Could deciphering cellular-mesenchymal epithelial transition factor/hepatocyte growth factor network dynamics unlock novel biomarker-driven therapies for colorectal cancer?

Abstract

Colorectal cancer (CRC) poses a substantial global health challenge. Its pathogenesis involves intricate genetic and signaling pathway aberrations, among which the cellular-mesenchymal epithelial transition factor (c-Met)/hepatocyte growth factor (HGF) axis functions as a pivotal regulatory hub. Encoded by a proto-oncogene, the transmembrane receptor c-Met is activated by HGF, driving CRC cell proliferation, migration, invasion, and metastasis via critical signal transduction cascades. The c-Met factor overexpression is observed in 30%-70% of CRC tumors. This review elucidates c-Met/HGF-mediated carcinogenesis, emphasizing its crosstalk with epidermal growth factor receptor, vascular endothelial growth factor, and insulin-like growth factor 1 receptor pathways. Notably, c-Met amplification contributes to epidermal growth factor receptor inhibitor resistance, increasing signaling network complexity. MicroRNA-1 and microRNA-137 modulate c-Met expression to suppress CRC progression, while advancements in c-Met-targeted molecular imaging facilitate precise diagnosis and treatment monitoring. Progress in c-Met/HGF-targeted therapies, including small-molecule inhibitors, monoclonal antibodies, and tyrosine kinase inhibitors, shows promise in suppressing tumors and overcoming resistance. Future efforts should focus on optimizing combination therapies, refining patient stratification via imaging, and addressing drug resistance to enable personalized, efficacious CRC treatments leveraging this axis.

Key Words: Clinical translation; Cell signal transduction; Colorectal cancer; Hepatocyte growth factor; Cellular-mesenchymal epithelial transition factor

Core Tip: This comprehensive review delineates the complex cellular-mesenchymal epithelial transition factor (c-Met)/hepatocyte growth factor signaling network as a central driver of colorectal cancer progression, metastasis, and resistance to epidermal growth factor receptor-targeted therapies. We highlight innovative insights, including the distinct tumor-suppressive roles of microRNA-1 and microRNA-137 in regulating c-Met, the critical function of the transcriptional activator metastasis associated in colon cancer 1, and the pathway’s extensive crosstalk with vascular endothelial growth factor and insulin-like growth factor-1 receptor. The review synthesizes recent advances in c-Met-targeted agents (inhibitors and monoclonal antibodies) and emerging non-invasive molecular imaging techniques. It proposes novel, biomarker-driven combination strategies and patient stratification approaches to overcome therapeutic resistance, paving the way for personalized treatment in colorectal cancer.

INTRODUCTION

Colorectal cancer (CRC) has evolved into a substantial global public health challenge. By 2020, CRC stood as the third most prevalent cancer diagnosis, impacting around 1.9 million individuals[1]. Furthermore, it ranked as the second leading cause of cancer-related mortality, contributing to over 900000 deaths worldwide, constituting approximately 10% of all cancer cases and fatalities[2]. Of noteworthy concern is the foreseen substantial surge in new CRC cases and associated mortality in numerous countries from 2020 to 2040, driven by population expansion and demographic aging trends[1,3,4]. Projections anticipate a rise to approximately 4.7 million cases by 2070[5], with the potentiality of CRC incidence among younger cohorts simultaneously on the rise[6]. Consequently, CRC undeniably constitutes a noteworthy facet of the global cancer burden[7].

From a histological standpoint, CRC results from the aberrant proliferation of glandular epithelial cells[8]. This intricate cascade involves a myriad of genetic mutations occurring in specific oncogenes within the gastrointestinal epithelial cells[9]. The predominant variant of CRC is adenocarcinoma, while sarcomas and neuroendocrine tumors represent relatively infrequent occurrences[10]. Normal epithelium progresses through a series of stages, encompassing the formation of hyperplastic mucosa, the emergence of benign adenomas, and culminating in the development of malignant tumors or distant metastases. This process is governed by mechanisms including microsatellite instability and chromosomal instability pathways[11].

Recent years have witnessed noteworthy advancements in the domain of CRC, primarily attributable to the strides made in early cancer screening, prompt diagnosis, and the evolution and implementation of tumor markers. A plethora of clinical biomarkers associated with the prognosis of CRC has been elucidated[12]. Despite these commendable strides, the widespread dissemination of early cancer screening and diagnosis has encountered challenges, largely due to economic disparities. Consequently, a substantial number of CRC patients are diagnosed belatedly, missing optimal windows for treatment initiation. In light of this, the imperative to pinpoint pivotal receptors and unravel underlying signaling pathways has intensified. This is driven by the pressing need to formulate efficacious targeted therapies, addressing the current exigencies in CRC treatment.

Among the myriad molecules associated with CRC, the cellular-mesenchymal epithelial transition factor (c-Met) stands out as an exceptionally promising target. Initially identified by Cooper et al[13] in human osteosarcoma cell lines, this receptor tyrosine kinase (RTK) is activated by its ligand, hepatocyte growth factor (HGF). The c-Met/HGF signaling pathway has captivated researchers for decades, given its pivotal regulatory role in physiological processes (Figure 1). Aberrant activation of this pathway in human cancer significantly contributes to tumor cell migration and progression[14-16]. Evidence from various studies demonstrates the overexpression of c-Met in diverse malignancies, including gastric cancer[17], liver cancer[18], breast cancer[19], and lung cancer[20]. This widespread overexpression underscores the potential significance of c-Met as a valuable target for early diagnosis and targeted therapy. Prior investigations indicate that c-Met is overexpressed in 30% to 70% of CRC tumors[21-23]. Moreover, comparative analyses with adjacent normal colonic mucosa reveal significantly elevated levels of c-Met microRNA and protein in CRC[24,25].

Figure 1 A comprehensive timeline summarizing the key advancements and discoveries in the field of cellular-mesenchymal epithelial transition factor/hepatocyte growth factor signaling pathway research. The cellular-mesenchymal epithelial transition factor (c-Met)/hepatocyte growth factor pathway journey began with hepatocyte growth factor’s discovery in 1984, followed by c-Met’s identification as its receptor in 1986. By 1995, mutations in the c-Met gene were linked to cancer progression. In 2000, the signaling mechanism was elucidated, leading to c-Met inhibitors’ development in 2008. In 2010, the pathway’s role in cancer metastasis was identified, and in 2014, its cross-talk with other signaling cascades was discovered. Recently, more drugs targeting this axis entered clinical trials, marking a significant milestone in translational medicine. HGF: Hepatocyte growth factor; c-Met: Cellular-mesenchymal epithelial transition factor.

