Met‐Related Receptor Tyrosine Kinase Ron in Tumor Growth and Metastasis

doi:10.1016/S0065-230X(08)00001-8

Advances in Cancer Research

Volume 100, 2008, Pages 1-33

https://doi.org/10.1016/S0065-230X(08)00001-8 Get rights and content

The Ron receptor is a member of the Met family of cell surface receptor tyrosine kinases and is primarily expressed on epithelial cells and macrophages. The biological response of Ron is mediated by binding of its ligand, hepatocyte growth factor‐like protein/macrophage stimulating‐protein (HGFL). HGFL is primarily synthesized and secreted from hepatocytes as an inactive precursor and is activated at the cell surface. Binding of HGFL to Ron activates Ron and leads to the induction of a variety of intracellular signaling cascades that leads to cellular growth, motility and invasion. Recent studies have documented Ron overexpression in a variety of human cancers including breast, colon, liver, pancreas, and bladder. Moreover, clinical studies have also shown that Ron overexpression is associated with both worse patient outcomes as well as metastasis. Forced overexpression of Ron in transgenic mice leads to tumorigenesis in both the lung and the mammary gland and is associated with metastatic dissemination. While Ron overexpression appears to be a hallmark of many human cancers, the mechanisms by which Ron induces tumorigenesis and metastasis are still unclear. Several strategies are currently being undertaken to inhibit Ron as a potential therapeutic target; current strategies include the use of Ron blocking proteins, small interfering RNA (siRNA), monoclonal antibodies, and small molecule inhibitors. In total, these data suggest that Ron is a critical factor in tumorigenesis and that inhibition of this protein, alone or in combination with current therapies, may prove beneficial in the treatment of cancer patients.

Section snippets

Ron Structure and Function

Cell surface growth factor receptors play a vital role in translating signals from the extracellular environment into an intracellular biologic response. One such receptor is the Ron receptor tyrosine kinase. Ron, also referred to as macrophage stimulating 1‐receptor (MST1R), is a receptor tyrosine kinase (RTK) of the hepatocyte growth factor (HGF)/Met receptor family. Ron was first identified as a novel protein tyrosine kinase by screening a library prepared from a mixture of human tumors. The

Ron Ligand Structure and Function

The ligand for Ron is hepatocyte growth factor‐like (HGFL) protein and is also known as MSP. HGFL was originally cloned from a human genomic library by screening for the characteristic kringle domains present in prothrombin and several other proteins in the blood coagulation system (Han et al., 1991). The protein sequence of the isolated gene was predicted to contain four kringle domains followed by a serine protease‐like domain. On the basis of domain structure, this protein was predicted to

Ron Chromosomal Location and Cancer

Interestingly, the genes for each of the two receptor–ligand pairs, that is Met and its ligand HGF and Ron and its ligand HGFL, are located close together on the same chromosomes. Met is located on 7q31.2, and HGF is located on 7q21.11; Ron and HGFL are both located on 3p21.31 (Human Protein Atlas Version: 3.0, 2007). Both the murine Ron gene and the HGFL murine counterpart are also located on chromosome 9qF2 (UCSC Genome Browser, 2007). The human chromosome 3p21 region has been frequently

Ron in Macrophages: Inflammation and Cancer

The determination of the expression of Ron in normal tissues and cells has helped to define its normal roles and the signaling pathways that are activated during transformation from normal cell to tumor cell. The initial characterization of the effect of HGFL was on mouse resident peritoneal macrophages. Stimulation by this ligand caused shape changes, altered response to chemoattractants, and stimulated phagocytosis in macrophages (Skeel et al., 1991). Through absorption studies, it was

Developmental Roles of Ron and Tumor Properties

The expression of Ron in normal development also may indicate some future role in tumorigenesis. The expression of Ron mRNA was determined in normal mouse tissues at different stages of development (Gaudino 1995, Quantin 1995). Expression of Ron was found in the liver as early as day 12.5, but expression in other tissues appeared at later stages of development, from day 13.5 to 16.5, and was present in the adult. There have been some contradictory reports concerning the expression of Ron in

Epithelial to Mesenchymal Transition

Another hallmark of the progression from normal epithelium to tumor development is termed the epithelial to mesenchymal transition (EMT). EMT is a process that is characterized by loss of epithelial differentiated morphology and reversion to mesenchymal phenotype. Cells undergoing EMT demonstrate a transition from cuboidal to spindle‐shaped morphology, a reorganized actin cytoskeleton, and the expression of mesenchymal cellular marker proteins. Ron activation by HGFL has been shown to induce a

