bone marrow (BM), or other secondary compartments, such as the blood and the lymph nodes, is the main reason for recurrence of patients with early stage epithelial cancers after "curative" resection of the primary tumor. There is increasing evidence, that the detection of DTC in BM aspirates may provide additional and independent prognostic information and aid in the stratification of these patients for adjuvant clinical treatment. However, the clinical relevance of micrometastases has not yet been firmly established. In addition, the molecular events and interactions that prevail in early metastatic disease and determine the formation or not of overt metastases remain poorly understood. The methods currently used for the detection of micrometastatic cells include extremely sensitive immunocytochemical and molecular assays, often in conjunction with enrichment techniques for the purification of tumor cells and additional increase of their sensitivity. Nevertheless, the specificity of these methods is mostly inadequate. After the impressive advances of molecular cytogenetics, a highly accurate and global assessment of the genetic status of tumors is now possible. Therefore, the greatest challenge of our time is the application of these novel technologies for the clarification of the key molecular events that initiate metastatic spread. This will further enable us to identify the highly specific and sensitive diagnostic and prognostic markers as well as the therapeutic targets which are so urgently needed.

Natural history of hepatic metastases from colorectal cancer - pathobiological pathways with clinical significance

“…It is believed that micrometastases are the final metastatic stage for the vast majority of malignant cells, which never succeed in surviving or adapting in the inhospitable environment of the foreign tissue. In accordance with that belief, cancer patients may present myriad of micrometastases in multiple organs and tissues, although without any clinical evidence [11,12] . This general pattern of carcinogenesis and metastasis applies to most cancer types with certain modifications and adaptations according to implicated cells, tissues and organs [1] .…”

GAS6 Receptor Status Is Associated with Dormancy and Bone Metastatic Tumor Formation

“…Importantly, if the primary tumors are removed, some of the animals develop metastatic bone lesions over the course of several months (18]. We therefore used this model to evaluate the expression of Axl and Tyro3 in both the primary s.c. tumors and DTCs in boney sites over time ( Figure 3A ) [25], [26], after first ensuring that recurrence in the primary site had not occurred ( Figure 3B ). …”

“…Fortunately, PCa recurrence is a rare event in most men, even when DTCs are present in the marrow [25], [26]. Likewise, in the s.c. model, when metastases do occur (less than 10% of the mice) they typically are identified months after inoculation [18].…”

Combined androgen blockade therapy can convert RT-PCR detection of prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) transcripts from positive to negative in the peripheral blood of patients with clinically localized prostate cancer and increase biochemical failure-free survival after curative therapy

“…Experimental models of metastasis show that its initial steps, such as neoangiogenesis, increasing motility of cancerous cells in the primary tumor, invasion of newly formed blood vessels and dissemination of tumor cells into PB, cancer cell survival in PB and the arrest in tissue microcirculation, followed by extravasation into the host tissues extracellular matrix, are events generally carried out efficiently by most tumor cells (32,33). Obviously, the majority of disseminated cancer cells into the host tissue do not progress to tumor growth and development of clinically apparent metastasis (34,35). Nevertheless, molecular evidence of tumor cell dissemination into sites outside the primary tumor, such as the PB, bone marrow, lymphatic vessels and lymph nodes, can define, at least in concept, the group of patients with high risk to develop clinically apparent metastasis (36).…”