Abstract
Colorectal carcinoma (CRC) stands as a pressing global health issue, marked by the unbridled proliferation of immature cells influenced by multifaceted internal and external factors. Numerous studies have explored the intricate mechanisms of tumorigenesis in CRC, with a primary emphasis on signaling pathways, particularly those associated with growth factors and chemokines. However, the sheer diversity of molecular targets introduces complexity into the selection of targeted therapies, posing a significant challenge in achieving treatment precision. The quest for an effective CRC treatment is further complicated by the absence of pathological insights into the mutations or alterations occurring in tumor cells. This study reveals the transfer of signaling from the cell membrane to the nucleus, unveiling recent advancements in this crucial cellular process. By shedding light on this novel dimension, the research enhances our understanding of the molecular intricacies underlying CRC, providing a potential avenue for breakthroughs in targeted therapeutic strategies. In addition, the study comprehensively outlines the potential immune responses incited by the aberrant activation of signaling pathways, with a specific focus on immune cells, cytokines, and their collective impact on the dynamic landscape of drug development. This research not only contributes significantly to advancing CRC treatment and molecular medicine but also lays the groundwork for future breakthroughs and clinical trials, fostering optimism for improved outcomes and refined approaches in combating colorectal carcinoma.
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Introduction
Colorectal carcinoma stands as a prominent contributor to cancer-related mortality on a global scale, and its intricate pathogenesis involves a multifaceted interplay of various factors. Genetic mutations, dysregulated signaling pathways, and compromised immune surveillance collectively contribute to the development and progression of this malignancy [1,2,3]. Many signaling pathways have been involved in the pathogenesis of colorectal carcinoma, that is so complex to understand the mechanisms. For example, the EGFR-mediated signaling pathway plays a crucial role in tumor cell proliferation, that influences cellular activities, such as nuclear transcription and mitochondrial metabolism [4,5,6]. In addition, hyperactivation of the Wnt signaling pathway is observed in most CRC cases. Approximately 85% of these cases exhibit loss of APC function, leading to destabilization of free β-catenin [7]. CXCLs and their cognate receptors are also implicated in mediating tumor growth and metastasis [8]. Notch, typically involved in maintaining progenitor/stem cell populations, is found to be constitutively activated in colon cancers [9]. Additionally, the transcription factor STAT3 plays a significant role in forming the tumor microenvironment [10]. Transmembrane receptors, such as JMJD6 and AXL, are associated with the proliferation and motility of tumor cells [11, 12]. So many signaling pathways have confused clinicians and physicians, that commanded a brief review about this.
Various agents targeting these molecules have been developed, including traditional Chinese medicines and small molecule inhibitors, with clinical trials underway to evaluate their efficacy. The heterogeneity of CRC broadens the scope for drug development, though it complicates the selection of the appropriate therapy. Organoids, derived from human induced pluripotent stem cells (iPSCs) or human embryonic stem cells (hESCs), has been considered as a good tool for drug screening in colorectal carcinoma patients recently [13]. However, In the quest for personalized treatment, cost-effectiveness analysis is emerging as a crucial facet, optimizing therapy selection for individual patients [14, 15]. As clinical trials progress and our understanding deepens, the intricate interplay of molecular pathways in CRC becomes increasingly discernible, paving the way for refined, tailored interventions and fostering hope for improved outcomes in the battle against colorectal carcinoma.