Oncogenic Potential of the Ron Receptor

The oncogenic potential of Ron and its role in cellular transformation has been investigated with in vitro and in vivo experimental systems. Stable expression of wild‐type and constitutively active murine Ron mutants in NIH3T3 mouse fibroblast cells were investigated for transforming potential. The point mutations in the Ron gene were analogous to those found in the Met receptor tyrosine kinase in hereditary papillary renal carcinoma (HPRC), and had also been found in somatic mutations in renal

Loss of Function Mouse Models for Ron

To dissect the function of Ron in vivo, several different mouse models with defects in Ron were produced. A mouse model with total loss of Ron protein was produced by a global deletion of exon 1–14 of the mouse Ron gene. This strategy knocks‐out completely a large genomic region of Ron containing Ron 5′‐flanking sequences, the extracellular domain, the transmembrane domain, and a portion of the intracellular domain of the Ron gene. Strikingly, mice with this large deletion of Ron are lethal at

Loss of Ron Function and Tumorigenesis

To examine the significance of Ron in mammary tumorigenesis and metastasis, mice with a global deletion of the Ron tyrosine kinase intracellular signaling domain (Ron TK^−/−) were crossed with mice predisposed to mammary cancer through expression of polyoma virus middle T antigen (pMT) under the control of the MMTV promoter (MMTV‐pMT) (Peace et al., 2005). The MMTV‐pMT mouse is a well‐characterized model in which 100% of the mice develop mammary tumors by three months of age. The mammary tumors

Gain of Function Mouse Models for Ron Overexpression in Tumors

Two mouse models that overexpress Ron in different organ systems have been developed, and the effect of the overexpression of Ron on tumor development in those organs has been analyzed. One model overexpressed the human Ron gene in the lung by driving expression of Ron with the lung‐specific surfactant C promoter (SPC) (Chen et al., 2002). Multiple adenomas developed at an early age in these mice. However, these adenomas did not progress to a malignant state. The adenomas were analyzed for

Mechanisms of Ron‐Induced Tumorigenesis: Signaling Through the Ron Receptor

The pathways by which the Ron receptor conducts signals from the extracellular environment to the intracellular environment have been studied. However, the relationships of these different pathways to the specific biologic responses that are relevant to tumor formation are still poorly defined. Certain pathways appear to be commonly activated in many tumor types, whereas the responses of other signals may be cell‐type specific. Ron activation by ligand binding and signaling via downstream

Receptor Cross‐Talk and Ron Activity in Tumorigenesis

Another means of activating Ron signaling may be through the interaction of Ron with other receptors. This interaction between receptors of different types has been termed receptor cross‐talk. Interaction between dissimilar receptors may play a role in stimulating receptor activity independent of ligand activity. However, receptor cross‐talk may also retain responsiveness to ligand‐induced activation. Both direct and indirect evidence exists that Ron interacts with other receptor types. This

Angiogenesis

It has been well established that progressive tumor growth requires de novo blood vessel production, and that tumors produce angiogenic chemokines to fulfill the recruitment and growth of these blood vessels. The development of antiangiogenic tyrosine kinase inhibitors, such as those that target vascular endothelial growth factor receptors (VEGFR), are an area of intensive research, and have moved rapidly into patient treatment (Kesisis et al., 2007). The role of the Ron receptor tyrosine

Genomic Instability and Cell Cycle Disruption

In recent work, the effect of Ron overexpression on genomic instability in the mouse model of mammary tumorigenesis has been examined (Zinser et al., 2006). Primary cells derived from tumors were shown to display aberrant cell cycle kinetics and mitotic defects. These tumor‐derived cells showed a high level of inherent DNA damage, as evidenced by the phosphorylation of substrates of ATM, and an accumulation of the cell cycle checkpoint protein Cdc25A. The accumulation of Cdc25A prompted the

Ron Expression in Human Tumors and Tumor‐Derived Cell Lines

The growing awareness of the potential role for Ron in human cancer has lead to a recent examination of Ron expression in a range of human tumor types and tumor‐derived cell lines (O'Toole et al., 2006). Panels of human tumor tissue were analyzed for the extent and intensity of Ron staining, and covered tumors of the breast, lung, prostate, gastric tissue, pancreas, and colon. The number of tumor tissues in these arrays ranged from 38 to 55. The percent of tissues that were positive for Ron

