Colorectal Cancer Therapy Research Articles

Mapping alternative splicing events in colorectal cancer

Although aberrant splicing events of genes are closely related to the development and progression of colorectal cancer (CRC), the mapping of abnormal splicing events, especially alternative splicing (AS) event types and the underlying effects, remain investigational. In the present study, we analyzed a public RNA-seq database (GSE138202) and identified 14,314 significant AS events in CRC patients compared to healthy individuals. Most of the key genes such as oncogenes involved in the development of CRC have different AS event types. Moreover, the results demonstrate that certain AS events may play a significant role in the functioning of key genes involved in splicing factors and microRNAs. Furthermore, we observed that the oncogene CDK4 in CRC tends to undergo exon 2 skipping AS events, resulting in a stronger tendency for protein expression to form complexes with CCND1, thereby inhibiting the cell cycle and weakening cell proliferation, while enhancing cell migration capability. These findings not only provide new insights into the mechanism of AS in regulating CRC, but also offers a theoretical basis for targeted splicing therapy in CRC.

Ramucirumab in second‑line advanced colorectal cancer therapy: A study on therapeutic outcomes and hepatic sinusoidal platelet aggregation.

The present study investigated the role of ramucirumab (RAM) in treating liver metastases (LMs) as a second-line or salvage treatment in patients with advanced CRC. Of the 36 patients, 21 (58%) received RAM plus folinic acid, fluorouracil and irinotecan (FOLFIRI) as second-line treatment, whereas 15 (42%) received it in a salvage setting. The median overall survival time was 23 months [95% confidence interval (CI), 12-34 months] for those in the second-line treatment group and 8 months (95% CI, 5-19 months) for those in the salvage treatment group. Of the 36 patients, 14 (39%) underwent surgical resection of LMs during chemotherapy. A total of 6 patients underwent surgical resection for LMs for the first time during second-line RAM plus FOLFIRI (RAM-LM); of the remaining 8 patients, 6 underwent resection of LMs during first-line bevacizumab (BEV)-based chemotherapy (BEV-LM). Immunohistochemical analysis of CD42b showed that the platelet aggregation score (CD42b score), which ranges from 0 (absence of deposition) to 3 (presence of linear deposition), tended to decrease with the increasing duration of treatment with both RAM and BEV. Although there was no significant difference in the mean duration of anti-VEGF antibody treatment between the BEV-LM and RAM-LM groups, the median CD42b score was higher in the RAM-LM group (median CD42b score, 3; range, 0-3) compared with that in the BEV-LM group (median CD42b score, 1; range, 0-3; P=0.01), suggesting that RAM induces a different degree of platelet aggregation in liver sinusoids compared to BEV.

Integrating UHPLC-Q-TOF-MS/MS, network pharmacology, bioinformatics and experimental validation to uncover the anti-cancer mechanisms of TiaoPi AnChang decoction in colorectal cancer

