HGF/c-MET pathway in cancer: from molecular characterization to clinical evidence

Fu, Jianjiang; Su, Xiaorui; Li, Zhihua; Deng, Ling; Liu, Xiawei; Feng, Xuancheng; Peng, Juan

doi:10.1038/s41388-021-01863-w

Cited by 120 publications

(104 citation statements)

References 188 publications

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“…6j, k ). Met kinase of WT cells was forcefully activated in vivo, which was perhaps due to the HGF ligands secreted from stromal cells, 49 thus as showed, WT cells and Y38E cells displayed no differences in pulmonary metastatic ability (Fig. 6j, k ).…”

Section: Resultsmentioning

confidence: 66%

Fis1 phosphorylation by Met promotes mitochondrial fission and hepatocellular carcinoma metastasis

Peng

Qian

et al. 2021

Sig Transduct Target Ther

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Met tyrosine kinase, a receptor for a hepatocyte growth factor (HGF), plays a critical role in tumor growth, metastasis, and drug resistance. Mitochondria are highly dynamic and undergo fission and fusion to maintain a functional mitochondrial network. Dysregulated mitochondrial dynamics are responsible for the progression and metastasis of many cancers. Here, using structured illumination microscopy (SIM) and high spatial and temporal resolution live cell imaging, we identified mitochondrial trafficking of receptor tyrosine kinase Met. The contacts between activated Met kinase and mitochondria formed dramatically, and an intact HGF/Met axis was necessary for dysregulated mitochondrial fission and cancer cell movements. Mechanically, we found that Met directly phosphorylated outer mitochondrial membrane protein Fis1 at Tyr38 (Fis1 pY38). Fis1 pY38 promoted mitochondrial fission by recruiting the mitochondrial fission GTPase dynamin-related protein-1 (Drp1) to mitochondria. Fragmented mitochondria fueled actin filament remodeling and lamellipodia or invadopodia formation to facilitate cell metastasis in hepatocellular carcinoma (HCC) cells both in vitro and in vivo. These findings reveal a novel and noncanonical pathway of Met receptor tyrosine kinase in the regulation of mitochondrial activities, which may provide a therapeutic target for metastatic HCC.

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Section: Resultsmentioning

confidence: 66%

Fis1 phosphorylation by Met promotes mitochondrial fission and hepatocellular carcinoma metastasis

Peng

Qian

et al. 2021

Sig Transduct Target Ther

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“…It interacts with MET to activate a signaling pathway that promotes cancer growth, survival, and invasion [87,88]. The constitutive activation of this pathway can occur through amplification or mutation in the MET gene in several tumors to evade regulatory mechanisms of cancer formation [89,90]. HGF can promote the transition from a preinvasive to an invasive phenotype of ductal carcinoma in situ (DCIS) cells.…”

Section: Communication Through Tgf-β/hgfmentioning

confidence: 99%

The Role of Cancer-Associated Fibroblasts in Cancer Invasion and Metastasis

Asif

Longobardi

Hahne

et al. 2021

Cancers

142

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Cancer-associated fibroblasts (CAFs) play a key role in cancer progression by contributing to extracellular matrix (ECM) deposition and remodeling, extensive crosstalk with cancer cells, epithelial-to-mesenchymal transition (EMT), invasion, metastasis, and therapy resistance. As metastasis is a main reason for cancer-related deaths, it is crucial to understand the role of CAFs in this process. Colorectal cancer (CRC) is a heterogeneous disease and lethality is especially common in a subtype of CRC with high stromal infiltration. A key component of stroma is cancer-associated fibroblasts (CAFs). To provide new perspectives for research on CAFs and CAF-targeted therapeutics, especially in CRC, we discuss the mechanisms, crosstalk, and functions involved in CAF-mediated cancer invasion, metastasis, and protection. This summary can serve as a framework for future studies elucidating these roles of CAFs.

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“…Cabozantinib was approved for marketing by FDA in treating medullary thyroid cancer ( 77 ). Capmatinib was confirmed to be effective for treating multiple cancers, such as patients with c-MET-dysregulated advanced solid tumors, glioblastoma, HCC, NSCLC, and colorectal cancer ( 43 ). On the other hand, monotherapy of targeting c-MET may be of no clinical importance, but the combinations of c-MET-targeted treatment have tremendous therapeutic potential for cancers.…”

Section: Discussionmentioning

confidence: 99%

“…According to the research results from phase 3 studies, tivantinib was shown to fail in treating advanced HCC. As reported, monotherapy of targeting c-MET has failed to exert significant clinical efficacy in the majority of malignancies (43). However, some c-MET inhibitors have been proved to serve as an effective therapeutic option for certain cancers.…”

Section: Perspectives Of C-met Inhibitormentioning

confidence: 99%

“…This study showed that patients with MET-high tumors had significantly shorter survival compared with the MET-low subgroup. As for another key factor of HGF/c-Met signaling, some investigators found that the high levels of circulating HGF might be an independent poor prognostic factor in patients with advanced cancers ( 43 ). α-Fetoprotein (AFP) is the serum biomarker most widely used in HCC, but it did not significantly contribute to predicting prognosis and monitor response to tivantinib therapy ( 41 ).…”

Section: Introductionmentioning

confidence: 99%

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Selective Inhibitor of the c-Met Receptor Tyrosine Kinase in Advanced Hepatocellular Carcinoma: No Beneficial Effect With the Use of Tivantinib?

Zhao

Wu²,

Jiang

et al. 2021

Front. Immunol.

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Advanced hepatocellular carcinoma (HCC) remains a formidable health challenge worldwide, with a 5-year survival rate of 2.4% in patients with distant metastases. The hepatocyte growth factor/cellular-mesenchymal-epithelial transition (HGF/c-Met) signaling pathway represents an encouraging therapeutic target for progressive HCC. Tivantinib, a non-adenosine triphosphate-competitive c-Met inhibitor, showed an attractive therapeutic effect on advanced HCC patients with high MET-expression in phase 2 study but failed to meet its primary endpoint of prolonging the overall survival (OS) in two phase 3 HCC clinical trials. Seven clinical trials have been registered in the “ClinicalTrials.gov” for investigating the safety and efficacy of tivantinib in treating advanced or unresectable HCC. Eight relevant studies have been published with results. The sample size ranged from 20 to 340 patients. The methods of tivantinib administration and dosage were orally 120/240/360 mg twice daily. MET overexpression was recorded at 34.6% to 100%. Two large sample phase 3 studies (the METIV-HCC study of Australia and European population and the JET-HCC study of the Japanese population) revealed that tivantinib failed to show survival benefits in advanced HCC. Common adverse events with tivantinib treatment include neutropenia, ascites, rash, and anemia, etc. Several factors may contribute to the inconsistency between the phase 2 and phase 3 studies of tivantinib, including the sample size, drug dosing, study design, and the rate of MET-High. In the future, high selective MET inhibitors combined with a biomarker-driven patient selection may provide a potentially viable therapeutic strategy for patients with advanced HCC.

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HGF/c-MET pathway in cancer: from molecular characterization to clinical evidence

Cited by 120 publications

References 188 publications

Fis1 phosphorylation by Met promotes mitochondrial fission and hepatocellular carcinoma metastasis

Fis1 phosphorylation by Met promotes mitochondrial fission and hepatocellular carcinoma metastasis

The Role of Cancer-Associated Fibroblasts in Cancer Invasion and Metastasis

Selective Inhibitor of the c-Met Receptor Tyrosine Kinase in Advanced Hepatocellular Carcinoma: No Beneficial Effect With the Use of Tivantinib?

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