Trends in Molecular Medicine
Cancer therapy: can the challenge be MET?
Introduction
A cancer-research axiom describes tumorigenesis as a multi-step process, in which genetic events that activate oncogenes or inactivate tumor-suppressor genes are sequentially acquired, frequently in a genetically unstable background. In this scenario, even if it is well established that oncogenes have a pivotal role in tumor formation, growth and maintenance, the possibility that their targeting could be effective for cancer treatment was considered, until recently, poor. In fact, it was believed that the inactivation of a single mutant gene product would be insufficient to obtain tumor regression. Moreover, the constitutive and prolonged inactivation of a normal proto-oncogene counterpart, which is usually essential for cellular function, was expected to be toxic for normal cells.
In spite of these theoretical concerns, recent evidence showed that in mouse models even a transient inactivation of a transforming oncogene (such as Ras, Myc or Bcr–Abl) was sufficient to revert the transformed phenotype, even in highly malignant tumors on the background of multiple genetic lesions [1]. Although the main drawback of these experiments is that they have been performed in mice, evidence that oncogene inactivation might result in tumor regression has recently been obtained in humans. Clinical examples of this new therapeutic approach include the activity of antibodies specific for the Her-2 receptor, used to treat patients with metastatic breast cancer, and the striking effects of the BCR–ABL kinase inhibitor imatinib mesylate (Glivec) in chronic myelogenous leukemia (CML) and gastrointestinal-associated stromal tumors (GISTs) [1].
The main questions arising from these data are: how can the inactivation of a single oncogene lead to tumor regression and is that true for all oncogenes? One of the working hypotheses is that the multistage process of carcinogenesis is not a simplistic sum of effects deriving from activated oncogenes or inactivated tumor-suppressor genes, with all the actors having the same importance on the stage [2]. Oncogenes that encode proteins with multiple roles in complex and interacting networks could have a major role not only in generating but also in maintaining the cancer phenotype.
This could be true for the Met oncogene, which encodes the tyrosine kinase receptor (RTK) for hepatocyte growth factor (HGF) and controls genetic programs leading to cell growth, invasion and protection from apoptosis. The role of MET in human tumors emerged from several experimental approaches [3] and was unequivocally proved by the discovery of MET-activating mutations in inherited forms of human renal papillary carcinomas [4]. Moreover, recent data showed that Met functionally interacts with receptors of different families, all individually believed to be involved in cancer progression, such as B plexins 5, 6, members of the EGF-receptor family [7], Fas [8], integrin α6β4 [9] and CD44 [10]. These newly discovered receptor–receptor interactions suggest a novel role for Met as a lead actor in several types of cancer.
Here, we highlight how these features make Met a good target for cancer therapy and the numerous efforts for the development of specific and efficient Met inhibitors.
Section snippets
The Met (HGF receptor) tyrosine kinase.
Met, which was discovered as an oncogene two decades ago 11, 12, encodes for an RTK that binds to, and is activated by, the growth and motility factor HGF (also named scatter factor 1). Met is a disulphide-linked heterodimer [11] composed of an extracellular 50-kDa α chain and a transmembrane 145-kDa β chain. The extracellular moiety contains a conserved ‘sema’ domain of 500 amino acids, which is known to be a protein–protein interaction domain, and a cysteine-rich motif of 80 amino acids,
Met and invasive growth
Met activation evokes pleiotropic biological responses, both in vitro and in vivo, often referred to as ‘invasive growth’. This is a complex genetic program that is specifically induced by the scatter factor receptors Met and Ron. It consists of a series of obligate rate-limiting steps that occur physiologically during embryogenesis and tissue repair. In the first step of this process, cells acquire the ability to dissociate from their neighbors by breaking intercellular adherent junctions
Met and cancer
In transformed tissues, deregulation of the invasive growth program is responsible for cancer progression and metastasis. Constitutive Met activation forces neoplastic cells to disaggregate from the tumor mass, erode basement membranes, infiltrate stromal matrices and eventually colonize new territories to form metastases [11].
Data produced by many laboratories provide compelling evidence that HGF–Met signaling has an important role in the development and malignant progression of tumors,
Mechanisms of Met activation in cancer
In physiological conditions, Met activation is a transient event, whereas in tumor cells Met is often constitutively activated. This deregulated activation can be due to different molecular alterations and is either HGF dependent or independent. This has to be carefully considered when selecting suitable targets for cancer therapy and HGF and Met are regarded as potential candidates. Obviously, when the ligand is dispensable for Met activation, HGF targeting is useless.
MET activation in human
Met interaction with other receptor families
Increasing data prove the existence of cross-talk between Met and different membrane receptors, suggesting a role in complex and interacting networks (Figure 1). The physiological meaning of these interactions and their consequences is not completely understood because adequate animal models to study them are unavailable. However, in vitro data suggest that this cross-talk is not essential for cell survival, but that it enables a better integration of signals present in the extracellular
Targeting Met signaling
The first attempts to interfere with cancer progression by targeting the HGF–Met system came in the late 1990s and aimed at preventing HGF binding to Met through the use of antagonist compounds (competitors; see Glossary). The most thoroughly characterized HGF competitor is NK4, a molecule composed of the N-terminal hairpin and the four-kringle domain of HGF. NK4 binds to Met without inducing receptor activation and thus behaves as a full antagonist. Moreover, this molecule is further endowed
Concluding remarks
Several reasons make the Met–HGF complex a good target for cancer therapy, because Met activation is involved in different steps of tumor formation, growth and spreading. Moreover, this receptor does not seem to be strictly required for the maintenance of tissue homeostasis in the adult. Even if Met could have a cyto- and tissue-protective role in the liver, kidney and other organs [65], it is conceivable to target it without the occurrence of important and life-threatening adverse effects. Met
Acknowledgements
We apologize for not being able to cite all the important works published in the field owing to space constraints. We thank L. Tamagnone, M.F. Di Renzo and our colleagues for helpful discussions and A. Adezati for editing the manuscript. This work was supported by AIRC grants to S.G.
Glossary: strategies available to inhibit RTKs
- Ligand antagonist:
- a molecule that competes with the ligand for receptor binding, without leading to its activation.
- Neutralizing antibody:
- an antibody that binds to the receptor and inhibits its activation, either by blocking the interaction with the ligand or by inducing receptor internalization and degradation. Herceptin (Trastuzumab), which is a humanized monoclonal antibody against the HER2 receptor and mainly acts by inducing receptor internalization, gave striking results for the treatment
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