Ethnopharmacological relevanceThe TiaoPi AnChang Decoction (TPACD), a Traditional Chinese Medicine (TCM) prescription based on Xiangsha Liujunzi Decoction, has demonstrated clinical efficacy as an adjuvant therapy for colorectal cancer (CRC) patients. However, its specific ingredients and potential mechanisms of action remain unclear. Aim of the studyTo identify the primary active ingredients of TPACD, their molecular targets, and potential mechanisms underlying the efficacy of TPACD in CRC treatment. Materials and methodsThis study investigated the clinically validated TCM formula TPACD. In vitro and in vivo experiments were used to demonstrate TPACD's regulatory effects on various malignant phenotypes of tumors, providing basic research support for its anti-cancer activity. To understand its pharmacodynamic basis, we utilized ultra-high performance liquid chromatography-quadrupole-time-of-flight-mass spectrometry/mass spectrometry (UHPLC-Q-TOF-MS/MS) to analyze TPACD constituents present in the bloodstream. Network pharmacology and bioinformatics analyses were used to identify potential active components and their molecular targets for TPACD's therapeutic effects in CRC. Subsequent experiments further elucidated its pharmacological mechanism. ResultsTPACD inhibits various malignant cellular processes, such as cell proliferation, apoptosis, migration, and invasion, and has shown potential anti-CRC activities both in vitro and in vivo. Following the identification of 109 constituents absorbed into the blood from TPACD, network pharmacology analysis predicted 42 potential anti-CRC targets. Clinical analyses highlighted three genes as prognostic key genes of TPACD's therapeutic action: C-X-C motif chemokine ligand 8 (CXCL8), fatty acid binding protein 4 (FABP4), and matrix metallopeptidase 3 (MMP3). Drug sensitivity analyses, molecular docking simulations and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) identified MMP3 as the most promising target for TPACD's anti-CRC action. Enzyme activity assays confirmed that TPACD inhibits MMP3 enzyme activity. Surface plasmon resonance (SPR) characterized the binding affinity between MMP3 and effective active components of TPACD, including luteolin, quercetin, kaempferol, and liensinine. ConclusionsTPACD exhibits anti-CRC activity in vitro and in vivo, with MMP3 identified as a critical target. The active compounds, including luteolin, quercetin, kaempferol, and liensinine, absorbed into the bloodstream, contribute to TPACD's efficacy by targeting MMP3.

Characterization and optimization of colon specific nanosponges immobilized polymeric microbeads formulation for the combined delivery of 5-fluorouracil and curcumin

Introductionand purpose: Site-specific delivery systems are highly advantageous for local cancer treatment as they allow a more significant delivery of the drug to the tumor with minimal systemic side effects. Furthermore, combination therapy is a promising approach that attracts more attention in cancer treatment due to its synergistic effects. In this work, nanosponges immobilized polymeric microbeads for colon-specific delivery systems were developed for a drug combination of 5-fluorouracil and curcumin to treat colorectal cancer. MethodsSodium alginate and low molecular chitosan polymers were used to create microbead-based formulations containing curcumin-encapsulated nanosponges and 5-fluorouracil. To improve curcumin's low solubility, Diphynylacarbonate (DPC) hyper cross-linking of β-CD was used to create curcumin-loaded β-CD nanosponges that further incorporated in the polymeric microbeads along with free 5-fluorouracil. ResultsThe optimized microbeads were spherical with a mean particle size of 1.1 ± 0.05 mm. The produced beads were subsequently coated with a multilayer coating of ethyl cellulose and Eudragit S100 polymers, which functioned as pH-dependent and time-dependent coatings to ensure drug delivery to the colon. The developed formulation (Coated MB5) showed controlled release of the drug and sustained cytotoxic effect. The release profiles of 5-fluorouracil and curcumin from Coated MB5 were best described by zero-order followed by first-order release functions. About 66.4 % of 5-FU and 73.1 % of curcumin were released for 24 h. In vivo roentgenographic evaluation in a rabbit model indicated that the optimized coated microbeads successfully reached the colon 7–9 h after administration. ConclusionsAs a prospective colon-specific drug delivery system, a successful formulation (Coated MB5) was developed for the combined delivery of 5-fluorouracil and curcumin. More in vivo studies are needed to demonstrate the therapeutic efficacy of optimized formulations and their potential to improve colorectal cancer therapy by providing a more targeted administration of combination medicines with fewer undesirable side effects.

Inhibition of DUSP18 impairs cholesterol biosynthesis and promotes anti-tumor immunity in colorectal cancer