Ron as a Target of Cancer Therapy

In the last 10 years, progress has been made in developing new drug therapies for cancer by targeting specific overexpressed growth factor receptors that characteristically appear in solid tumors. Most of these growth factor receptors, like the Ron receptor, are activated by and transmit signal cascades by tyrosine phosphorylation. The drug therapies include both monoclonal antibodies and small molecule inhibitors. Some of the recently approved or experimental drug targets include the EGFR (

Conclusions

In conclusion, accumulating evidence shows that Ron plays an important role in human cancers. Data summarized here elucidate critical signaling pathways that are downstream of Ron and are important mediators of Ron‐induced tumorigenesis. In the future, more precise anticancer drugs that block Ron activity may be important additions to cancer therapy.

Acknowledgements

The authors would like to acknowledge the contribution of Claudia Hinzman for the artwork provided in this manuscript.

References (117)

D. Angeloni et al.
The soluble sema domain of the RON receptor inhibits macrophage‐stimulating protein‐induced receptor activation
J. Biol. Chem.
(2004)
Q. Chen et al.
Co‐expression and regulation of Met and Ron proto‐oncogenes in human hepatocellular carcinoma tissues and cell lines
Hepatology
(1997)
L.A. Chodosh et al.
Protein kinase expression during murine mammary development
Dev. Biol.
(2000)
A. Cottage et al.
Three receptor genes for plasminogen related growth factors in the genome of the puffer fish Fugu rubripes
FEBS Lett.
(1999)
A. Danilkovitch‐Miagkova et al.
Integrin‐mediated RON growth factor receptor phosphorylation requires tyrosine kinase activity of both the receptor and c‐Src
J. Biol. Chem.
(2000)
A. Danilkovitch et al.
Interaction of macrophage‐stimulating protein with its receptor. Residues critical for beta chain binding and evidence for independent alpha chain binding
J. Biol. Chem.
(1999)
A. Danilkovitch et al.
Macrophage stimulating protein‐induced epithelial cell adhesion is mediated by a PI3‐K‐dependent, but FAK‐independent mechanism
Exp. Cell Res.
(1999)
S. Germano et al.
Geldanamycins trigger a novel Ron degradative pathway, hampering oncogenic signaling
J. Biol. Chem.
(2006)
C. Ghigna et al.
Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene
Mol. Cell
(2005)
K.A. Hess et al.
The receptor tyrosine kinase Ron is expressed in the mouse ovary and regulates inducible nitric oxide synthase levels and ovulation
Fertil. Steril.
(2003)

P.Y. Hsu et al.

Collaboration of RON and epidermal growth factor receptor in human bladder carcinogenesis

J. Urol.

(2006)

A. Iwama et al.

Molecular cloning of a novel receptor tyrosine kinase gene, STK, derived from enriched hematopoietic stem cells

Blood

(1994)

F. Lapraz et al.

RTK and TGF‐beta signaling pathways genes in the sea urchin genome

Dev. Biol.

(2006)

M.A. Leonis et al.

Deletion of the Ron receptor tyrosine kinase domain in mice provides protection from endotoxin‐induced acute liver failure

Hepatology

(2002)

B.Q. Li et al.

Macrophage‐stimulating protein activates Ras by both activation and translocation of SOS nucleotide exchange factor

Biochem. Biophys. Res. Commun.

(1995)

P. Maggiora et al.

The RON and MET oncogenes are co‐expressed in human ovarian carcinomas and cooperate in activating invasiveness

Exp. Cell Res.

(2003)

O. Massot et al.

Estradiol increases the production of alpha 1‐antichymotrypsin in MCF7 and T47D human breast cancer cell lines

Mol. Cell Endocrinol.

(1985)

A. Mera et al.

Induction of cell shape changes through activation of the interleukin‐3 common beta chain receptor by the RON receptor‐type tyrosine kinase

J. Biol. Chem.

(1999)

B.E. Peace et al.

Cross‐talk between the receptor tyrosine kinases Ron and epidermal growth factor receptor

Exp. Cell. Res.

(2003)

M.M. Santoro et al.

The MSP receptor regulates alpha6beta4 and alpha3beta1 integrins via 14‐3‐3 proteins in keratinocyte migration

Dev. Cell

(2003)

A. Shimamoto et al.

Hepatocyte growth factor‐like protein is identical to macrophage stimulating protein

FEBS Lett.

