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Hypothetical model of HGF/SF activation in cancer. There are two major pathways in the activation of HGF/SF in tumor tissue. One is HGFA-mediated pathway that is closely linked to activation of the coagulation cascade. Another pathway is TTSPs-mediated one, in which matriptase likely has a signiificant role. Cellular Kunitz-type serine protease inhibitors, HAI-1 and HAI-2, have crucial roles in the regulation of these HGF/SF-activating proteases in tumor tissues.
Source publication
Hepatocyte growth factor/scatter factor (HGF/SF) plays critical roles in cancer progression through its specific receptor, MET. HGF/SF is usually synthesized and secreted as an inactive proform (pro-HGF/SF) by stromal cells, such as fibroblasts. Several serine proteases are reported to convert pro-HGF/SF to mature HGF/SF and among these, HGF activa...
Context in source publication
Context 1
... this review we summarized evidence regarding the roles of HGF/SF-activating proteases and the critical HGF/SF regulators, HAI-1 and HAI-2, in carcinogenesis and cancer cell biology. Our hypothetical model for the molecular interactions and cascades that occur during HGF/SF activation in cancer tissues is shown in Figure 1. One is HGFA-mediated pathway that is closely linked to activation of the coagulation cascade. ...
Citations
... Hepatocyte growth factor (HGF) is a potent growth factor present in various tissues, including the lungs, liver, pancreas, gastrointestinal tract, brain, and kidney (Frisch et al., 2016). It is initially secreted as a single-chain precursor, pro-HGF, and its activation involves extracellular processing into a mature twochain form (Kawaguchi and Kataoka, 2014). HGF acts as a ligand for the MET tyrosine kinase receptor (c-MET), leading to the activation of the MAPK and PI3-kinase/AKT signaling pathways (Bottaro et al., 1991;Naldini et al., 1991). ...
Interactions and correlations between metabolites, pancreatic hormones, and growth factors. Note the gender differences, frequently opposite among metabolites, insulin and glucagon with growth factors, as well as the effect of metabolic disturbances induced by Diabetes type 2. The size of the arrows indicates the strength of the correlation and the direction whether the correlation was straight or inverse.
... Both tumor and stromal cells can secrete proteases that modify the ECM, including matrix metalloproteinases (MMPs), serine proteases, cathepsins, and a disintegrin and metalloproteinases (ADAMs), as well as members of the ADAMTS (a disintegrin and metalloproteinases with thrombospondin motifs) family [44,45]. These proteases, such as HGFA, matrix enzymes, and MMP-2, not only convert scHGF into its mature form, tcHGF, but also facilitate the release of HGF bound to ECM, leading to autostimulation [46]. Certain growth factors released from the ECM, such as transforming growth factor alpha (TGF-α), can interact with c-MET by activating their epidermal growth factor receptors, triggering signal transduction in the absence of ligands [47]. ...
The mutation of MET plays a crucial role in the initiation of cancer, while the Hedgehog (Hh) pathway also plays a significant role in cell differentiation and the maintenance of tumor stem cells. Conventional chemotherapy drugs are primarily designed to target the majority of cell populations within tumors rather than tumor stem cells. Consequently, after a brief period of remission, tumors often relapse. Moreover, the exclusive targeting of tumor stemness cell disregards the potential for other tumor cells to regain stemness and acquire drug resistance. As a result, current drugs that solely target the HGF/c-MET axis and the Hh pathway demonstrate only moderate efficacy in specific types of cancer. Mounting evidence indicates that these two pathways not only play important roles in cancer but also exert significant influence on the development of resistance to single-target therapies through the secretion of their own ligands. In this comprehensive review, we analyze and compare the potential impact of the Hh pathway on the tumor microenvironment (TME) in HGF/c-MET-driven tumor models, as well as the interplay between different cell types. Additionally, we further substantiate the potential and necessity of dual-pathway combination therapy as a critical target in MET addicted cancer treatment.
Video Abstract
Supplementary Information
The online version contains supplementary material available at 10.1186/s12964-023-01333-8.