In summary, c-Met is pivotal in both the initiation and progression of CRC, underscoring its substantial potential as a promising target for therapeutic interventions and diagnostic applications. This manuscript endeavors to provide a comprehensive overview of the structural and functional facets of c-Met, delving into its expression patterns and the underlying mechanisms within CRC tissues. Additionally, our focus will extend to the latest advancements in research concerning targeted therapies against CRC, leveraging c-Met as a therapeutic focal point. Through an in-depth exploration of the intricate interactions involving the c-Met/HGF pathway, alongside other signaling cascades and RTKs, we aim to uncover innovative strategies and insights for the treatment and diagnosis of CRC. This pursuit ultimately aspires to enhance prognoses and elevate the quality of life for individuals afflicted by CRC.

DECODING C-MET: STRUCTURE, FUNCTIONS, AND EXPRESSION IN CANCER

The c-Met manifests as a heterodimeric glycoprotein, featuring a molecular weight of 190 kDa. Comprising an extracellular α-chain and a transmembrane β-chain, the α-chain intricately links to the β-chain through disulfide bonds within the extracellular domain. This domain encompasses a semaphoring domain, a plexin-semaphorin-integrin domain, and four immunoglobulin-like plexin transcription domains. Significantly, these domains share immunoglobulin-like folds common to plexins and transcription factors[26]. Crucial regulatory roles are attributed to residues Ser-975 and Tyr-1003 within the juxtamembrane region of c-Met, exerting profound effects on its functionality[27]. Concerning its tissue-specific expression, c-Met predominantly finds expression in epithelial cells. Contrastingly, expression in neurons, hematopoietic cells, and capsule cells is notably more limited[28-30].

The complicated interplay between c-Met and its ligand HGF occupies a key position in coordinating the proliferation, survival, and mobility of both normal and neoplastic intestinal epithelial cells. This dynamic involvement extends its significant influence over intestinal injury responses and the complex landscape of tumor development. In the context of programmed death 1-targeted monotherapy[31], c-Met emerges as a mediator of resistance signaling, laying the theoretical groundwork for synergistic anti-tumor effects through the combination of immune checkpoint inhibitors and c-Met inhibition. Furthermore, c-Met itself emerges as a potential tumor-specific antigen, offering strategic guidance for the precise elimination of tumor cells by T cells in immunotherapy. The mechanisms governing c-Met hyperactivation are diverse and complex, encompassing gene amplification[32], overexpression[33], mutations[34], RTK transactivation, and alterations in ligand-induced autocrine or paracrine signaling (Figure 2)[35,36]. Researchers have revealed a significant elevation in the level of c-Met protein in late-stage CRC compared to the early stages. From this novel perspective, c-Met, as a critical RTK in cell signal transduction and tumor development, holds the promise of providing innovative insights and approaches for cancer medical research and diagnosis and treatment through an in-depth exploration of its structure, functions, and interactions with molecules.

Figure 2 The mechanisms of cellular-mesenchymal epithelial transition factor hyperactivation. c-Met: Cellular-mesenchymal epithelial transition factor; HGF: Hepatocyte growth factor; PTPRZ1-MET: Protein tyrosine phosphatase receptor zeta 1-mesenchymal epithelial transition factor; CLIP2-MET: Containing linker protein 2-mesenchymal epithelial transition factor; TRIM4-MET: Tripartite motif containing 4- mesenchymal epithelial transition factor.

C-MET AND HGF: ORCHESTRATING A MOLECULAR BALLET IN CELLULAR REGULATION

HGF, a member of the heparin-binding growth factors endowed with angiogenic potential, functions as a versatile growth factor[37]. This monomeric, inactive protein, following secretion, undergoes activation mediated by extracellular proteases, culminating in its acquisition of a biologically active form. The mature HGF comprises an α-chain subunit and a β-chain subunit, forming a heterodimer through disulfide bonds[38,39].

The interaction between HGF and the c-Met receptor initiates receptor activation through autophosphorylation at Tyr-1234 and Tyr-1235 residues within the intracellular tyrosine kinase domain. Subsequently, this activation induces phosphorylation at Tyr-1349 and Tyr-1356 residues, facilitating the recruitment of intracellular adaptor molecules such as growth factor receptor-bound protein-1, growth factor receptor-bound protein-2, and Src[40,41]. The binding of c-Met and HGF elicits several crucial signal transduction pathways, including Src/focal adhesion kinase, phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), and rat sarcoma (RAS)/mitogen-activated protein kinases (MAPK), which are integral to governing cellular processes such as proliferation, survival, motility, migration, invasion, and angiogenesis[42].

Notably, the E3 ubiquitin ligase casitas B cell lymphoma serves as a key negative regulator of c-Met receptor activity. The K1 Loop structure located at the N-terminus of the α-chain provides a high-affinity binding site for c-Met; however, in isolation, it proves insufficient for c-Met activation. Only upon c-Met binding to the α-chain of HGF does the β-chain of HGF bind with low affinity, initiating the activation of c-Met. Upon ligand binding, phosphorylation of amino acid residues Tyr-1234 and Tyr-1235 on c-Met occurs, subsequently activating downstream pathways[43-45]. Post c-Met activation, casitas B cell lymphoma recognizes and binds to the phosphorylated Tyr-1003 residue in the juxtamembrane region. This interaction initiates polyubiquitination and subsequent degradation of c-Met in the lysosomal compartment through a proteasome-dependent mechanism, finely regulating the activity of c-Met[46,47].

In summary, the physiological interaction between c-Met and HGF holds a crucial role in cellular signal transduction, overseeing diverse biological processes. A comprehensive exploration of the intricate steps and interactions characterizing this dynamic partnership contributes significantly to unraveling the complexities inherent in the c-Met/HGF pathway.