Tumor cells reprogram their metabolism to produce specialized metabolites that both fuel their own growth and license tumor immune evasion. However, the relationships between these functions remain poorly understood. Here, we report CRISPR screens in a mouse model of colo-rectal cancer (CRC) that implicates the dual specificity phosphatase 18 (DUSP18) in the establishment of tumor-directed immune evasion. Dusp18 inhibition reduces CRC growth rates, which correlate with high levels of CD8+ T cell activation. Mechanistically, DUSP18 dephosphorylates and stabilizes the USF1 bHLH-ZIP transcription factor. In turn, USF1 induces the SREBF2 gene, which allows cells to accumulate the cholesterol biosynthesis intermediate lanosterol and release it into the tumor microenvironment (TME). There, lanosterol uptake by CD8+ T cells suppresses the mevalonate pathway and reduces KRAS protein prenylation and function, which in turn inhibits their activation and establishes a molecular basis for tumor cell immune escape. Finally, the combination of an anti-PD-1 antibody and Lumacaftor, an FDA-approved small molecule inhibitor of DUSP18, inhibits CRC growth in mice and synergistically enhances anti-tumor immunity. Collectively, our findings support the idea that a combination of immune checkpoint and metabolic blockade represents a rationally-designed, mechanistically-based and potential therapy for CRC.

Enhancing precision in colorectal cancer surgery: development of an LGR5-targeting RSPO1 peptide mimetic as a contrast agent for intraoperative fluorescence molecular imaging

ABSTRACT Colorectal cancer (CRC) is the third most common cancer worldwide. In the United States alone, CRC was responsible for approximately 52,550 deaths in 2023, with an estimated 153,020 new cases. CRC presents with synchronous peritoneal spread in 5–10% of patients, and up to 20–50% of patients with recurrent disease will develop metachronous colorectal cancer peritoneal metastatic (CRC-PM) disease. Eradication of the tumor, tumor margins and microscopic residual disease is paramount, as microscopic residual disease is associated with local recurrences, with 5-year survival rates of less than 35%. The success of resection and reduction of residual disease depends on the accuracy with which cancer cells and normal tissue can be intra-operatively distinguished. Fluorescence Molecular Imaging (IFMI) and tumor-targeted contrast agents represent a promising approach for intraoperative detection and surgical intervention. Proper target selection, the development of scalable imaging agents and enhanced real-time tumor and tumor microenvironment imaging are critical to enabling enhanced surgical resection. LGR5 (leucine-rich repeat-containing G-protein-coupled receptor 5), a colonic crypt stem cell marker and the receptor for the R-spondins (RSPO) in the Wnt signaling pathway, is also expressed on colorectal cancer stem cells (CSC) and on CRC tumors and metastases, suggesting it could be a useful target for imaging of CRC. However, there are numerous diverging reports on the role of LGR5 in CRC therapy and outcomes. Herein, we report on the synthesis and validation of a 37 amino acid RSPO1-mimetic peptide, termed RC18, that was specifically designed to access the R-spondin binding site of LGR5 to potentially be used for interoperative imaging of CRC-PM. The receptor-binding capabilities of the RC18 indicate that direct interactions with LGR5 neither significantly increased LGR5 signaling nor blocked RSPO1 binding and signal transduction, suggesting that the RSPO1-mimetic is functionally inert, making it an attractive contrast agent for intraoperative CRC-PM imaging.

Repurposing cyclovirobuxine D as a novel inhibitor of colorectal cancer progression via modulating the CCT3/YAP axis.

Colorectal cancer (CRC) ranks second in mortality worldwide and requires effective and affordable remedies. Cyclovirobuxine D (CVB-D) is the main effective component of Huangyangning tablet, an approved traditional patent medicine, which is mainly used for cardiovascular treatment. As a multibioactive natural compound, CVB-D possesses underlying anticancer activities. Cell viability and clone-forming ability were determined in human CRC lines. Western blot, immunofluorescence assay, transmission electron microscopy and senescence-associated β-galactosidase (SA-β-Gal) staining were utilized to investigate cell autophagy and senescence. The molecular mechanisms were explored by virtual prediction and experimental validation. Patient-derived xenograft (PDX), dextran sulfate sodium salt (DSS), and azomethane (AOM)/DSS mouse models were employed for in vivo studies. CVB-D inhibited the growth and development of advanced CRC cells / mice by inducing autophagic and senescent activities through the chaperonin containing TCP1 subunit 3 (CCT3)/yes-associated protein (YAP) axis. CVB-D acted as a promising inhibitor of CCT3 by interacting with its ATP site. In PDX tumours, CVB-D showed potential therapeutic effects by targeting CCT3. Treatment with CVB-D alleviated the mouse model of colitis induced by DSS and attenuated AOM/DSS-induced formation of adenomatous polyps by its action on CCT3. Our study has provided a scientific basis for the suggestion that CVB-D may be recognized as a prospective drug candidate for the therapy of CRC in patients.

