Progression and dormancy in metastatic thyroid cancer: concepts and clinical implications

Abstract

Distant metastasis classically has been defined as a late-stage event in cancer progression. However, it has become clear that metastases also may occur early in the "lifetime" of a cancer and that they may remain stable at distant sites. This stability of metastatic cancer deposits has been termed "metastatic dormancy" or, as we term it, "metastatic progression dormancy" as the progression either may reflect growth of already existing metastases or new cancer spread. Biologically, dormancy is the presence of nongrowing, static metastatic cells that survive over time. Clinically, dormancy is defined by stability in tumor markers, imaging, and clinical course. Metastatic well-differentiated thyroid cancer offers an excellent tumor type to understand these processes for several reasons: (1) primary therapy often includes removal of the entire gland with ablation of residual normal tissue thereby removing one source for new metastases; (2) the presence of a sensitive biochemical and radiographic monitoring tests enabling monitoring of metastasis throughout the progression process; and (3) its tendency toward prolonged clinical dormancy that can last for years or decades be followed by progression. This latter factor provides opportunities to define therapeutic targets and/or markers of progression. In this review, we will discuss concepts of metastatic progression dormancy and the factors that drive both long-term stability and loss of dormancy with a focus on thyroid cancer.

Keywords: Dormancy; Metastasis; Progression; Thyroid cancer.

Figure 1.. Model of Thyroid Cancer Metastatic Progression.

Primary tumors release factors (blue circles) that include chemokines and cytokines, nucleic acids, and exosomes and other microvesicles to create a receptive environment for cancer cells. The cancer cells (red pentagons) along with stromal cells invade locally and also into blood vessels and follow the chemokines to metastatic sites with relative specificity for different subtypes. Once in the metastatic sites, the cancer deposits can remain dormant influenced by MPSs (such as KiSS-1, NM23, and RCAN 1.4 in thyroid cancer) and a tumor growth inhibiting microenvironment characterized by absent angiogenesis, the inability to degrade tissue matrix, and immune surveillance. Progression in the metastatic sites is enhanced by loss of MPSs, the development of new growth promoting changes, and the development of a tumor growth promoting microenvironment with enhanced angiogenesis, the development of invasive properties (e.g EMT), and a tumor promoting immune environment.