EXPLORING ABERRANT ACTIVATION AND THERAPEUTIC OPPORTUNITIES OF THE C-MET/HGF PATHWAY IN CRC

Hyperactivation of the c-Met/HGF pathway in CRC is tightly associated with disease progression and therapeutic resistance, characterized by CRC-specific aberrations and regulatory mechanisms that hold critical translational implications. Among the structural modifications driving pathway activation in CRC, mutations in the intracellular tyrosine kinase domain of c-Met are the most prevalent, with exon 14 skipping mutations also contributing to constitutive c-Met activation[48]. Of particular clinical relevance is c-Met amplification, which exhibits a distinct association with poor prognosis in young-onset CRC (defined as patients aged 50 years or younger). Recent cohort studies have demonstrated that the prevalence of c-Met amplification is 1.8-fold higher in young-onset CRC compared to elderly patients (aged 65 years or older)[6]. This aberration is independently linked to advanced tumor stage (Stage III/IV), increased risk of liver metastasis, and a 42% reduction in 5-year overall survival among young CRC patients[22,49], underscoring the urgency of targeting c-Met in this subgroup-a population facing a rising incidence of CRC and unmet therapeutic needs.

Within the CRC tumor microenvironment (TME), cancer cells secrete high levels of HGF to activate c-Met via autocrine signaling. Concurrently, paracrine HGF released by cancer-associated fibroblasts and tumor-associated macrophagesfurther amplifies c-Met/HGF pathway activation[50]. This autocrine-paracrine loop reinforces an aggressive tumor phenotype: The c-Met overexpression, observed in 30% to 70% of CRC tumors[21-23], correlates with enhanced cell migration, invasion, and resistance to cytotoxic chemotherapy. Comparative analyses between CRC tissues and adjacent normal colonic mucosa have confirmed significantly elevated c-Met microRNA and protein levels in CRC, with higher expression intensity associated with lymph node metastasis and unfavorable clinical outcomes[24,25,51].

A key CRC-specific regulatory mechanism involves metastasis associated in colon cancer 1 (MACC1), a transcriptional activator of c-Met that is frequently overexpressed in mCRC. Upon stimulation by HGF, MACC1 translocates to the nucleus, binds to the c-Met promoter, and initiates c-Met transcriptional activation-forming a feedforward loop that amplifies c-Met/HGF signaling[52-54]. MACC1 overexpression is detected in 45% to 60% of advanced mCRC cases, and co-overexpression of MACC1 and c-Met predicts earlier disease recurrence and shorter progression-free survival[55-57]. This MACC1-c-Met axis thus represents a core driver of CRC metastasis and a potential biomarker for prognostic stratification.

A major translational roadblock arises from c-Met-mediated resistance to epidermal growth factor receptor (EGFR)-targeted therapy, a cornerstone of mCRC treatment. c-Met and EGFR share downstream signaling pathways [e.g., RAS/MAPK, PI3K/AKT], and c-Met amplification compensates for EGFR inhibition by sustaining proliferative signaling[50,56,58]. Up to 22.6% of CRC patients with refractory disease following EGFR inhibitor treatment harbor c-Met amplification[53,59-61], and this aberration directly mediates resistance to cetuximab or panitumumab in kirsten rat sarcoma viral oncogene homolog (KRAS) wild-type mCRC[62-64], a patient population that typically benefits from EGFR-targeted therapy. This resistance mechanism poses a significant barrier to effective CRC treatment and highlights the need for combinatorial strategies co-targeting c-Met and EGFR.

Collectively, c-Met/HGF pathway activation in CRC is driven by amplification, TME-derived HGF, and MACC1-mediated transcriptional regulation, all of which promote tumor progression and therapeutic resistance. The pathway’s role as a critical translational roadblock in EGFR-targeted therapy further confirms its utility as a precision therapeutic target for CRC.

THE SIGNALING LABYRINTH IN CRC: THE CROSSTALK NETWORK OF THE C-MET/HGF PATHWAY

Beyond its independent role, the c-Met/HGF pathway interacts with multiple signaling cascades, which is critical for understanding therapy resistance. The intricate interplay within the c-Met/HGF axis and its connections to other signaling pathways and RTKs have become a central focus of contemporary research (Figure 3). This attention stems from its potential implications in deciphering the mechanisms behind resistance to targeted therapies. The pathway elaborately regulates various signal cascades that promote angiogenesis by indirectly modulating the expression of angiogenic factors like vascular endothelial growth factor (VEGF), and concurrently suppressing the activity of anti-angiogenic mediators such as thrombospondin1[65,66].

Figure 3 Crosstalk network of cellular-mesenchymal epithelial transition factor/hepatocyte growth factor pathway (partial). VEGR: Vascular endothelial growth factor; EGFR: Epidermal growth factor receptor; HGF: Hepatocyte growth factor; c-Met: Cellular-mesenchymal epithelial transition factor; HGFLP: Hepatocyte growth factor-like protein; IGF1R: Insulin-like growth factor 1 receptors; MAPK: Mitogen-activated protein kinases; SCR: Selective catalytic reduction; FAK: Focal adhesion kinase; STAT3: Signal transducer and activator of transcription 3; PI3K: Phosphoinositide 3-kinase; AKT: Protein kinase B; APK: Activated protein kinases; RAS: Rat sarcoma; GRB2: Growth factor receptor-bound protein-2; GAB1: Growth factor receptor-bound protein-1.

In LoVo CRC cells and their oxaliplatin-resistant counterparts, the phosphorylation of c-Met correlates with diminished VEGF expression. The introduction of recombinant VEGF to the cell cultures leads to decreased c-Met activation, implying that the activation of c-Met serves as a compensatory mechanism in response to anti-VEGF therapy. Considering these observations and the varied drug-resistant phenotypes evident in different CRC cell lines, a combined targeted therapeutic approach targeting both c-Met and VEGF may prove pivotal in extending survival and overcoming drug resistance[67,68].

In c-Met/HGF signaling, HGF selectively binds to c-Met’s semaphorin domain, activating the receptor[68-70]. This triggers phosphorylation in c-Met’s cytoplasmic tail, recruiting adapter proteins like growth factor receptor-bound protein-2 and growth factor receptor-bound protein-1 for downstream RAS/MAPK, PI3K/AKT, and Janus kinase/signal transducer of activation (STAT) signaling[71-74]. The significant crosstalk between c-Met/HGF and insulin-like growth factor 1 (IGF-1)/IGF-1 receptor (IGF-1R) is notable. Activated IGF-1R stimulates the RAS/rapidly accelerated fibrosarcoma/MAPK and PI3K/AKT/mammalian target of rapamycin pathways[75]. Both c-Met and IGF-1R play crucial roles in tumor cell migration and invasion. Studies in CRC cells reveal their involvement, with c-Met inhibition blocking IGF-1-mediated migration and invasion. In CRC subclasses, overactivation of c-Met and IGF-1R correlates with poor survival in metastatic CRC[76]. Consequently, c-Met and IGF-1R expression levels are considered factors in resistance to EGFR inhibitors like cetuximab in mCRC.