Current standard treatment
The pivotal role of effective first-line therapy in determining colorectal carcinoma (CRC) outcomes cannot be overstated, as clinicians navigate through a myriad of factors that shape their choices in clinical decision-making. The location of the tumor within the colorectum emerges as a crucial factor influencing therapeutic decisions [16,17,18,19]. Notably, patients with left-sided tumors stand to gain significant benefits from certain treatment modalities. This observation underscores the importance of tailoring therapies based on tumor location to optimize outcomes. Conversely, the scenario differs for patients with right-sided tumors, where the efficacy of initial epidermal growth factor receptor (EGFR)-based therapy may be limited. Beyond the initial response rate, the benefits of such therapies may not be as pronounced in this subgroup of patients. This nuanced understanding of the varying responses based on tumor location adds a layer of complexity to the selection of first-line therapies for CRC. It emphasizes the need for personalized treatment strategies that consider the specific characteristics of the tumor, ultimately aiming to maximize the effectiveness of therapeutic interventions and improve overall outcomes for individuals facing colorectal carcinoma. A worse prognosis for OS, PFS, and ORR has been observed in patients with right-sided tumor compared with those with left-sided tumor. The determination of second-line treatment hinges on the outcomes and responses observed during the administration of first-line systemic therapies, a pivotal step in the sequential management of colorectal carcinoma. Notably, anti-angiogenic agents, such as bevacizumab, emerge as frequently employed components in the second-line treatment regimen [20]. These agents, designed to inhibit angiogenesis and disrupt the tumor's blood supply, play a crucial role in extending the spectrum of therapeutic options available for patients post-first-line intervention. The utilization of anti-angiogenic agents underscores the strategic consideration of targeted therapies that address specific aspects of tumor progression, contributing to a comprehensive and personalized approach in the ongoing battle against colorectal carcinoma. The selection and customization of third-line treatments are intricately tied to the identification of specific molecular markers, thereby tailoring therapeutic approaches to the unique characteristics of the colorectal carcinoma (CRC). In cases where CRC exhibits a wild-type RAS status, the emphasis is often on utilizing kinase inhibitors designed to target and modulate specific molecular pathways associated with tumor progression [21]. This tailored strategy acknowledges the importance of aligning treatment with the molecular profile of the tumor, optimizing the chances of therapeutic success. Furthermore, in CRC cases characterized by high microsatellite instability (MSI), third-line interventions often incorporate immunotherapy as a key component. Agents such as pembrolizumab, nivolumab, or ipilimumab, known for their immune checkpoint inhibitory properties, are strategically employed to leverage the body's immune system against the tumor. This personalized approach, based on the presence of specific molecular markers, not only reflects the evolving landscape of precision medicine but also underscores the importance of leveraging targeted therapies and immunomodulation for enhanced efficacy in the management of advanced colorectal carcinoma.
The therapeutic landscape for metastatic colorectal carcinoma (mCRC) has evolved, and in 2004, a notable recommendation emerged for the management of mCRC resistant to irinotecan-based therapy. Specifically, the combination of an epidermal growth factor receptor (EGFR) antibody with irinotecan was endorsed as a strategic intervention for cases where the tumor expresses EGFR. This combination therapy represented a significant advancement, introducing a targeted approach to address resistance issues observed with irinotecan-based regimens [22]. The landscape of metastatic colorectal carcinoma (mCRC) witnessed a significant development in 2006 with the approval of panitumumab, a fully human IgG2 monoclonal antibody, for third-line treatment in cases where the tumor expresses epidermal growth factor receptor (EGFR) [23]. This milestone marked a substantial stride in the quest for effective and targeted therapies tailored to the molecular characteristics of mCRC. Panitumumab might offer a more effective long-term treatment option for mCRC patients compared to cetuximab [24, 25]. Unfortunately, intrinsic and extrinsic resistance limits its use in colorectal cancer. Various strategies, including new EGFR-targeted inhibitors, combination therapies, novel cytotoxic drugs, and metabolic regulators, have been employed to overcome this resistance [26]. Bevacizumab, a humanized anti-VEGF monoclonal antibody, demonstrated promising preclinical and clinical efficacy against CRC, especially when combined with chemotherapy, leading to its approval in 2004 [27]. To counter the resistance of bevacizumab, targeting tumor cell-derived CCL2, a candidate gene involved in ETV5 + colorectal cancer, has been identified. The combination of bevacizumab with an anti-CCL2 antibody has shown a synergistic effect in inhibiting tumor growth and angiogenesis [28].
The effectiveness of EGFR (epidermal growth factor receptor) and VEGFR (vascular endothelial growth factor receptor) inhibitors faces limitations in KRAS wild-type colorectal carcinoma (CRC). In cases where the KRAS gene is wild-type, the use of inhibitors targeting EGFR and VEGFR pathways has demonstrated a certain level of efficacy. However, it is essential to acknowledge that neither cetuximab (an EGFR inhibitor) nor bevacizumab (a VEGFR inhibitor) has exhibited superior efficacy in the context of first-line treatment among patients with KRAS-mutated metastatic colorectal carcinoma (mCRC) [29], while combinations such as EGFR inhibitors with PARP, which is a family of proteins involved in a number of cellular process, such as DNA repair and genomic stability, inhibitors (olaparib) have effectively curbed tumor growth in KRAS-mutant cancer cell-derived xenograft models [30]. Vigilant consideration of adverse effects is paramount in the comprehensive evaluation of treatment options for colorectal carcinoma. Notably, the combination of XELIRI (capecitabine plus irinotecan) with bevacizumab, a regimen that has demonstrated promising response rates, demands careful attention due to the prevalence of certain side effects, most notably neutropenia, in patients undergoing this treatment [31]. Clinical evidence has demonstrated that pegfilgrastim plays a pivotal role in diminishing the incidence of grade 3/4 febrile neutropenia (FN). Pegfilgrastim, a form of granulocyte colony-stimulating factor (G-CSF), stands out as a proactive therapeutic intervention designed to address the heightened risk of FN, particularly in individuals undergoing treatments associated with a high risk of neutropenia. [32].
