Cancer does not grow and spread on its own. It depends on signals that tell tumor cells to survive, divide, move, and resist treatment. One of the most important of these signaling systems is the HGF/MET axis.

 

MET is a receptor found on the surface of certain cells. It works like an antenna, receiving growth signals from outside the cell. Its best-known partner is hepatocyte growth factor (HGF). When HGF binds to MET, it switches on a cascade of signals inside the cell that can promote growth, survival, movement, and tissue repair. Under normal conditions, this pathway is essential for embryonic development, organ formation, and regeneration after injury. In cancer, however, the same pathway can be hijacked and turned into a powerful engine of disease progression.

 

Abnormal activation of MET has been identified as a key driver in several solid tumors. This can happen in different ways, including MET exon 14 skipping mutations, MET gene amplification, or HGF-dependent activation from the tumor microenvironment. Once activated, the pathway can continuously stimulate tumor cell proliferation, invasion, metastasis, and drug resistance. In non-small cell lung cancer, the selective MET inhibitor capmatinib has shown clear clinical activity in patients with MET exon 14-altered tumors [1]. In colorectal cancer, HGF can reactivate MET signaling and help tumor cells escape from EGFR inhibitor treatment, showing that the HGF/MET axis is not only a direct cancer driver but also an important bypass pathway in targeted therapy resistance [2]. These findings have made HGF/MET one of the most important targets in solid tumor drug development.

Image source: Structure and molecular signalling components of HGF/c-Met.
 

In the body, HGF and MET normally work through a tightly controlled paracrine system. HGF is mainly produced by stromal or mesenchymal cells, while MET is expressed on epithelial cells and, in many cases, on malignant tumor cells. This means that MET activity depends not only on the tumor cell itself, but also on whether the surrounding tissue can supply enough HGF. The HGF/MET pathway is also involved in normal tissue repair. Genetic studies have shown that liver-specific deletion of Met in mice leads to severely impaired liver regeneration and repair [3]. This tells us that the pathway is not simply “cancer-specific.” It is part of a broader biological system that controls both normal regeneration and abnormal tumor behavior.

That is why evaluating HGF/MET-targeted drugs is not as simple as asking whether a compound blocks MET kinase activity. In a living tumor, pathway output depends on at least two major variables: how much HGF is available in the microenvironment, and how much MET is present and activated on the tumor cell surface. A useful in vivo model therefore needs to capture the full chain of events, from ligand supply to receptor activation, downstream signaling, and, finally, changes in tumor growth and behavior.
 

A major challenge is that the interaction between HGF and MET is species-specific. Mouse HGF does not efficiently bind to or activate human MET [4]. This creates a natural barrier in conventional mouse models. Even if human MET-positive tumor cells are transplanted into mice, the animals may still fail to reproduce the human HGF/MET signaling environment. As a result, traditional xenograft systems can underestimate how strongly some tumors depend on this pathway.
 

To overcome this problem, researchers have developed human HGF transgenic or knock-in mouse models. These models provide human HGF in vivo and can better support the growth of tumors that rely on human MET signaling. Earlier studies showed that human MET-expressing tumors grew more efficiently in mice engineered to express human HGF [5]. More recent work has gone even further, demonstrating that in tumors carrying MET exon 14 skipping mutations, the presence of human HGF is not just supportive but may be essential for tumor formation in vivo [6]. This finding highlights how strongly some cancers depend on a human-compatible HGF/MET signaling context.
 

For this reason, the development of hHGF/hMET humanized mice is important. These models are not simply “mice carrying human genes.” Their real value is that they can rebuild a more human-like HGF/MET signaling environment inside a living animal. That makes them potentially useful for candidate screening, mechanism studies, and dose regimen optimization in HGF/MET-targeted drug development. In short, they offer a more biologically relevant platform for studying how this pathway drives cancer and how it can be blocked more effectively.

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