In the complicated regulation of c-Met/HGF signaling, the transcriptional control of c-Met expression assumes a crucial role, encompassing the Wnt, activating protein-1, and hypoxia pathways. Within the intestinal epithelium, Wnt signaling stands out as a major driver of c-Met transcription[77]. Notably, CD44, functioning as a co-receptor for c-Met and a key transcriptional target of Wnt signaling, exhibits high expression in intestinal stem cells and adenomas. Activation of the Wnt pathway leads to CD44 overexpression, further amplifying c-Met levels. The activation of the c-Met/HGF/CD44 signal reportedly significantly augments the metastatic resistance of CRC to EGFR inhibitors[78]. Additionally, heightened HGF levels can induce resistance to cetuximab in CRC cells through binding to SRY-Box transcription factor 8, underscoring the pivotal role of c-Met/HGF in CRC treatment resistance[79]. Beyond the well-established Wnt signaling pathway, hypoxic signaling is recognized as a significant contributor to c-Met regulation in advanced cancer. Within invasive mCRC, hypoxia prevails, fostering the stabilization of hypoxia-inducible factor-1α. Notably, c-Met assumes a crucial position as a transcriptional target in the HIF-1α regulatory network, essential for sustaining tumor cell viability in hypoxic environments. Moreover, the upregulation of c-Met induced by hypoxia enhances tumor cell responsiveness to HGF secreted by cancer-associated fibroblasts and tumor-associated macrophages, thereby augmenting tumor cell migration and facilitating metastasis through the c-Met/HGF pathway[80,81].

In recent research, the co-expression of EGFR and c-Met in tumors, along with their interplay, has garnered substantial attention. These receptors share common downstream signaling pathways, including extracellular signal-regulated kinase, MAPK, PI3K, and AKT, as evidenced in hepatocellular carcinoma (HCC)[82]. Remarkably, the administration of cetuximab in advanced gastric cancer has been linked to mutations and amplifications in the c-Met gene[83], implying that EGFR-targeted therapy may induce drug resistance by activating the c-Met pathway. Further investigations spotlight the pivotal role of crosstalk between c-Met and EGFR in mediating tumor resistance[44,84]. Moreover, elevated c-Met signaling acts as a compensatory mechanism in attenuated EGFR signaling, sustaining the proliferative capacity of chemoresistant breast tumor cells[85]. Both in vitro and in vivo experiments consistently affirm that a dual approach targeting c-Met and EGFR synergistically inhibits the proliferation of resistant cells, presenting a promising avenue for cancer treatment. Numerous clinical studies have validated the efficacy of this combined therapeutic strategy[86-88].

Additionally, RON, a member of the RTK family, has garnered significant attention owing to its structural and functional resemblance to c-Met. Activation of RON can instigate signaling pathways activation, including MAPK and PI3K, utilizing HGF-like protein as its ligand[89]. Primarily secreted by hepatocytes, HGF-like protein exists in an inactive, single-chain precursor form. Notably, RON and c-Met co-expression and mutual activation are observed in various tumors. These receptors play pivotal roles not only in embryonic development and organ formation but also demonstrate overexpression or abnormal activation in multiple cancers[90,91]. Research conducted by Zhao et al[92] unveiled that RON knockout intensifies the strength and duration of c-Met signaling, suggesting that c-Met signaling can compensate for the loss of RON signaling. Consequently, RON and c-Met collaboratively contribute to tumor initiation and progression.

MICRORNAS: THE SILENCING POWER OF C-MET IN CRC

MicroRNAs are small non-coding RNA molecules that regulate gene expression via RNA interference. They have emerged as critical modulators of c-Met activity in CRC, with specific microRNAs such as miR-1 and miR-137 gaining attention for their ability to target the c-Met oncogene and suppress tumor progression. A foundational observation across CRC studies is the significant downregulation of miR-1 in CRC tissues relative to adjacent normal colonic mucosa: Quantitative reverse transcription-polymerase chain reaction analyses of 82 paired CRC and normal samples show a marked reduction in miR-1 expression in tumors, and this downregulation correlates with increased c-Met microRNA levels[92,93]. Functional studies further confirm miR-1’s role: Reintroducing miR-1 mimic into CRC cell lines reduces c-Met protein expression by nearly half and inhibits c-Met-driven cellular processes, including a notable decrease in migration and a significant induction of G0/G1 cell cycle arrest[93,94]. These findings position miR-1 as a candidate for mitigating c-Met-dependent proliferation and motility in metastatic CRC, though its efficacy is constrained by its narrow functional scope.

Complementary to miR-1, miR-137 exhibits distinct and more potent regulatory effects on c-Met and CRC progression. RNA sequencing of 18 colorectal adenocarcinoma samples identified a strong inverse correlation between miR-137 levels and tumor stage, with stage IV tumors showing substantially lower miR-137 expression than stage I tumors[95]. In vitro validation confirms that miR-137 targets c-Met directly: Dual-luciferase reporter assays in LoVo cells demonstrate that miR-137 binds two non-overlapping sites in the c-Met 3’ untranslated region, whereas miR-1 binds only one conserved site[62,95]. This difference in binding specificity translates to greater c-Met suppression: MiR-137 mimic reduces c-Met protein levels by more than half in CRC cell lines, substantially more than miR-1 and exerts broader anti-tumor effects. Beyond inhibiting proliferation and migration, miR-137 strongly suppresses invasion and liver metastasis: In immunocompromised mice injected with miR-137-overexpressing HT29 cells, liver metastatic nodules were drastically reduced compared to control mice[95]. This enhanced activity stems from miR-137’s dual targeting of c-Met and Mecp-2, while miR-1 acts exclusively on c-Met; Mecp-2 is a DNA methylation CpG-binding protein that epigenetically silences tumor suppressors in CRC[62,95]. Collectively, these data highlight that while both microRNAs inhibit c-Met, miR-137 exhibits higher targeting potency and broader anti-metastatic activity, making it a more promising candidate for CRC therapy, albeit with shared delivery challenges (Figure 4).

Figure 4 The antioncogenic microRNAs suppress colorectal cancer progression by repressing the translation of cellular-mesenchymal epithelial transition factor mircoRNA. c-Met: Cellular-mesenchymal epithelial transition factor.

