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Review
. 2020 Mar 12;5(1):28.
doi: 10.1038/s41392-020-0134-x.

Molecular principles of metastasis: a hallmark of cancer revisited

Jawad Fares  1   2 , Mohamad Y Fares  3   4 , Hussein H Khachfe  3   4 , Hamza A Salhab  3   4 , Youssef Fares  4
Affiliations
Review

Molecular principles of metastasis: a hallmark of cancer revisited

Jawad Fares et al. Signal Transduct Target Ther. .

Abstract

Metastasis is the hallmark of cancer that is responsible for the greatest number of cancer-related deaths. Yet, it remains poorly understood. The continuous evolution of cancer biology research and the emergence of new paradigms in the study of metastasis have revealed some of the molecular underpinnings of this dissemination process. The invading tumor cell, on its way to the target site, interacts with other proteins and cells. Recognition of these interactions improved the understanding of some of the biological principles of the metastatic cell that govern its mobility and plasticity. Communication with the tumor microenvironment allows invading cancer cells to overcome stromal challenges, settle, and colonize. These characteristics of cancer cells are driven by genetic and epigenetic modifications within the tumor cell itself and its microenvironment. Establishing the biological mechanisms of the metastatic process is crucial in finding open therapeutic windows for successful interventions. In this review, the authors explore the recent advancements in the field of metastasis and highlight the latest insights that contribute to shaping this hallmark of cancer.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Overview of the metastatic cascade: The five key steps of metastasis include invasion, intravasation, circulation, extravasation, and colonization
Fig. 2
Fig. 2
Determinants of metastasis: The activation of invasion and metastasis is triggered by epigenetic factors that are induced by environmental stimuli, such as aging and circadian disruptions; adhesive signals from extracellular matrix (ECM) components, such as collagen and fibrin; ECM mechanical pressures, including tension and compression; cell–cell interactions; soluble signals, such as growth factors and cytokines; and the intratumoral microbiota
Fig. 3
Fig. 3
Epithelial–mesenchymal transition (EMT): EMT occurs through single-cell dissemination or through collective migration. The process consists of several transition stages between the initial epithelial cell and the invasive mesenchymal cell
Fig. 4
Fig. 4
Cancer cells circulate as single units or in clusters. After arresting at secondary sites or becoming stuck in capillaries, circulating tumor cells (CTCs) extravasate and colonize their new niches. Some cells undergo dormancy as an adaptation mechanism to the new stressful environment
Fig. 5
Fig. 5
Metastastatic Organotropism: Clinical observations suggest that most cancers metastasize to specific target organs, a process known as “metastatic organotropism”
Fig. 6
Fig. 6
Dormancy and reactivation of cancer cells: The genetic and signaling pathways that govern cancer cell dormancy and subsequent reactivation involve intracellular signaling, extracellular signaling, and induction signals originating from the bone marrow niche
Fig. 7
Fig. 7
Metastasis suppressor genes that have been identified in the literature: Metastasis suppressors halt metastatic proliferation at the secondary site without changing the primary cancer. They work through oncogenic signaling pathways to suppress invasion and eventual colonization
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