... HGF, also named scatter factor (SF), may improve cell viability and invasiveness, stimulate angiogenesis and function as a tumor progression factor (12). Met tyrosine kinase receptor is the HGF receptor; the HGF/Met pathway plays a prominent role in cell migration, survival, growth and cardiovascular remodeling following tissue injury (13). Notably, SPINT2 binds to and inactivates HGFA, impairing the conversion of inactive pro-HGF/SF into bioactive HGF/SF (14). SPINT2 may therefore play an important role in cancer cell biology by regulating the function of HGF/SF-activating proteases. ...
Thoracic aortic dissection (TAD) is a severe and extremely dangerous cardiovascular disease. Proliferation, migration and phenotypic switching of vascular smooth muscle cells (SMCs) are major pathogenetic mechanisms involved in the development of TAD. The present study was designed to investigate the expression and potential function of serine peptidase inhibitor Kunitz type 2 (SPINT2) in TAD. The gene expression profile data for ascending aorta from patients with TAD were downloaded from the GEO database with the accession number GSE52093. Bioinformatics analysis using GEO2R indicated that the differentially expressed SPINT2 was prominently decreased in TAD. The expression levels of SPINT2 mRNA and protein in aortic dissection specimens and normal aorta tissues were measured using reverse transcription-quantitative PCR and western blotting. SPINT2 expression was downregulated in clinical samples from aortic dissection specimens of patients with TAD compared with the corresponding expression noted in tissues derived from patients without TAD. In vitro, platelet-derived growth factor BB (PDGF-BB) was applied to induce the isolated primary mouse aortic SMC phenotypic modulation (a significant upregulation in the expression levels of synthetic markers), and the SMCs were infected with the adenoviral vector, Ad-SPINT2, to construct SPINT2-overexpressed cell lines. SMC viability was detected by an MTT assay and SMC proliferation was detected via the presence of Ki-67-positive cells (immunofluorescence staining). To explore the effects of SPINT2 on SMC migration, a wound healing assay was conducted. ELISA and western blotting assays were used to measure the content and expression levels of MMP-2 and MMP-9. The expression levels of vimentin, collagen I, α-SMA and SM22α were measured using western blotting. The PDGF-BB-induced proliferation and migration of SMCs were recovered by SPINT2 overexpression. The increase in the expression levels of SPINT2 reduced the expression levels of active matrix metalloproteinases (MMPs), MMP-2 and MMP-9. Overexpression of SPINT2 suppressed SMC switching from a contractile to a synthetic type, as evidenced by decreased vimentin and collagen I expression levels along with increased α-smooth muscle actin and smooth muscle protein 22-α expression levels. Furthermore, activation of ERK was inhibited in SPINT2-overexpressing SMCs. A specific ERK agonist, 12-O-tetradecanoylphorbol-13-acetate, reversed the SPINT2-mediated inhibition of SMC migration and the phenotypic switching. Collectively, the data indicated that SPINT2 was implicated in the proliferation, migration and phenotypic switching of aortic SMCs, suggesting that it may be involved in TAD progression.
... The extracellular domain is the binding site of its ligand, HGF, and consists of the semaphorin (SEMA), plexin semaphorin integrin (PSI), and immunoglobulin plexin transcription factor (IPT) domains. The intracellular domain consists of the juxtamembrane (JM) domain with the E3 ubiquitin ligase casitas B-lineage lymphoma (c-CBL) binding site, tyrosine kinase (TK) domain, and C-terminal multifunctional docking site ( Figure 1) [2,[6][7][8]. Binding of the ligand HGF to the SEMA domain on the extracellular portion of the MET receptor induces MET homodimerization and the subsequent autophosphorylation of the tyrosine residues at codon Y1234 and Y1235 (NM_000245 (Y1252 and Y1253 NM_0001127500)) in the intracellular TK domain, thus leading to the activation of the kinase domain. This is followed by the phosphorylation of Y1349 and Y1356 (NM_000245 (Y1367 and Y1374 NM_0001127500)) in the multifunctional docking site, which opens and forms a docking site for intracellular adaptors that recruit SRC (SRC proto-oncogene, non-receptor tyrosine kinase) adapter protein; additionally, the subsequent activation of several downstream pathways occurs, such as the PI3K/AKT pathway, RAS mitogen activated protein kinase (MAPK) cascade, signal transducer and activator of transcription (STAT), and NF-κB pathway [4]. ...