Despite their in vitro and preclinical efficacy, the clinical translation of miR-1 and miR-137 in CRC is hindered by three critical in vivo delivery bottlenecks, supported by preclinical pharmacokinetic and biodistribution studies. First, poor circulatory stability limits their bioavailability: Naked miR-1 and miR-137 are rapidly degraded by serum nucleases (e.g., ribonuclease A) and have an extremely short half-life in both mouse and human plasma, insufficient time to reach CRC primary tumors or liver metastases[38,95]. Second, inadequate tumor targeting leads to off-target accumulation: Systemic injection of fluorescently labeled naked miR-137 in orthotopic CRC mouse models shows that most of the dose accumulates in the liver and kidneys via the reticuloendothelial system, while only a small fraction reaches primary colon tumors and even less localizes to liver metastases[39,56]. This off-targeting not only diminishes therapeutic efficacy but also poses safety risks: In mice treated with high-dose naked miR-137, nick-end labeling staining revealed mild hepatocyte apoptosis, attributed to unintended Mecp-2 silencing in normal hepatocytes[95]. Third, low intracellular uptake further impairs efficacy: Even when microRNAs reach the TME, the negatively charged cell membrane and dense extracellular matrix of CRC tumors restrict entry. In vitro studies with CRC organoids show that only a small percentage of tumor cells internalize fluorescently labeled miR-137 mimic within 24 hours of exposure, with most mimic trapped in the ECM[49,80,95].

In summary, miR-1 and miR-137 represent promising tools to target c-Met in CRC, with miR-137 offering greater potency and broader anti-tumor activity due to its dual targeting of c-Met and Mecp-2. However, their clinical potential hinges on overcoming in vivo delivery barriers. Specifically, improving circulatory stability, enhancing tumor targeting (especially across the colonic mucus layer), and boosting intracellular uptake. Future research should prioritize CRC-tailored delivery systems (e.g., mucus-penetrating lipid nanoparticles or antibody-conjugated polymers) to harness these microRNAs’ therapeutic capacity, while leveraging their distinct targeting efficiencies to design subtype-specific strategies.

TARGETED THERAPY AGAINST THE C-MET/HGF PATHWAY IN CRC

In recent decades, substantial progress has been achieved in the domains of early diagnosis, combination chemotherapy, targeted therapeutics, and surgical interventions for CRC. However, there still exist limitations in the efficacy of these approaches. Current targeted therapeutics display limited efficacy against specific CRC subtypes, underscoring the imperative to delve deeper into the molecular intricacies of tumor development for optimizing targeted drug effectiveness. Research reveals a significant correlation between heightened c-Met expression in CRC and the propensity for tumor invasion and liver metastasis[96]. In recent investigations, considerable attention has been devoted to unraveling the sophisticated role of the c-Met/HGF signaling pathway in CRC, positioning it as a promising therapeutic target (Figure 5). Therefore, relevant inhibitors and monoclonal antibodies (mAbs) have been widely incorporated into CRC treatment research (Table 1). The following section will provide a detailed overview of several innovative formulations.

Figure 5 Inhibitors and monoclonal antibodies targeting the cellular-mesenchymal epithelial transition factor/hepatocyte growth factor signaling pathway. HGF: Hepatocyte growth factor; TAK: Transforming growth factor-β-activated kinase; CT: Computed tomography; ABT-700: Aminobenzotriazole-700; SEMA: Semaglutide; PSI: Patient-specific instrument; PI3K: Phosphoinositide 3-kinase; STAT3: Signal transducer and activator of transcription 3; RAS: Rat sarcoma.

Table 1 Clinical trials on targeted therapies against the cellular-mesenchymal epithelial transition factor/hepatocyte growth factor pathway in colorectal cancer.

Inhibitor	Patient population	Agents	First posted	Last update posted	Number enrolled	Phase	Clinical trials gov identifier	State	Status
c-Met inhibitor	Colorectal cancer	Crizotinib (PF-02341066)	July 28, 2015	July 13, 2021	82	I	NCT02510001	United Kingdom	Completed
c-Met inhibitors	Metastatic colorectal cancer	Capmatinib (INC280)	July 31, 2014	January 22, 2019	13	I	NCT02205398	United States	Terminated
c-Met inhibitors	Colorectal cancer	Capmatinib (INC280)	March 12, 2015	September 21, 2023	65	I	NCT02386826	United States	Completed
c-Met inhibitors	Metastatic colorectal cancer	Tivantinib (ARQ197)	July 4, 2013	September 9, 2022	43	II	NCT01892527	Italy	Completed
c-Met inhibitors	Advanced colorectal cancer	AL2846	April 8, 2020	July 21, 2020	56	II	NCT04337879	China	Unknown
c-Met inhibitors	Colorectal cancer	Crizotinib (PF-02341066)	June 8, 2015	February 15, 2024	6452	II	NCT02465060	United States	Active, not recruiting
Anti-c-Met monoclonal antibody	Colorectal cancer	Onartuzumab (MetMAb)	August 17, 2011	May 30, 2017	194	II	NCT01418222	United States	Completed
Anti-HGF monoclonal antibody	Colorectal cancer	Rilotumumab (AMG-102)	November 11, 2008	July 20, 2015	153	II	NCT00788957	Not provided	Completed
Tyrosine kinase inhibitors	Colorectal cancer	Axitinib	December 6, 2011	February 10, 2016	27	Not applicable	NCT01486251	France	Completed
Tyrosine kinase inhibitors	Metastatic colorectal cancer	Masitinib	June 14, 2018	December 8, 2020	219	III	NCT03556956	Czechia, France, Russian Federation	Completed
Tyrosine kinase inhibitors	Solid cancer	Regorafenib (BAY73-4506)	March 26, 2019	June 28, 2023	6	II	NCT03890731	United States, Germany, Italy	Completed
Tyrosine kinase inhibitors	Recurrent colon cancer, stage IVA colon cancer	Linifanib	June 3, 2011	August 26, 2014	30	II	NCT01365910	United States	Terminated
Tyrosine kinase inhibitors	Recurrent colon cancer, stage IVA colon cancer	Dasatinib	July 19, 2007	May 19, 2014	19	II	NCT00504153	United States	Completed
Tyrosine kinase inhibitors	Colorectal cancer	Regorafenib (BAY73-4506)	August 14, 2023	October 26, 2023	98	II	NCT05985109	China	Recruiting
Tyrosine kinase inhibitors	MSI-H colorectal cancer	Regorafenib (BAY73-4506)	August 23, 2023	August 23, 2023	154	II	NCT06006923	United States	Completed
Tyrosine kinase inhibitors	Colorectal cancer	Anlotinib	August 25, 2023	January 23, 2024	75	I	NCT06010901	China	Recruiting
Tyrosine kinase inhibitors	Colorectal cancer	Cabozantinib	May 29, 2018	July 13, 2023	117	I/II	NCT03539822	United States	Active, not recruiting
Tyrosine kinase inhibitors	Colorectal cancer	Cabozantinib	September 7, 2023	November 22, 2023	270	I	NCT06026410	United States	Recruiting
Tyrosine kinase inhibitors	Colorectal cancer	Pazopanib	October 8, 2007	November 29, 2017	25	I	NCT00540943	France	Completed
Tyrosine kinase inhibitors	Colorectal cancer	Nilotinib	June 6, 2013	February 8, 2019	15	I	NCT01871311	United States	Terminated
Tyrosine kinase inhibitors	Unresectable metastatic colorectal cancer	Anlotinib	October 5, 2021	October 20, 2021	120	II	NCT05068206	China	Recruiting
Tyrosine kinase inhibitors	Colorectal cancer stage IV	Regorafenib (BAY73-4506)	May 19, 2022	May 17, 2023	182	II	NCT05382741	Italy	Recruiting
Tyrosine kinase inhibitors	Colorectal cancer	Pexidartinib	May 19, 2016	September 5, 2021	48	I	NCT02777710	France	Completed
Tyrosine kinase inhibitors	Advanced solid tumors	KBP-5209	May 13, 2015	March 4, 2022	35	I	NCT02442414	United States	Completed
Tyrosine kinase inhibitors	Advanced solid tumors	Lenvatinib	January 9, 2019	October 31, 2023	590	II	NCT03797326	United States	Active, not recruiting
Tyrosine kinase inhibitors	Colorectal cancer	Crizotinib (PF-02341066)	June 8, 2015	February 15, 2024	6452	II	NCT02465060	United States	Active, not recruiting

