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  • Review Article
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MSP–RON signalling in cancer: pathogenesis and therapeutic potential

Nature Reviews Cancer volume 13, pages 466–481 (2013)Cite this article

Subjects

Key Points

  • Macrophage-stimulating protein (MSP; also known as MST1 and hepatocye growth factor-like (HGFL)), is a serum-derived growth factor that activates the RON receptor tyrosine kinase. RON signalling is essential for the survival of embryos during the peri-implantation period. Cancer cells use MSP–RON signalling for survival, migration, angiogenesis and chemoresistance, which has pathogenic implications.

  • Crystal structure analyses have shown that a central cleft harbouring three amino acid residues in the putative catalytic site of the MSP β-chain interacts with an interface created by two RON semaphorin (SEMA) domains. This supports a model in which one MSP molecule binds two RON molecules to cause receptor dimerization and activation.

  • Aberrant RON activation, which is induced by overexpression of protein and the generation of oncogenic isoforms and is indicated by the persistent activation of multi-intracellular signalling cascades, occurs in various types of cancers. RON signalling is also necessary for cancer cell growth and survival. These features render RON as a drug target for cancer therapy.

  • MSP–RON signalling activates two classical signalling pathways, RAS–ERK and PI3K–AKT, both of which interact with various other pathways to create a complex signalling network. RON also crosstalks with other receptor tyrosine kinases and viral oncoproteins. Such intricate interactions highlight the importance of RON signalling in cancer pathogenesis.

  • Overexpression of RON in primary tumours such as colon and breast cancer is predictive of patient survival and correlates with clinical and pathological parameters.

  • Studies from mouse xenograft models have revealed that inhibition of RON by tyrosine kinase inhibitors and monoclonal antibodies blocks tumour growth. However, combinations with chemoagents achieve maximum therapeutic benefit. The tyrosine kinase inhibitor BMS-777607 and the RON-specific antibody narnatumab are currently in Phase I clinical trials.

Abstract

Since the discovery of MSP (macrophage-stimulating protein; also known as MST1 and hepatocyte growth factor-like (HGFL)) as the ligand for the receptor tyrosine kinase RON (also known as MST1R) in the early 1990s, the roles of this signalling axis in cancer pathogenesis has been extensively studied in various model systems. Both in vitro and in vivo evidence has revealed that MSP–RON signalling is important for the invasive growth of different types of cancers. Currently, small-molecule inhibitors and antibodies blocking RON signalling are under investigation. Substantial responses have been achieved in human tumour xenograft models, laying the foundation for clinical validation. In this Review, we discuss recent advances that demonstrate the importance of MSP–RON signalling in cancer and its potential as a therapeutic target.

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Figure 1
Figure 2: Schematic representation of MSP, RON and RON isoforms.
Figure 3: Structures of the human MSP β-chain and the RON SEMA–PSI domain and their interactions.
Figure 4: Signalling pathways activated by MSP and RON.
Figure 5: Crosstalk between RON and signalling proteins.

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Acknowledgements

This work was supported in part by US National Institutes of Health grant R01 CA91980 (M.H.W.) and a grant from the Amarillo Area Foundation (M.H.W.). R.W.Z. was supported by NIH grants R01 CA112029 and CA121211. Support was also provided by Research Subproject #2011ZZ01 to M.H.W. from State Key Laboratory for Diagnosis & Treatment of Infectious Diseases in First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, P. R. China. The assistance of S. Denney (Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, Texas, USA) in editing the manuscript is greatly appreciated.

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  1. Hang-Ping Yao and Yong-Qing Zhou: These authors contributed equally to this work.

Authors and Affiliations

  1. Viral Oncogenesis Section in State Key Laboratory for Diagnosis & Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine,

    Hang-Ping Yao & Ming-Hai Wang

  2. Department of Neurosurgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, P. R. China

    Yong-Qing Zhou

  3. Cancer Biology Research Center, School of Pharmacy, Texas Tech University Health Sciences Center,

    Ruiwen Zhang & Ming-Hai Wang

  4. Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center,

    Ruiwen Zhang

  5. Department of Biomedical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1406 Coulter Street, Suite 1117, Amarillo, 79106, Texas, USA

    Ming-Hai Wang

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Glossary

Protein truncation

A biochemical process by which a portion of amino acid residues is removed from either the amino or the carboxyl terminus, resulting in a protein isoform.

Multifunctional docking site

A tandemly arranged sequence in the carboxy-terminal tail of MET and RON that recruits multiple SH2-containing molecules such as PI3K.

Epithelial-to-mesenchymal transition

(EMT). A phenotypic change of epithelial cells characterized by spindle cell morphology, loss of epithelial properties and gain of mesenchymal markers with increased cell motility.

Kringle domains

Protein structures formed roughly by 80 amino acids that fold into a triple disulphide-linked loop resembling the shape of a Scandinavian pastry known as kringle.

Friend leukaemia virus

(FLV). A strain of mouse retrovirus also known as Friend spleen focus-forming virus that infects mouse erythroid cells and subsequently causes erythroleukaemia.

Jaagsiekte sheep retrovirus

(JSRV). A strain of retrovirus that is the causative agent of a contagious lung cancer called ovine pulmonary adenocarcinoma in sheep.

Epstein–Barr virus

(EBV). A herpes virus that causes infectious mononucleosis, transforms B lymphocytes and is associated with lymphoid malignancies such as Burkett's lymphoma.

Signalling-compensatory mechanism

A biochemical event in which an alternative signalling pathway is activated, allowing continued cell growth and survival when other pathways are inhibited or disrupted by molecularly targeted therapeutics.

Hemidesmosomes

Small rivet-like structures on the inner basal surface of epithelial cells, which attach one cell to the extracellular matrix for cell adhesion.

Polycythemia

An abnormal status in which the concentration of red cells increases as a percentage of total blood volume owing to reduced plasma volume or intrinsic growth of the myeloid stem cells.

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Yao, HP., Zhou, YQ., Zhang, R. et al. MSP–RON signalling in cancer: pathogenesis and therapeutic potential. Nat Rev Cancer 13, 466–481 (2013). https://doi.org/10.1038/nrc3545

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