Simple Summary
A variety of MET aberrations that lead to the dysregulation of the MET oncogene and thus the activation of various signaling pathways have been described. These include MET overexpression, the activation of MET mutations comprising exon 14 skipping mutations, MET gene amplifications, and MET fusions. Patients with such aberrations can be treated using a targeted inhibitor such as crizotinib, cabozantinib, tepotinib, and capmatinib. Therefore, the implementation of high-quality and sensitive methods for the detection of the various MET aberrations is essential.
Abstract
MET tyrosine kinase receptor pathway activation has become an important actionable target in solid tumors. Aberrations in the MET proto-oncogene, including MET overexpression, the activation of MET mutations, MET mutations that lead to MET exon 14 skipping, MET gene amplifications, and MET fusions, are known to be primary and secondary oncogenic drivers in cancer; these aberrations have evolved as predictive biomarkers in clinical diagnostics. Thus, the detection of all known MET aberrations in daily clinical care is essential. In this review, current molecular technologies for the detection of the different MET aberrations are highlighted, including the benefits and drawbacks. In the future, another focus will be on the standardization of detection technologies for the delivery of reliable, quick, and affordable tests in clinical molecular diagnostics.
... HGF is an inactive single-chain polypeptide (scHGF) when secreted, but in the tumor microenvironment, scHGF is transformed into active two-chain HGF (tcHGF) by specific serine protease-mediated processing between the K4 domain and the SP domain ( Figure 3A). 20 HGF-inhibitory peptide-8 (HiP-8) is an inhibitory macrocyclic peptide that specifically binds to tcHGF ( Figure 3B). We have previously reported that HiP-8 potently inhibits the HGF-MET interaction. ...
Background:
Entrectinib is an effective drug for treating solid tumors with NTRK gene rearrangement and non-small cell lung cancer (NSCLC) with ROS1 gene rearrangement. However, its efficacy is limited by tolerance and acquired resistance, the mechanisms of which are not fully understood. The growth factors produced by the tumor microenvironment, including hepatocyte growth factor (HGF) produced by tumor-associated fibroblasts, critically affect the sensitivity to targeted drugs.
Methods:
We investigated whether growth factors that can be produced by the microenvironment affect sensitivity of NTRK1-rearranged colon cancer KM12SM cells and ROS1-rearranged NSCLC HCC78 cells to entrectinib both in vitro and in vivo.
Results:
Among the growth factors assessed, HGF most potently induced entrectinib resistance in KM12SM and HCC78 cells by activating its receptor MET. HGF-induced entrectinib resistance was reversed by the active-HGF-specific macrocyclic peptide HiP-8 and the MET kinase inhibitor capmatinib in vitro. In addition, HGF-producing fibroblasts promoted entrectinib resistance in vitro (culture model) and in vivo (subcutaneous tumor model). The use of capmatinib circumvented entrectinib resistance in a subcutaneous tumor model inoculated with KM12SM and HGF-producing fibroblasts.
Conclusion:
Our findings suggest that growth factors in the tumor microenvironment, such as HGF, may induce resistance to entrectinib in tumors with NTRK1 or ROS1 rearrangements. Our results further suggest that optimally co-administering inhibitors of resistance-inducing growth factors may maximize the therapeutic efficacy of entrectinib.
... Matriptase activation is mediated by autoactivation or by other trypsin-like proteases. Recent studies have revealed that matriptase autoactivation is promoted in an acidic environment [22,23], and is tightly regulated by the cellular chemical environment. Another study revealed that matriptase proteolysis induced by UV irradiation or reactive oxygen species may exert short-term protective effects and contribute to the recovery from acute epidermal damage and/or pathology of skin with chronic sun damage [24]. ...