Development and Characterization of Curcumin-Loaded TPGS/F127/P123 Polymeric Micelles as a Potential Therapy for Colorectal Cancer.

Colorectal cancer (CRC) is the third most prominent cancer worldwide, and the second leading cause of cancer death. Poor outcomes and limitations of current treatments fuel the search for new therapeutic options. Curcumin (CUR) is often presented as a safer alternative for cancer treatment with a staggering number of molecular targets involved in tumor initiation, promotion, and progression. Despite being promising, its therapeutic potential is hindered due to its hydrophobic nature. Hence, the ongoing development of optimal delivery strategies based on nanotechnology, such as polymeric micelles (PMs), to overcome issues in CUR solubilization and delivery to tumor cells. In this sense, this study aimed to optimize the development and stability of CUR-loaded P123:F127:TPGS PMs (PFT:CUR) based on the thin-film approach and evaluate their therapeutic potential in CRC. Overall, the results revealed that the solubility of CUR was improved when room temperature was used to hydrate the film. The PFT-CUR hydrated at room temperature presents an average hydrodynamic diameter of 15.9 ± 0.3 nm with a polydispersity index (PDI) of 0.251 ± 0.103 and a zeta potential of -1.5 ± 1.9 mV, and a 35.083 ± 1.144 encapsulation efficiency (EE%) and 3.217 ± 0.091 drug loading (DL%) were observed. To ensure the stability of the optimized PFT-CUR nanosystems, different lyophilization protocols were tested, the use of 1% of glycine (GLY) being the most promising protocol. Regarding the critical micellar concentration (CMC), it was shown that the cryoprotectant and the lyophilization process could impact it, with an increase from 0.064 mg/mL to 0.119 mg/mL. In vitro results showed greater cytotoxic effects when CUR was encapsulated compared to its free form, yet further analysis revealed the heightened cytotoxicity could be attributed to the system itself. Despite challenges, the developed CUR-loaded PM shows potential as an effective therapeutic agent for CRC. Nonetheless, the system must undergo refinements to enhance drug entrapment as well as improve overall stability.

Curcumin-shellac nanoparticle-loaded GelMA/SilMA hydrogel for colorectal cancer therapy

In this study, a novel approach was employed to develop a therapeutic system for colorectal cancer treatment. Specifically, a GelMA/SilMA hydrogel loaded with curcumin-shellac nanoparticles (Cur@Lac NPs) was created. A microfluidic swirl mixer was utilized to formulate stable Cur@Lac NPs, ensuring their consistent and effective encapsulation. The pH-specific release of curcumin from the NPs demonstrated their potential for colon cancer treatment. By carefully regulating the ratio of GelMA (gelatin methacrylate) and SilMA (silk fibroin methacrylate), a GelMA/SilMA dual network hydrogel was generated, offering controlled release and degradation capabilities. The incorporation of SilMA notably enhanced the mechanical properties of the dual network matrix, improving compression resistance and mitigating deformation. This mechanical improvement is crucial for maintaining the structural integrity of the hydrogel during in vivo applications. In comparison to the direct incubation of curcumin, the strategy of encapsulating curcumin into NPs and embedding them within the GelMA/SilMA hydrogel resulted in more controlled release mechanisms. This controlled release was achieved through the disintegration of the NPs and the swelling and degradation of the hydrogel matrix. The encapsulating strategy also demonstrated enhanced cellular uptake of curcumin, leveraging the advantages of both NPs and in-situ hydrogel injection. This combination ensures a more efficient and sustained delivery of the therapeutic agent directly to the tumor site. Overall, this approach holds significant promise as a smart drug delivery system, potentially improving the efficacy of colorectal cancer treatments by providing targeted, controlled, and sustained drug release with enhanced mechanical stability and biocompatibility.

