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Axis of evil: molecular mechanisms of cancer metastasis

Abstract

Although the genetic basis of tumorigenesis may vary greatly between different cancer types, the cellular and molecular steps required for metastasis are similar for all cancer cells. Not surprisingly, the molecular mechanisms that propel invasive growth and metastasis are also found in embryonic development, and to a less perpetual extent, in adult tissue repair processes. It is increasingly apparent that the stromal microenvironment, in which neoplastic cells develop, profoundly influences many steps of cancer progression, including the ability of tumor cells to metastasize. In carcinomas, the influences of the microenvironment are mediated, in large part, by bidirectional interactions (adhesion, survival, proteolysis, migration, immune escape mechanisms lymph-/angiogenesis, and homing on target organs) between epithelial tumor cells and neighboring stromal cells, such as fibroblasts as well as endothelial and immune cells. In this review, we summarize recent advances in understanding the molecular mechanisms that govern this frequently lethal metastatic progression along an axis from primary tumor to regional lymph nodes to distant organ sites. Affected proteins include growth factor signaling molecules, chemokines, cell–cell adhesion molecules (cadherins, integrins) as well as extracellular proteases (matrix metalloproteinases). We then discuss promising new therapeutic approaches targeting the microenvironment. We note, however, that there is still too little knowledge of how the many events are coordinated and integrated by the cancer cell, with conspiratorial help by the stromal component of the host. Before drug development can proceed with a legitimate chance of success, significant gaps in basic knowledge need to be filled.

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Acknowledgements

We thank all the members of the Herlyn lab for helpful discussions. Due to editorial constrictions, citations are rather illustrative than comprehensive, with a strong emphasis on review articles. We apologize to all investigators whose ground-breaking work could not be cited. Our research on metastasis is supported by the NIH Grants CA-47159 and CA-25874.

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Bogenrieder, T., Herlyn, M. Axis of evil: molecular mechanisms of cancer metastasis. Oncogene 22, 6524–6536 (2003). https://doi.org/10.1038/sj.onc.1206757

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