We have previously reported that ultrasound (US)-mediated microbubble (MB) cavitation (US-MB) changed the permeability of the skin and significantly enhanced transdermal drug delivery (TDD) without changing the structure of the skin. In this study we found that US-MB enhanced TDD via disruption of epidermal cell-cell junctions and increased matriptase activity. Matriptase is a membrane-bound serine protease regulated by its inhibitor hepatocyte growth factor activator inhibitor-1 (HAI-1), and it is expressed in most epithelial tissues under physiologic conditions. Matriptase is expressed in mice after chronic exposure to UV radiation. This study found that US-MB can be used to monitor active matriptase, which rapidly formed the canonical 120-kDa matriptase-HAI-1 complex. These processes were observed in HaCaT human keratinocytes when matriptase activation was induced by US-MB. The results of immunoblot analysis indicated that the matriptase-HAI-1 complex can be detected from 10 min to 3 h after US-MB. Immunohistochemistry (IHC) of human skin revealed that US-MB rapidly increased the activated matriptase, which was observed in the basal layer, with this elevation lasting 3 h. After 3 h, the activated matriptase extended from the basal layer to the granular layer, and then gradually decayed from 6 to 12 h. Moreover, prostasin expression was observed in the epidermal granular layer to the spinous layer, and became more obvious in the granular layer after 3 h. Prostasin was also detected in the cytoplasm or on the cell membrane after 6 h. These results suggest that matriptase plays an important role in recovering from US-MB-induced epidermal cell-cell junction disruption within 6 h. US-MB is therefore a potentially effective method for noninvasive TDD in humans.
... c-MET is a cell surface receptor that binds HGF and activates a signaling pathway downstream. The c-MET proto-oncogene encodes c-MET, and it is created as a single-chain precursor before being converted to the mature form [9,10]. Mature MET is composed of 50 kDa beta-chain and 145 kDa alpha-chain [11]. The plexin-semaphorin-integrin (PSI domain), immunoglobulin-like fold-plexin-transcription factor (IPT domain), and N-terminal Sema domain comprise c-extracellular MET's region [12]. ...
Ovarian cancer is the fifth leading cause of cancer deaths in women and is regarded as one of the most difficult cancers to treat. Currently, studies are being conducted to develop therapeutic agents for effective treatment of ovarian cancer. In this review, we explain the properties of the hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (c-MET) and how the signaling pathway of HGF/c-MET is activated in different cancers and involved in tumorigenesis and metastasis of ovarian cancer. We present the findings of clinical studies using small chemicals or antibodies targeting HGF/c-MET signaling in various cancer types, particularly in ovarian cancer. We also discuss that HGF/c-MET-targeted therapy, when combined with chemo drugs, could be an effective strategy for ovarian cancer therapeutics.
... The HGF/c-Met axis is strictly controlled by various mechanisms in normal tissues, and regulated by the amount of active HGF accurately. Two HGF protease inhibitors have been identified, HGF activator inhibitor (HAI)-1 and/or HAI-2, which control the activation of HGF ligand to limit the production of active HGF (Kaido et al., 2004;Kawaguchi and Kataoka, 2014). The HGF-specific antagonist NK4, which is similar to HGF, can bind to C-Met and competitively antagonize downstream phosphorylation induced by HGF (Date et al., 1998;Mizuno and Nakamura, 2013). ...
Hepatocyte growth factor (HGF) is a peptide-containing multifunctional cytokine that acts on various epithelial cells to regulate cell growth, movement and morphogenesis, and tissue regeneration of injured organs. HGF is sequestered by heparin-like protein in its inactive form and is widespread in the extracellular matrix of most tissues. When the liver loses its average mass, volume, or physiological and biochemical functions due to various reasons, HGF binds to its specific receptor c-Met (cellular mesenchymal-epithelial transition) and transmits the signals into the cells, and triggers the intrinsic kinase activity of c-Met. The downstream cascades of HGF/c-Met include JAK/STAT3, PI3K/Akt/NF-κB, and Ras/Raf pathways, affecting cell proliferation, growth, and survival. HGF has important clinical significance for liver fibrosis, hepatocyte regeneration after inflammation, and liver regeneration after transplantation. And the development of HGF as a biological drug for regenerative therapy of diseases, that is, using recombinant human HGF protein to treat disorders in clinical trials, is underway. This review summarizes the recent findings of the HGF/c-Met signaling functions in liver regeneration.