Adverse event costs of systemic therapies for metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy and biologics in the US.

Aim: The objective of this study was to compare adverse event (AE) management costs for fruquintinib, regorafenib, trifluridine/tipiracil (T/T) and trifluridine/tipiracil+bevacizumab (T/T+bev) for patients with metastatic colorectal cancer (mCRC) previously treated with at least two prior lines of therapy from the US commercial and Medicare payer perspectives. Materials & methods: A cost-consequence model was developed to calculate the per-patient and per-patient-per-month (PPPM) AE costs using rates of grade 3/4 AEs with incidence ≥5% in clinical trials, event-specific management costs and duration treatment. Anchored comparisons of AE costs were calculated using a difference-in-differences approach with best supportive care (BSC) as a common reference. AE rates and treatment duration were obtained from clinical trials: FRESCO and FRESCO-2 (fruquintinib), RECOURSE (T/T), CORRECT (regorafenib) and SUNLIGHT (T/T, T/T+bev). AE management costs for the commercial and Medicare perspectives were obtained from publicly available sources. Results: From the commercial perspective, the AE costs (presented as per-patient, PPPM) were: $4015, $1091 for fruquintinib (FRESCO); $4253, $1390 for fruquintinib (FRESCO-2); $17,110, $11,104 for T/T (RECOURSE); $9851, $4691 for T/T (SUNLIGHT); $8199, $4823 for regorafenib; and $11,620, $2324 for T/T+bev. These results were consistent in anchored comparisons: the difference-in-difference for fruquintinib based on FRESCO was -$1929 versus regorafenib and -$11,427 versus T/T; for fruquintinib based on FRESCO-2 was -$2257 versus regorafenib and -$11,756 versus T/T. Across all analyses, results were consistent from the Medicare perspective. Conclusion: Fruquintinib was associated with lower AE management costs compared with regorafenib, T/T and T/T+bev for patients with previously treated mCRC. This evidence has direct implications for treatment, formulary and pathways decision-making in this patient population.

Innovative Strategies to Combat 5-Fluorouracil Resistance in Colorectal Cancer: The Role of Phytochemicals and Extracellular Vesicles.

Colorectal cancer (CRC) is a significant public health challenge, with 5-fluorouracil (5-FU) resistance being a major obstacle to effective treatment. Despite advancements, resistance to 5-FU remains formidable due to complex mechanisms such as alterations in drug transport, evasion of apoptosis, dysregulation of cell cycle dynamics, tumor microenvironment (TME) interactions, and extracellular vesicle (EV)-mediated resistance pathways. Traditional chemotherapy often results in high toxicity, highlighting the need for alternative approaches with better efficacy and safety. Phytochemicals (PCs) and EVs offer promising CRC therapeutic strategies. PCs, derived from natural sources, often exhibit lower toxicity and can target multiple pathways involved in cancer progression and drug resistance. EVs can facilitate targeted drug delivery, modulate the immune response, and interact with the TME to sensitize cancer cells to treatment. However, the potential of PCs and engineered EVs in overcoming 5-FU resistance and reshaping the immunosuppressive TME in CRC remains underexplored. Addressing this gap is crucial for identifying innovative therapies with enhanced efficacy and reduced toxicities. This review explores the multifaceted mechanisms of 5-FU resistance in CRC and evaluates the synergistic effects of combining PCs with 5-FU to improve treatment efficacy while minimizing adverse effects. Additionally, it investigates engineered EVs in overcoming 5-FU resistance by serving as drug delivery vehicles and modulating the TME. By synthesizing the current knowledge and addressing research gaps, this review enhances the academic understanding of 5-FU resistance in CRC, highlighting the potential of interdisciplinary approaches involving PCs and EVs for revolutionizing CRC therapy. Further research and clinical validation are essential for translating these findings into improved patient outcomes.