All clinical trials are accessible for download on the website www.clinicaltrials.gov (accessed August 1, 2025). c-Met: Cellular-mesenchymal epithelial transition factor; HGF: Hepatocyte growth factor; MSI-H: Microsatellite instability-high.

The c-Met inhibitors

As a novel class of anti-cancer drugs, c-Met inhibitors are gradually becoming a research focus in the field of CRC treatment. Among these, norcantharidin (NCTD), a demethylated derivative of cantharidin, has demonstrated notable anti-tumor efficacy. Research indicates that NCTD effectively hinders the proliferation of CRC cells by diminishing the expression of EGFR and c-Met, leading to cell cycle arrest at the G2/M phase[97]. This finding highlights the potential of NCTD as a promising therapeutic candidate, poised for anticipated clinical effectiveness and safety.

In addition to NCTD, another c-Met inhibitor, SU11274, has also demonstrated anti-tumor effects in CRC treatment. SU11274 exerts its action by specifically inhibiting the phosphorylation of c-Met. Gao and collaborators’ investigation revealed that SU11274 effectively impedes the proliferation of four CRC cell lines[98]. Moreover, studies by GAO and team further confirmed that SU11274 can induce G1 phase arrest in CRC cells in vitro, inhibiting their survival[99,100].

Additionally, Jia et al[97] explored the effects of PHA665752, an alternative c-Met inhibitor, on the radiosensitivity of CRC and xenografts. Their findings indicate that c-Met inhibitors not only promote the formation of DNA double-strand breaks but also alleviate tumor hypoxia, rendering CRC cells more responsive to radiation. This discovery provides new insights and approaches for radiotherapy in CRC. As research progresses and clinical data accumulates, we can expect the emergence of more innovative c-Met inhibitors in the future.

Anti-HGF monoclonal antibodies

Among the numerous drugs targeting CRC, anti-HGF monoclonal antibodies have garnered significant attention. In this category, AMG-102 (rilotumumab), a humanized IgG2 mAb, has emerged as a notable candidate. It specifically targets HGF and effectively inhibits its interaction with c-Met, thereby restraining tumor growth and dissemination[101,102]. In recent investigations, it has been demonstrated through randomized clinical trials that the amalgamation of panitumumab with either rilotumumab or placebo yields substantial clinical efficacy in the treatment of advanced CRC patients harboring wild-type KRAS. However, despite encouraging initial results, there is currently no further evidence suggesting rilotumumab’s efficacy in treating advanced CRC. To fully leverage the therapeutic potential of rilotumumab, future studies need to more precisely select tumors with c-Met positivity, evaluating the efficacy of rilotumumab separately in both wild-type and mutant KRAS tumors. This approach will enhance our precision in comprehending the drug's indications and therapeutic effectiveness, thereby furnishing robust evidence for its extensive application in the treatment of CRC[103].

Anti-c-Met monoclonal antibodies

MetMAb, also known by its generic name onartuzumab (Eli Lilly, IN 46285, United States), is a humanized monovalent anti-c-Met antibody currently under clinical evaluation for CRC[104,105]. This agent blocks the HGF-c-Met interaction, inhibits ligand-induced c-Met dimerization and intracellular domain activation, and thereby suppresses c-Met/HGF-driven tumor growth in xenograft models[106,107]. Preclinical data further show triple blockade of c-Met, EGFR and VEGF, achieved by combining onartuzumab with EGFR or VEGF antagonists, yields greater anti-tumor efficacy than dual-drug combinations[108]. Notably, the antibody also demonstrated promising activity in orthotopic glioblastoma mouse models, including near-complete tumor growth inhibition[109].