... identified HiP-8 (macrocyclic peptide, 1.6 KDa), as a novel functionally active two-chain HGF (tcHGF) 67,68 binding peptide that strongly inhibited the interaction of HFG with c-Met with subnanomolar potency. 47 Noninvasive screening/visualization and inhibition of HGF/c-Met was observed after iv administration of HiP-8 followed by PET imaging in a mouse model. ...
... All the other c-Met negative lesions were heterogeneously distributed intra-and interindividually and mostly present as lung and liver metastases. 68 Ga-EMP-100 was physiologically accumulated in the urinary bladder content and kidneys, and only moderate to low uptake was measured in the liver, spleen, pancreas, and intestine. The clinical success of the reported study warrants further research studies investigating the clinical use of 68 Ga-EMP-100 and other similar probes as a biomarker in mRCC patients. ...
... 68 Ga-EMP-100 was physiologically accumulated in the urinary bladder content and kidneys, and only moderate to low uptake was measured in the liver, spleen, pancreas, and intestine. The clinical success of the reported study warrants further research studies investigating the clinical use of 68 Ga-EMP-100 and other similar probes as a biomarker in mRCC patients. ...
Tyrosine‐protein kinase Met—also known as c‐Met or HGFR—is a membrane receptor protein with associated tyrosine kinase activity physiologically stimulated by its natural ligand, the hepatocyte growth factor (HGF), and is involved in different ways in cancer progression and tumourigenesis. Targeting c‐Met with pharmaceuticals has been preclinically proved to have significant benefits for cancer treatment. Recently, evaluating the protein status during and before c‐Met targeted therapy has been shown of relevant importance by different studies, demonstrating that there is a correlation between the status (e.g., aberrant activation and overexpression) of the HGFR with therapy response and clinical prognosis. Currently, clinical imaging based on positron emission tomography (PET) appears as one of the most promising tools for the in vivo real‐time scanning of irregular alterations of the tyrosine‐protein kinase Met and for the diagnosis of c‐Met related cancers. In this study, we review the recent progress in the imaging of c‐Met aberrant cancers with PET. Particular attention is directed on the development of PET probes with a range of different sizes (HGF, antibodies, anticalines, peptides, and small molecules), and radiolabeled with different radionuclides. The goal of this review is to report all the preclinical imaging studies based on PET imaging reported until now for in vivo diagnosis of c‐Met in oncology to support the design of novel and more effective PET probes for in vivo evaluation of c‐Met.
... Activation of MET in cancer cells has been shown to induce cancer cell proliferation, survival, cell scattering, epithelial-to-mesenchymal transition (EMT), migration, and primary and acquired resistance to anti-cancer therapy 3,[15][16][17][18][19][20][21][22][23] . Although HGF is mostly expressed by cancer-associated fibroblasts and activates MET receptor on tumor cells in a paracrine fashion, tumor cells have also been shown to express HGF [24][25][26] . ...
... HGF is released from cells as an inactive single-chain pro-factor, pro-HGF, which can bind the MET receptor but cannot activate MET signaling 40 . Proteolytic activation of pro-HGF is a rate-limiting step in HGF/MET signaling 25,41 . One of the three serine proteases, matriptase, hepsin, or HGFA, are required for site-specific proteolytic processing of pro-HGF into an active protein, capable of binding and activating the receptor 25 . ...
... Proteolytic activation of pro-HGF is a rate-limiting step in HGF/MET signaling 25,41 . One of the three serine proteases, matriptase, hepsin, or HGFA, are required for site-specific proteolytic processing of pro-HGF into an active protein, capable of binding and activating the receptor 25 . The HGF-activating proteases are upregulated in lung cancer tissue compared to non-cancerous lung tissue 25,42,43 . ...
