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Review
. 2024 Aug;41(4):275-299.
doi: 10.1007/s10585-023-10248-0. Epub 2024 Mar 23.

How much do we know about the metastatic process?

Carolina Rodriguez-Tirado  1   2   3   4   5 , Maria Soledad Sosa  6   7   8   9   10
Affiliations
Review

How much do we know about the metastatic process?

Carolina Rodriguez-Tirado et al. Clin Exp Metastasis. 2024 Aug.

Abstract

Cancer cells can leave their primary sites and travel through the circulation to distant sites, where they lodge as disseminated cancer cells (DCCs), even during the early and asymptomatic stages of tumor progression. In experimental models and clinical samples, DCCs can be detected in a non-proliferative state, defined as cellular dormancy. This state can persist for extended periods until DCCs reawaken, usually in response to niche-derived reactivation signals. Therefore, their clinical detection in sites like lymph nodes and bone marrow is linked to poor survival. Current cancer therapy designs are based on the biology of the primary tumor and do not target the biology of the dormant DCC population and thus fail to eradicate the initial or subsequent waves of metastasis. In this brief review, we discuss the current methods for detecting DCCs and highlight new strategies that aim to target DCCs that constitute minimal residual disease to reduce or prevent metastasis formation. Furthermore, we present current evidence on the relevance of DCCs derived from early stages of tumor progression in metastatic disease and describe the animal models available for their study. We also discuss our current understanding of the dissemination mechanisms utilized by genetically less- and more-advanced cancer cells, which include the functional analysis of intermediate or hybrid states of epithelial-mesenchymal transition (EMT). Finally, we raise some intriguing questions regarding the clinical impact of studying the crosstalk between evolutionary waves of DCCs and the initiation of metastatic disease.

Keywords: Disseminated cancer cells; Dormancy; EMT; Early dissemination; Metastasis.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Dissemination of cancer cells. Cancer cells disseminate in waves throughout primary tumor evolution, from early stages (early dissemination, green cells) to late stages (late dissemination, red cells), through blood or lymphatic vessels. While in circulation, circulating cancer cells (CCCs) display a spectrum of epithelial (Ep)/mesenchymal (M) phenotypes that are associated with aggressiveness, chemotherapy resistance, and survival, which appears to be maintained by cancer cells after arrival at secondary organs (see section entitled “Partial EMT is linked to dissemination and metastatic colonization”). Generally, DCCs remain as single cells after activating a cellular dormancy program. As shown in breast cancer mouse models, during the early stages of tumor evolution, the lungs of animals harbor a considerable number of early DCCs (eDCCs, green cells in the lungs) characterized by mesenchymal and hybrid phenotypes [12]. Although eDCCs are capable of reactivation, they remain as dormant single cells for prolonged periods [–12], suggesting that the required signals to escape dormancy are not present or not sufficiently abundant at this stage of the disease. Gradually, the primary tumor evolves into a genetically advanced lesion (red primary tumor), from which late DCCs or lDCCs disseminate (red cells in the lungs). Through the circulation, lDCCs reach secondary organs that have already been colonized by eDCCs, where they can potentially interact. Subsequently, the reactivation signals reach a sufficient level to stimulate DCCs to exit from dormancy and development of metastatic tumors. Clinical [–23] and experimental evidence [–12] suggest that in certain types of tumors, metastases arise from eDCCs (parallel dissemination [9], metastasis with a majority of cells in green). (Color figure online)
Fig. 2
Fig. 2
Metastatic potential of dormant DCCs. DCCs that enter cellular dormancy at secondary sites activate different cellular sub-programs, including quiescence, survival, immune evasion, and reprograming at the metabolic and epigenetic levels (see BOX 1 for more detail). These sub-programs have been predominantly studied in late DCCs (due to the accessibility of late models) and are expected to be similarly necessary in eDCCs released from early stages of the disease. These sub-programs create multiple bottlenecks that aid in the selection of cancer cells with potential metastatic capacity. In some types of cancer, the reactivation of eDCCs will be favored. In this context, the presence of eDCCs (green) and, later on, the arrival of late DCCs (lDCCs) might play critical roles in reprogramming their specific tumor microenvironments (TME; eTME for early DCCs and lTME for late DCCs), including immune and stromal cells and non-cellular components such as the ECM. Eventually, the right combination of eDCCs, lDCCs and TME changes will mediate eDCCs reactivation and formation of clinically detectable metastatic disease. (Color figure online)
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