Despite these preclinical successes, onartuzumab (MetMAb) failed to meet primary endpoints of progression-free survival and overall survival in a phase III trial for c-Met-positive metastatic CRC[104,105]. Post-hoc analyses identified two key CRC-specific resistance mechanisms underlying this failure, supported by clinical and preclinical evidence. First, bypass signaling activation emerged as a major barrier. Among patients with progressive disease (PD), 38% showed enhanced activation of alternative RTKs that converge on c-Met downstream cascades, particularly EGFR, VEGF receptor 2 (VEGFR2) and IGF-1R[104]. Immunohistochemical analysis of post-treatment tumor biopsies revealed a 2.1-fold increase in EGFR phosphorylation at Tyr-1068 (a critical activation site) vs baseline, sustaining RAS/MAPK signaling despite c-Met blockade[50,104]. Concurrently, 27% of PD patients had a median 45% rise in plasma VEGF levels; this elevated VEGF activated VEGFR2-PLCγ-PKC signaling to phosphorylate and stabilize Gab1, a key c-Met effector, restoring PI3K/AKT activity[67,104]. IGF-1R activation, observed in 19% of PD patients, further compensated for c-Met inhibition by activating mammalian target of rapamycin signaling, a core mediator of CRC cell proliferation[76]. Second, the TME adaptation exacerbated resistance. Patients with pre-treatment plasma HGF levels > 800 pg/mL had a 62% lower objective response rate and 3.4-month shorter progression-free survival than those with levels < 400 pg/mL[49,104]. Onartuzumab’s monovalent design prevents free HGF sequestration, and cancer-associated fibroblasts, primary sources of paracrine HGF in CRC TME, continued secreting HGF at concentrations > 1200 pg/mL during treatment. In vitro studies confirmed cancer-associated fibroblast-conditioned media abrogated the antibody’s inhibitory effects on CRC cell lines (LoVo, HCT116), restoring c-Met phosphorylation and cell migration[49,104]. Additionally, tumor-associated macrophages in CRC TME secreted interleukin-6, which upregulated c-Met expression by 1.8-fold in tumor cells via signal transducer and activator of transcription 3 activation[81]. This stromal-driven c-Met overexpression exceeded onartuzumab’s binding capacity: 71% of post-treatment biopsies from patients with high TAM infiltration (CD68+ cells > 15 per high-power field) still showed detectable c-Met expression[104].

Collectively, these findings highlight critical translational implications. Future trials of c-Met-targeted agents should use multi-biomarker panels, incorporating c-Met expression, plasma HGF levels and RTK activation status for patient stratification, as single biomarkers fail to predict response[104]. Preclinical studies show combining onartuzumab with EGFR inhibitors (cetuximab) or VEGFR2 inhibitors (bevacizumab) reduces resistance rates by 50% in CRC xenografts[108], supporting clinical evaluation of such combinations. Furthermore, next-generation anti-c-Met agents with bivalent HGF-neutralizing capacity (aminobenzotriazole-700) or bispecific designs (targeting c-Met and EGFR) may overcome TME-mediated resistance by sequestering free HGF and blocking parallel RTK signaling[110].

TKIs

Tyrosine kinase inhibitors (TKIs) exert their anti-tumor effects by preventing receptor autophosphorylation and recruiting downstream effectors. The evolution of TKIs takes varied trajectories, with certain agents distinctly honing in on the c-Met receptor, while others concentrate on pathways orchestrated by alternative growth factors like VEGFR, platelet-derived growth factor receptors, among others. Preclinical investigations have substantiated the capacity for selective inhibition of tumor growth, migration, and survival by TKIs in diverse models.

Regorafenib, classified as a multikinase inhibitor, strategically targets a spectrum of RTKs implicated in angiogenesis, metastasis, tumorigenesis, and tumor immunity[111]. Its current approval for treating refractory mCRC patients signifies a pivotal stride in therapeutic advancements[112,113]. Notably, when used in combination with immunotherapeutic agents, its inhibitory effects on tumor growth are more pronounced than when used alone[114-116].

Sunitinib has demonstrated the capability to impede the HGF/signal transducer and activator of transcription 3/SRY-box transcription factor 13/c-Met axis, resulting in a significant reduction of SRY-box transcription factor 13-mediated migration, invasion, and metastasis in CRC[117]. In a study, the radiosensitivity of cetuximab-resistant CRC cell lines was assessed with the inclusion of sunitinib, revealing its efficacy in augmenting the sensitivity of these cell lines to radiotherapy[118]. Additionally, Delord et al[119] conducted a clinical investigation involving the combination of cabozantinib and cetuximab for the treatment of c-Met-positive mCRC. The outcomes indicated favorable tolerance to this combined therapy, with observed tumor shrinkage in a subset of patients.

Tivantinib (ARQ197) emerges as a meticulously crafted c-Met inhibitor, demonstrating high selectivity and oral availability, a non-adenosine 5’-triphosphate competitive attribute developed under the auspices of ArQule. Evident from cellular, enzymatic assays, Tivantinib exhibits marked activity against c-Met[120-122]. Phase I trials have scrutinized this drug’s impact on last-stage cancer patients, concurrently probing its potential synergy with the EGFR TKI erlotinib. Preliminary research suggests that tivantinib may be an effective agent for treating tumors associated with the microphthalmia transcription factor family[123]. In the treatment of CRC patients, tivantinib exhibits a certain level of tolerance and activity. Data suggests that whether used alone or in combination with erlotinib, tivantinib may demonstrate therapeutic effects. Presently, various phase II trials are underway, investigating the efficacy of tivantinib in combination with irinotecan and cetuximab or placebo for the treatment of advanced CRC patients with wild-type KRAS[124,125]. Notwithstanding the initial promising findings, it is imperative to acknowledge that a phase II study (NCT01075048) reported by Eng et al[124] failed to yield a substantial improvement in progression-free survival among mCRC patients subjected to the combination of tivantinib and cetuximab. This outcome aligns with the findings of Rimassa et al[125]. in liver cancer, indicating potential constraints in the application of tivantinib for CRC treatment. Robust clinical trials and in-depth research endeavors are imperative to substantiate and broaden the specific efficacy and applicability profile of tivantinib.

ADVANCEMENTS IN NON-INVASIVE MOLECULAR IMAGING FOR REAL-TIME ASSESSMENT OF C-MET ACTIVATION IN CRC

Given the active role of c-Met in tumorigenesis and malignant progression, the real-time assessment and detection of c-Met activation status are particularly crucial for targeted therapy against the c-Met/HGF pathway in CRC. This is not only instrumental in identifying patient populations who could benefit from the treatment but also in monitoring treatment response, preventing drug resistance, and assessing patient prognosis. While prevailing diagnostic approaches encompass the identification of c-Met via immunohistochemistry or fluorescence in situ hybridization, their reliance on repetitive biopsies introduces potential discomfort for patients. Hence, there exists an imperative demand for the advancement of novel, efficacious, and non-invasive detection methodologies. These innovations aim to enhance our comprehension of c-Met’s expression patterns and activation statuses, contributing to more refined diagnostic procedures in CRC.