EGFR mediated signaling transduction
Aberrant activation of the epidermal growth factor receptor (EGFR), characterized by dysregulated cascade reactions, plays a pivotal role in the uncontrolled formation of tumor masses and the release of cytokines. This aberration in EGFR signaling pathways provides a crucial window of opportunity for disease control, making EGFR antibodies a cornerstone in the standard therapy for colorectal carcinoma (CRC) patients. However, the persistent challenge of resistance has restricted the widespread application of EGFR antibodies over the years. In response to resistance mechanisms, a paradigm shift in therapeutic strategies has been witnessed. The introduction of ATP-competitive and covalent binding inhibitors is aimed at targeting downstream molecules within the intricate signaling network, including RAS-RAF-MEK-ERK and PI3K-AKT-mTOR pathways. By addressing these downstream components, therapeutic interventions seek to overcome resistance and re-establish control over the tumor's growth and survival mechanisms. Understanding the intricate biological effects of these pathways assumes considerable significance in the quest to enhance the efficacy of clinical treatment for CRC. Insights into the crosstalk and interplay within these signaling cascades provide a foundation for develo** targeted therapies that can navigate around resistance mechanisms. This elucidation becomes a cornerstone in refining treatment strategies, offering the potential for more effective interventions and improved outcomes in the dynamic landscape of colorectal carcinoma management.
RAS-RAF-MEK-ERK implications in colon cancer
The downstream signaling pathway, RAS-RAF-MEK-ERK, constitutes a crucial component of the extensive serine-threonine kinase family, exerting profound influence on various aspects of cellular behavior. This intricate cascade plays a multifaceted role in key cellular processes, including cell proliferation, metastasis, angiogenesis, and extracellular matrix degradation [33]. EGFR, also known as ERBB, a glycoprotein with intracellular tyrosine kinase and extracellular protein ligands, but the ERBB receptors are subfamily of four tyrosine kinase receptors including EGFR, HER2/neu, HER3, and HER4 (https://www.ncbi.nlm.nih.gov/books/NBK482459/). Upon the binding of epidermal growth factor (EGF) to the epidermal growth factor receptor (EGFR), a cascade of molecular events is initiated at the membrane's inner face. This intricate process involves the recruitment of growth-factor-receptor bound protein 2 (GRB2) and son of sevenless (SOS) to the membrane, marking a critical step in the activation of the GTP-binding protein RAS. This molecular signaling pathway plays a pivotal role in transducing extracellular signals into the cell, ultimately influencing key cellular processes. In recent years, there has been a substantial expansion in our understanding of the intricacies of this signaling pathway, particularly in the context of colorectal carcinoma (CRC). The molecular events triggered by EGFR activation and the subsequent activation of RAS have been scrutinized with increased precision. This heightened comprehension extends beyond the basic mechanics of the pathway and delves into the specific alterations and dysregulations that characterize colorectal cancer [34]. Aberrant activations within cellular signaling pathways have been identified as key contributors to pathological conditions, and this includes dysregulation in the epidermal growth factor receptor (EGFR), RAS, and BRAF. The intricate interplay of these components often leads to abnormal signaling cascades within the cell. In particular, the downstream effector, extracellular signal-regulated kinase (ERK), has been implicated in aberrant activation, representing a significant facet of these perturbed signaling pathways [35]. The influence of aberrant activations, including EGFR, RAS, and BRAF, extends beyond the initial signaling events to impact downstream molecules crucial for cellular regulation. Notably, downstream effectors such as cyclin D1, MMP1, P53, and c-MYC are intricately influenced by these dysregulated signaling pathways [36].
