https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5423226/D.ap wrote: ↑Sun Jun 19, 2022 7:26 am Abstract
Tumor cells leave the primary tumor and enter the circulation. Once there, they are called circulating tumor cells (CTCs). A fraction of CTCs are capable of entering distant sites and persisting as disseminated tumor cells (DTCs). An even smaller fraction of DTCs are capable of progressing toward metastases. It is known that the DTC microenvironment plays an important role in sustaining their survival, regulating their growth, and conferring resistance to therapy. But we still have much to learn about the nature of these rare cell populations to predict which will progress and what exactly should cause concern for future relapse. Although recent technological advances in our ability to detect and molecularly and functionally characterize CTCs and DTCs promise to unravel this ambiguity, the timing of dissemination and the precise source of CTCs and DTCs profiled will impact the conclusions that can be made from these endeavors. In this review, we discuss the biology of CTCs and DTCs; the technologies to detect, isolate, and profile these cells; and the exceptions we must apply to our understanding of what role these cells play in the metastatic process. We conclude that a greater effort to understand the unique biology of these cells in context will positively impact our ability to use these cells to predict outcome, monitor treatment efficacy, and reveal therapeutically relevant targets to deplete these populations and ultimately prevent metastasis.
Keywords: chemoresistance, circulating tumor cells, disseminated tumor cells, dormancy, metastatic microenvironment, perivascular niche
1. Introduction
Perhaps the most important discovery in the last 15 years of basic metastasis research is the finding that tumor cells disseminate at the so‐called in situ stage (Braun et al., 2005; Gruber et al., 2016; Sänger et al., 2011), well before detection of the primary tumor. In retrospect, this should not have been so surprising. Five to ten percent of all cases of metastatic cancer are cancer of unknown primary (Abbruzzese et al., 1994; Klein, 2009; Massard et al., 2011; van de Wouw et al., 2002), where the metastatic lesion is detected before the primary tumor. The implications of early dissemination – that disseminated tumor cells (DTCs) a) lack many of the genomic abnormalities that characterize the primary tumor, and b) evolve in parallel with the primary tumor – have great relevance now that we are at the dawn of personalized medicine.
The question is how to instigate a paradigm shift in metastasis research so that personalized medicine is applied to DTCs and their circulating counterparts, CTCs, rather than solely to the primary tumor. How do we shift the focus from treating metastasis to preventing metastasis when we currently do not have any drugs that specifically target DTCs or CTCs? What approaches are necessary to identify actionable targets that could lead to CTC and/or DTC depletion? This is essentially the only way to test the logical assumption that successful depletion of these cell populations would result in prolonged metastasis‐free survival. And lastly, once we successfully develop these approaches, we must understand heterogeneity within and among patients so that we can determine which patients would benefit from such therapies.
Addressing these challenges not only requires bold thinking, it necessitates the development of technologies and models to study rare cell populations in context. In this review, we shine a spotlight on these harbingers of metastasis with a focus on early stages of the disease. We highlight the biology that implicates CTCs and DTCs in metastasis; the technologies and models developed to detect, profile, and study these cells; the clinical implications of current findings; and what is left to uncover.
The meaning of HARBINGER is something that foreshadows a future event : something that gives an anticipatory sign of what is to come