(1993)

A. Skeel et al.

Alpha 1‐antichymotrypsin is the human plasma inhibitor of macrophage ectoenzymes that cleave pro‐macrophage stimulating protein

J. Biol. Chem.

(2001)

E. van den Akker et al.

Tyrosine kinase receptor RON functions downstream of the erythropoietin receptor to induce expansion of erythroid progenitors

Blood

(2004)

R.C. Wahl et al.

Chicken macrophage stimulating protein is a ligand of the receptor protein‐tyrosine kinase Sea

J. Biol. Chem.

(1999)

S.E. Waltz et al.

Hepatocyte nuclear factor‐4 is responsible for the liver‐specific expression of the gene coding for hepatocyte growth factor‐like protein

J. Biol. Chem.

(1996)

S.E. Waltz et al.

Functional characterization of domains contained in hepatocyte growth factor‐like protein

J. Biol. Chem.

(1997)

M.H. Wang et al.

Macrophage‐stimulating protein inhibits induction of nitric oxide production by endotoxin‐ or cytokine‐stimulated mouse macrophages

J. Biol. Chem.

(1994)

M.H. Wang et al.

Macrophage‐stimulating protein induces proliferation and migration of murine keratinocytes

Exp. Cell. Res.

(1996)

C. Bardella et al.

Truncated RON tyrosine kinase drives tumor cell progression and abrogates cell‐cell adhesion through E‐cadherin transcriptional repression

Cancer Res.

(2004)

F. Barlesi et al.

Gefitinib (ZD1839, Iressa) in non‐small‐cell lung cancer: A review of clinical trials from a daily practice perspective

Fundam. Clin. Pharmacol.

(2005)

J.A. Bezerra et al.

Biological effects of targeted inactivation of hepatocyte growth factor‐like protein in mice

J. Clin. Invest.

(1998)

A.S. Bhatt et al.

Quantitation of membrane type serine protease 1 (MT‐SP1) in transformed and normal cells

Biol. Chem.

(2003)

A.S. Bhatt et al.

Coordinate expression and functional profiling identify an extracellular proteolytic signaling pathway

Proc. Natl. Acad. Sci. USA

(2007)

S. Brunelleschi et al.

Macrophage stimulating protein (MSP) evokes superoxide anion production by human macrophages of different origin

Br. J. Pharmacol.

(2001)

E.R. Camp et al.

Tyrosine kinase receptor RON in human pancreatic cancer: Expression, function, and validation as a target

Cancer

(2007)

F. Caponigro et al.

Monoclonal antibodies targeting epidermal growth factor receptor and vascular endothelial growth factor with a focus on head and neck tumors

Curr. Opin. Oncol.

(2005)

E.L. Chan et al.

Ron tyrosine kinase receptor regulates papilloma growth and malignant conversion in a murine model of skin carcinogenesis

Oncogene

(2005)

Y.Q. Chen et al.

Activation of the RON receptor tyrosine kinase inhibits inducible nitric oxide synthase (iNOS) expression by murine peritoneal exudate macrophages: Phosphatidylinositol‐3 kinase is required for RON‐mediated inhibition of iNOS expression

J. Immunol.

(1998)

Y.Q. Chen et al.

Multiple pulmonary adenomas in the lung of transgenic mice overexpressing the RON receptor tyrosine kinase. Recepteur d'origine nantais

Carcinogenesis

(2002)

H.L. Cheng et al.

Co‐expression of RON and MET is a prognostic indicator for patients with transitional‐cell carcinoma of the bladder

Br. J. Cancer

(2005)

M.H. Cohen et al.

United States Food and Drug Administration Drug Approval summary: Gefitinib (ZD1839; Iressa) tablets

Clin. Cancer Res.

(2004)

C. Collesi et al.

A splicing variant of the RON transcript induces constitutive tyrosine kinase activity and an invasive phenotype

Mol. Cell Biol.

(1996)

P. Conrotto et al.

Interplay between scatter factor receptors and B plexins controls invasive growth

Oncogene

(2004)

P.H. Correll et al.

Deregulated inflammatory response in mice lacking the STK/RON receptor tyrosine kinase

Genes Funct.

(1997)

A. Danilkovitch‐Miagkova

Oncogenic signaling pathways activated by RON receptor tyrosine kinase

Curr. Cancer Drug Targets

(2003)

A. Danilkovitch‐Miagkova et al.

Oncogenic mutants of RON and MET receptor tyrosine kinases cause activation of the beta‐catenin pathway

Mol. Cell. Biol.