Molecular imaging, a non-invasive approach that provides accurate and real-time in vivo information, could be a breakthrough in the diagnosis of CRC by detecting c-Met activation. Depending on the type of labeled compound, molecular imaging probes can be classified into antibody-based, peptide-based, small protein-based, and small molecule TKIs. Furthermore, based on the imaging modality, they can be divided into optical molecular probes that utilize fluorescent dyes or bioluminescent nanomaterials, single photon emission computed tomography/computed tomography and positron emission tomography radionuclide molecular probes that rely on radionuclide tracing, and magnetic resonance molecular imaging probes labeled with magnetic resonance tracers[126].

Over the past two decades, several mAbs targeting the c-Met/HGF signaling pathway, including rilotumumab, ficlatuzumab, and onartuzumab, have undergone thorough investigations in both preclinical and clinical trials. Hay et al[127] conducted preliminary work on a radiolabeled tracer mixture based on mAb for molecular imaging of c-Met. The radiolabeled mAb mixture (¹²⁵I-MetMAb) comprised anti-c-Met mAb and anti-HGF mAb, allowing for both direct and indirect targeting of tumor cells through binding to c-Met and HGF, respectively. The radiolabeling efficiency of the two antibodies in the synthesized ¹²⁵I-MetMAb mixture were greater than 60% and 85%, respectively. Burggraaf et al[128] were the first to develop a fluorescent probe, GE-137-Cy5.5-1, for optical imaging of c-Met by conjugating the c-Met-targeted peptide GE-137, composed of 26 amino acids, with the cyanine dye Cy5.5. Following intravenous injection of GE-137, accumulation of this optical probe was observed in the tumor sites of c-Met-positive tumor mice. This peptide exhibited strong affinity (Kd = 2 nM) and good biosafety compared to other peptides. Furthermore, this probe was the first fluorescent probe to be used in the diagnosis of colonic adenomas, which are precursor lesions of CRC in humans. Despite the limited patient enrollment in this study, it transcended the constraints associated with the introduction of fluorescent molecular probes into clinical practice, thereby showcasing additional prospects for clinical applications. Additionally, Esfahani et al[129] labeled GE137 with Cy5.5 to create the fluorescent probe GE137-Cy5.5-2 for assessing liver metastases in human HCC and mCRC. In mouse models of orthotopic HCC and mCRC, fluorescent imaging at different time points after probe injection was used to observe differences in probe accumulation. The results showed that approximately 81% of CRC exhibited c-Met expression. Compared to the control group with prostate cancer, the positive group exhibited higher fluorescence signal intensity, which was positively correlated with c-Met expression levels. When this optical probe was co-injected with unlabeled peptides into model mice, minimal fluorescence signal uptake was observed in the tumor sites at different time points, indicating that the unlabeled peptides blocked the binding of the fluorescent probe to the tumor, suggesting specific uptake of the probe by the tumor.

THE IMPACT OF C-MET ON TREATMENT RESISTANCE IN CRC TREATMENT

Currently, the primary therapeutic approach for mCRC patients involves a combination of chemotherapy and targeted treatments. Specifically, the use of mAbs such as cetuximab or panitumumab to target EGFR has demonstrated clinical benefits in a substantial number of cancer patients with wild-type RAS, effectively decelerating tumor growth[130,131]. However, it is noteworthy that initially responsive tumors to this treatment eventually develop resistance. The development of this resistance may be linked to selective genetic changes in specific subclones, causing tumors to grow independently of EGFR. This includes oncogenic mutations in KRAS, neuroblastoma rat sarcoma virus, and BRAF, or mutations in the extracellular domain of EGFR[132,133]. Additionally, mutations or amplifications in human EGFR 2 and c-Met are also considered crucial factors contributing to resistance[134,135].

Beyond the intrinsic genetic factors mentioned above, signals released by the TME may crucially contribute to the development of primary or acquired resistance[136,137]. Especially in mCRC, blocking EGFR requires precise targeting of non-mutated physiological signaling pathways that tumor cells evidently depend on, known as “non-oncogene addiction”. However, this blocking strategy may be bypassed due to the enhanced activity of parallel growth factor signaling pathways to EGFR. Multiple lines of evidence indicate that the c-Met signal serves as a significant bypass, capable of inducing therapeutic resistance (Figure 6). Illustratively, murine studies have substantiated that both c-Met and EGFR signals actively contribute to adenoma formation in vivo, exhibiting mutually substitutable roles in fostering the growth and differentiation of intestinal stem cells into micro-organoids, observed in both normal and tumor-bearing murine models.

Figure 6 Schematic of epidermal growth factor receptor/cellular-mesenchymal epithelial transition factor axis in colorectal cancer treatment resistance. EGFR: Epidermal growth factor receptor; c-Met: Cellular-mesenchymal epithelial transition factor; RAS: Rat sarcoma; RAF: Rapidly accelerated fibrosarcoma; MAPK: Mitogen-activated protein kinases.

In summary, during the treatment of mCRC, strategies directed at the inhibition of EGFR may confront interference from the c-Met signaling pathway, contributing to the emergence of treatment resistance. Consequently, forthcoming research endeavors should prioritize investigating approaches that concurrently suppress both the EGFR and c-Met signaling pathways, aiming to augment the therapeutic effectiveness of mCRC.

CONCLUSION

The c-Met/HGF pathway is a pivotal therapeutic target and a central driver of CRC progression and treatment resistance. While traditional small-molecule inhibitors and monoclonal antibodies have shown promise in suppressing tumor growth and overcoming EGFR-targeted therapy resistance, rigorous clinical validation remains essential. Recent breakthroughs, including c-Met proteolysis targeting chimeras and bispecific antibody-drug conjugates, offer innovative ways to address bypass resistance through irreversible degradation and dual-pathway blockade.

To manage the inherent complexity of the tumor microenvironment, future research should prioritize combinatorial strategies, such as pairing c-Met inhibitors with immune checkpoint inhibitors or epigenetic regulators to modulate anti-tumor immunity and rewire transcriptional programs. A critical actionable step involves developing a multi-biomarker “c-Met gene signature” (incorporating c-Met, PD-L1, MACC1, and IL-6R) to refine patient stratification and guide personalized therapy. Complementing these therapeutic advances, non-invasive molecular imaging facilitates real-time assessment of c-Met activation, enabling treatment monitoring and early detection. Despite persistent challenges regarding acquired resistance and heterogeneous responses, deciphering the c-Met/HGF network provides a foundational framework for precise, biomarker-driven management of the global CRC burden.