Controversies in clinical cancer dormancy

Abstract

Clinical cancer dormancy is defined as an unusually long time between removal of the primary tumor and subsequent relapse in a patient who has been clinically disease-free. The condition is frequently observed in certain carcinomas (e.g., breast cancer), B-cell lymphoma, and melanoma, with relapse occurring 5-25 y later. Clinical data suggest that a majority of breast cancer survivors have cancer cells for decades but can remain clinically cancer-free for their lifetime. Thus, there is a major effort to characterize the molecular mechanisms responsible for inducing tumor cell dormancy using experimental models or studying the early phases of cancer growth in humans. Many molecules and signaling pathways have been characterized and have led to concepts that dominate the field, such as the possible role of innate and adaptive immunity in immune surveillance and initiation and maintenance of dormancy. However, recent clinical data do not support many of these concepts. Several areas need further study to determine their relevance to clinical cancer dormancy. We suggest hypotheses that may contribute to elucidation of the mechanisms underlying the dormant state.

Fig. 1.

Diagram of clinical cancer dormancy. Cells from the primary tumor are shed into the circulation (CTCs) and a small percentage lodge in tissue including bone marrow. A portion of the CTCs are in cell-cycle arrest and are chemo- and radio-resistant, that is, stem-like cells. These are colored red. Later, these initial cells, a differentiated subset of them, or a different cell type proliferate and establish micrometastases in tissue. There is a steady-state balance between cell proliferation and cell death. Some of the cells that are destined to die are shed into the blood (CTCs). In some patients, the balance changes and metastatic growth occurs (relapse). Solid lines represent dormancy pathways; dotted lines represent pathways for conventional metastatic growth.