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Reprogramming metastatic tumour cells with embryonic microenvironments

Key Points

  • Aggressive tumour cells, such as melanoma, share many characteristics with embryonic progenitors, which contribute to the conundrum of tumour cell plasticity. The challenge is to better understand the aetiology of the plastic, multipotent phenotype and to develop strategies that might include their differentiation and subsequent targeting.

  • A complex and still enigmatic relationship exists between stem cells and their microenvironment that has a crucial role in the determination of cell fate. Current studies identifying the molecular pathways that regulate stem cell plasticity are also examining the epigenetic role of the microenvironment.

  • The microenvironment of human embryonic stem cells can epigenetically reprogramme multipotent metastatic melanoma cells to assume a melanocyte-like phenotype. In addition, the 'reverted' melanoma cells show significantly reduced invasive and tumorigenic ability.

  • The embryonic neural crest microenvironment of the chick provides an attractive model system to explore melanoma tumour cell reprogramming. Human metastatic melanoma cells transplanted into the chick embryonic microenvironment did not form tumours, and a subset of these tumour cells were reprogrammed to a neural crest cell-like phenotype. The melanoma cells also followed neural crest migratory pathways and populated host peripheral structures in a programmed manner.

  • Recent findings using the embryonic zebrafish have illuminated a convergence in the molecular messengers that metastatic tumour and normal stem cells implement during their respective bi-directional communication with the microenvironment, leading to the identification of Nodal.

  • The inhibition of Nodal signalling reduces melanoma cell invasiveness, colony formation and tumorigenicity. Nodal inhibition also promotes the reversion of melanoma cells towards a melanocytic phenotype concomitant with loss of the plastic phenotype.

  • Nodal may represent a new diagnostic marker for disease progression and a novel target for the treatment of aggressive cancers. Additional strategic targets contributing to the Nodal signalling pathway, including SMAD2 and SMAD3, cripto and the activin-like-kinase (ALK) receptor complex, are worth further consideration for inhibiting the plastic tumour cell phenotype.

  • The discovery of key signalling pathways that underlie the commonality of plasticity of embryonic stem cells and multipotent tumour cells will probably result in new therapeutic strategies to suppress the metastatic phenotype.

Abstract

Aggressive tumour cells share many characteristics with embryonic progenitors, contributing to the conundrum of tumour cell plasticity. Recent studies using embryonic models of human stem cells, the zebrafish and the chick have shown the reversion of the metastatic phenotype of aggressive melanoma cells, and revealed the convergence of embryonic and tumorigenic signalling pathways, which may help to identify new targets for therapeutic intervention. This Review will summarize the embryonic models used to reverse the metastatic melanoma phenotype, and highlight the prominent signalling pathways that have emerged as noteworthy targets for future consideration

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Figure 1: Human embryonic stem cell microenvironment model.
Figure 2: Transplantation of metastatic melanoma cells into the zebrafish embryo.
Figure 3: Embryonic chick model to investigate whether metastatic melanoma cells can be reverted back to their cellular derivatives by the neural crest microenvironment.
Figure 4: The Nodal signalling pathway.

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Acknowledgements

The authors would like to gratefully acknowledge the help of J. Topczewska, J. Topczewski, N. Margaryan, A. Hess and B. Nickoloff. This research was supported by a grant from the National Cancer Institute.

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Glossary

Tumour cell plasticity

The ability of aggressive tumour cells to express multiple molecular phenotypes similar to pluripotent, embryonic-like stem cells.

Neovascularization

A formation of functional microvascular networks with red blood cell perfusion that differs from angiogenesis, which is characterized by the protrusion and outgrowth of capillary buds and sprouts from pre-existing blood vessels.

Synoviosarcoma

A malignant neoplasm arising in the synovial membrane of the joints and in the synovial cells of tendons and bursae; also called malignant synovioma and synovial sarcoma.

Phaeochromocytoma

A tumour that forms in the centre of the adrenal gland that causes it to make too much adrenaline.

Ewings sarcoma

A highly malignant, metastatic, small round-cell tumour of the bone that usually occurs in the diaphyses (shafts) of long bones, ribs and flat bones of children or adolescents.

Spheroid

A spherical aggregation of tumour cells, grown in tissue culture, that reflects many of the properties of solid tumours. Spheroids have been used for studying the penetration of anticancer drugs into tumour tissue.

Amelanotic

A complete lack of the pigment melanin in pigment-derived cells and tissues.

Feeder-free matrices

The growth of embryonic stem cells in vitro in the absence of an underlying layer of mouse-derived fibroblasts.

Animal pole

The point in the blastocyst that is farthest away from the yoke margin. In the zebrafish, mesoendoderm is not usually found here.

Dorsal organizer

A group of cells on the dorsal lip of the blastopore that induces the differentiation of cells in the embryo, controlling the growth and development of adjacent parts that eventually form the body axis.

Neural tube

In the developing vertebrate nervous system, the neural tube is the precursor of the central nervous system, which comprises the brain and spinal cord.

Embryonic axis

An imaginary line from the head end to the tail end of an embryo or, before that, the line of elongation of the primitive streak and groove.

Filopodial extensions

Filopodia are slender cytoplasmic projections that extend from the leading edge of migrating cells and contain actin filaments crosslinked into bundles by actin-binding proteins. They form focal adhesions that function to link the cell surface to the substratum and facilitate cell motility.

Morpholinos

Morpholino oligos are short chains of about 25 Morpholino subunits comprised of a nucleic acid base, a morpholine ring and a non–ionic phosphorodiamidate intersubunit linkage. Their high mRNA-binding affinity and specificity permits them to sterically block translation initiation in the cytosol, modify pre-mRNA splicing in the nucleus or directly block miRNA activity to effectively knock down the expression of targeted genes.

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Hendrix, M., Seftor, E., Seftor, R. et al. Reprogramming metastatic tumour cells with embryonic microenvironments. Nat Rev Cancer 7, 246–255 (2007). https://doi.org/10.1038/nrc2108

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