(2001)

A. Danilkovitch et al.

Two independent signaling pathways mediate the antiapoptotic action of macrophage‐stimulating protein on epithelial cells

Mol. Cell. Biol.

(2000)

R. De Maria et al.

Feline STK gene expression in mammary carcinomas

Oncogene

(2002)

S.J. Degen et al.

Characterization of the mouse cDNA and gene coding for a hepatocyte growth factor‐like protein: Expression during development

Biochemistry

(1991)

A. Federico et al.

Chronic inflammation and oxidative stress in human carcinogenesis

Int. J. Cancer

(2007)

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Met‐Related Receptor Tyrosine Kinase Ron in Tumor Growth and Metastasis

Section snippets

Ron Structure and Function

Ron Ligand Structure and Function

Ron Chromosomal Location and Cancer

Ron in Macrophages: Inflammation and Cancer

Developmental Roles of Ron and Tumor Properties

Epithelial to Mesenchymal Transition

Oncogenic Potential of the Ron Receptor

Loss of Function Mouse Models for Ron

Loss of Ron Function and Tumorigenesis

Gain of Function Mouse Models for Ron Overexpression in Tumors

Mechanisms of Ron‐Induced Tumorigenesis: Signaling Through the Ron Receptor

Receptor Cross‐Talk and Ron Activity in Tumorigenesis

Angiogenesis

Genomic Instability and Cell Cycle Disruption

Ron Expression in Human Tumors and Tumor‐Derived Cell Lines

Ron as a Target of Cancer Therapy

Conclusions

Acknowledgements

J. Biol. Chem.

Hepatology

Dev. Biol.

FEBS Lett.

J. Biol. Chem.

J. Biol. Chem.

Exp. Cell Res.

J. Biol. Chem.

Mol. Cell

Fertil. Steril.

J. Urol.

Blood

Dev. Biol.

Hepatology

Biochem. Biophys. Res. Commun.

Exp. Cell Res.

Mol. Cell Endocrinol.

J. Biol. Chem.

Exp. Cell. Res.

Dev. Cell

FEBS Lett.

J. Biol. Chem.

Blood

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Exp. Cell. Res.

Truncated RON tyrosine kinase drives tumor cell progression and abrogates cell‐cell adhesion through E‐cadherin transcriptional repression

Cancer Res.

Gefitinib (ZD1839, Iressa) in non‐small‐cell lung cancer: A review of clinical trials from a daily practice perspective

Fundam. Clin. Pharmacol.

Biological effects of targeted inactivation of hepatocyte growth factor‐like protein in mice

J. Clin. Invest.

Quantitation of membrane type serine protease 1 (MT‐SP1) in transformed and normal cells

Biol. Chem.

Coordinate expression and functional profiling identify an extracellular proteolytic signaling pathway

Proc. Natl. Acad. Sci. USA

Macrophage stimulating protein (MSP) evokes superoxide anion production by human macrophages of different origin

Br. J. Pharmacol.

Tyrosine kinase receptor RON in human pancreatic cancer: Expression, function, and validation as a target

Cancer

Monoclonal antibodies targeting epidermal growth factor receptor and vascular endothelial growth factor with a focus on head and neck tumors

Curr. Opin. Oncol.

Ron tyrosine kinase receptor regulates papilloma growth and malignant conversion in a murine model of skin carcinogenesis

Oncogene

Activation of the RON receptor tyrosine kinase inhibits inducible nitric oxide synthase (iNOS) expression by murine peritoneal exudate macrophages: Phosphatidylinositol‐3 kinase is required for RON‐mediated inhibition of iNOS expression

J. Immunol.

Multiple pulmonary adenomas in the lung of transgenic mice overexpressing the RON receptor tyrosine kinase. Recepteur d'origine nantais

Carcinogenesis

Co‐expression of RON and MET is a prognostic indicator for patients with transitional‐cell carcinoma of the bladder

Br. J. Cancer

United States Food and Drug Administration Drug Approval summary: Gefitinib (ZD1839; Iressa) tablets

Clin. Cancer Res.

A splicing variant of the RON transcript induces constitutive tyrosine kinase activity and an invasive phenotype

Mol. Cell Biol.

Interplay between scatter factor receptors and B plexins controls invasive growth

Oncogene

Deregulated inflammatory response in mice lacking the STK/RON receptor tyrosine kinase

Genes Funct.