Mutations in the RAS gene family, encompassing KRAS, HRAS, and NRAS, represent a prevalent genetic alteration in colorectal carcinoma (CRC). Among these, KRAS mutations are particularly noteworthy, being identified in over 30% of CRC patients. Within KRAS mutations, there is a notable association with malignancy development, especially when occurring in codon 12 [37]. Another noteworthy mutation in colorectal carcinoma (CRC) involves the BRAF gene, which serves as a downstream molecule in the RAS signaling pathway. The mutation in BRAF represents a significant alteration and is among the most prevalent mutations observed in CRC [38]. While RAF is recruited by activated RAS, the activation mechanism of BRAF differs significantly, primarily taking place through a distinctive process involving dimerization with various forms of RAF. Unlike the straightforward activation process seen in other RAF family members, BRAF activation is intricately linked to the formation of dimers, representing a unique regulatory mechanism within the RAS-RAF-MEK-ERK signaling pathway [39]. MEK and ERK, downstream of RAF, are activated by RAF through phosphorylation, leading to the activation of ERK, mitogen-activated protein kinase (MAPK). Activated ERK regulates gene expression in the nucleus with the aid of transcription factors, including c-FOS, c-JUN, S6, and others. The signaling transduction is more complex than described, involving intricate pathways like MAPK, which includes ERK1/2, JNK, and P38. The function of c-FOS can be regulated by both JNK and ERK, occasionally by H-RAS [40].
Despite the development of EGFR antibodies, such as cetuximab and panitumumab, as targeted therapies for colorectal carcinoma (CRC), the clinical outcomes have presented challenges. The disease has shown progression in over 50% of patients treated with these EGFR antibodies, indicating the complexity of overcoming resistance mechanisms in CRC. KRAS mutations, found in 40–50% of patients, unsurprisingly diminished cetuximab's efficacy [41, 42]. RAS, a GTP-binding protein, has long presented a formidable challenge in therapeutic targeting due to its elusive nature. Despite extensive efforts, identifying effective targets for RAS inhibition has proven to be a complex task. However, recent advancements have seen the development of several inhibitors specifically designed to target a distinct mutation within the KRAS gene known as KRASG12C. The synergistic potential of combining anti-BRAF and anti-EGFR therapies has demonstrated noteworthy effectiveness in the management of metastatic colorectal carcinoma (mCRC) patients harboring the BRAFV600E mutation, particularly those who have undergone prior treatment with an anti-EGFR inhibitor [43]. Encorafenib combined with cetuximab is reported as the new standard care for BRAFV600E mCRC [44, 45]. Adding an MEK inhibitor to this regimen does not extend survival but increases the objective response rate (ORR) and toxicity. A recent study reveals that a chimeric receptor, CD16-158-valine on T cells, overcomes cetuximab resistance in KRAS mutant CRC, which indicates a new direction of CRC treatment, the combination of immune and molecule targets [46]. Other clinical trials have been summarized (Fig. 1), that phase 3 clinical trials have been activated in RAS inhibitors while those has been terminated in MEK and RAF inhibitors. Clinical trials in ERK inhibitors have limited in phase 1 clinical trials, which verified the safety but command much attentions.
Clinical information of inhibitors targeting CXCL/Notch involved signaling transduction. The information is limited in colon cancer
PI3K-AKT-mTOR is involved in tumor cell growth, proliferation, and differentiation
PI3K/Akt/mTOR, are crucial kinases that control essential functions of cells. Various biological molecules, such as epidermal growth factors, sonic hedgehog, IGF-1, insulin, and calmodulin, activate this signaling pathway. Other molecules antagonize this pathway, including phosphatase and tensin homolog (PTEN), glycogen synthase kinase 3β, and transcription factor HB9 [125], additional chemokines such as CXCL14, CXCL3, and CXCL12 serve as predictive factors [126,127,128]. In CRC metastasis, two distinct CXCL12 pathways are identified: CXCL12-CXCR4 and CXCL12-CXCR7 axes, with CXCL directly influencing metastasis through the Wnt-β-catenin signaling pathway [129].
Targeting CXCR, specifically the frizzled transmembrane Ca2 + signaling pathway, demonstrates significant potential in CRC treatment, encompassing CCR1, CCR5, and CXCR2 (Fig. 4). CCR1 antagonists curb CRC progression by targeting CCR1-expressing myeloid cells [130]. CCR5 shows high expression in both primary and liver metastatic masses, associated with a reduced cytotoxic/regulatory T cell ratio and diminished M2 macrophage polarization [131]. Maraviroc, a CCR5 inhibitor, curtails T cell recruitment to colorectal carcinoma and hinders liver metastasis in advanced refractory CRC [132, 133]. The safety and efficacy of pembrolizumab and maraviroc have been explored in phase 1 clinical trial (NCT03274804) [134]. A phase 2 clinical trial is investigating the combination effects of Navarixin, a CXCL1/2 inhibitor, with pembrolizumab in advanced microsatellite CRC (NCT03473925) [135]. Although many targeted inhibitors are used for treating hematological diseases, no CCR or CXCL inhibitors have been have been approved by FDA yet.
Clinical information of inhibitors targeting MAPK signaling pathway. The information is limited in colon cancer
Notch-related cell–cell contacts and signaling pathways
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