The Roles of RAC1 and RAC1B in Colorectal Cancer and Their Potential Contribution to Cetuximab Resistance.

Colorectal cancer (CRC) is one of the most diagnosed cancers and a leading contributor to cancer-related deaths in the United States. Clinically, standard treatment regimens include surgery, radiation, and chemotherapy; however, there has been increasing development and clinical use of targeted therapies for CRC. Unfortunately, many patients develop resistance to these treatments. Cetuximab, the first targeted therapy approved to treat advanced CRC, is a monoclonal antibody that targets the epidermal growth factor receptor and inhibits downstream pathway activation to restrict tumor cell growth and proliferation. CRC resistance to cetuximab has been well studied, and common resistance mechanisms include constitutive signal transduction through downstream protein mutations and promotion of the epithelial-to-mesenchymal transition. While the most common resistance mechanisms are known, a proportion of patients develop resistance through unknown mechanisms. One protein predicted to contribute to therapy resistance is RAC1, a small GTPase that is involved in cytoskeleton rearrangement, cell migration, motility, and proliferation. RAC1 has also been shown to be overexpressed in CRC. Despite evidence that RAC1 and its alternative splice isoform RAC1B play important roles in CRC and the pathways known to contribute to cetuximab resistance, there is a need to directly study the relationship between RAC1 and RAC1B and cetuximab resistance. This review highlights the recent studies investigating RAC1 and RAC1B in the context of CRC and suggests that these proteins could play a role in resistance to cetuximab.

Microbial Metabolites-Induced Epigenetic Modifications for Inhibition of Colorectal Cancer: Current Status and Future Perspectives.

Globally, one of the most prevalent cancers is colorectal cancer (CRC). Chemotherapy and surgery are two common conventional CRC therapies that are frequently ineffective and have serious adverse effects. Thus, there is a need for complementary and different therapeutic approaches. The use of microbial metabolites to trigger epigenetic alterations as a way of preventing CRC is one newly emerging field of inquiry. Small chemicals called microbial metabolites, which are made by microbes and capable of altering host cell behaviour, are created. Recent research has demonstrated that these metabolites can lead to epigenetic modifications such as histone modifications, DNA methylation, and non-coding RNA regulation, which can control gene expression and affect cellular behaviour. This review highlights the current knowledge on the epigenetic modification for cancer treatment, immunomodulatory and anti-carcinogenic attributes of microbial metabolites, gut epigenetic targeting system, and the role of dietary fibre and gut microbiota in cancer treatment. It also focuses on short-chain fatty acids, especially butyrates (which are generated by microbes), and their cancer treatment perspective, challenges, and limitations, as well as state-of-the-art research on microbial metabolites-induced epigenetic changes for CRC inhibition. In conclusion, the present work highlights the potential of microbial metabolites-induced epigenetic modifications as a novel therapeutic strategy for CRC suppression and guides future research directions in this dynamic field.

Proteomic Analysis of Caco-2 Cells Disrupted by EcN 1917-Derived OMVs Reveals Molecular Information on Bacteria-Mediated Cancer Cell Migration.

Escherichia coli Nissle 1917 (EcN 1917) exhibits distinct tumor-targeting activity, and early studies demonstrated that outer membrane vesicles (OMVs) mediate bacteria-host interactions. To decipher the molecular mechanism underlying the interaction between EcN 1917 and host cells via OMV-mediated communication, we investigated the phenotypic changes in Caco-2 cells perturbed by EcN 1917-derived OMVs and constructed proteomic maps of the EcN 1917-derived OMV components and OMV-perturbed host cells. Our findings revealed that the size of the EcN 1917-derived OMV proteome increased 4-fold. Treatment with EcN 1917-derived OMVs altered the proteomic and phosphoproteomic profiles of host cells. Importantly, for the first time, we found that treatment with EcN 1917-derived OMVs inhibited cancer cell migration by suppressing the expression of ANXA9. In addition, phosphoproteomic data suggested that the ErbB pathway may be involved in OMV-mediated cell migration. Taken together, our study provides valuable data for further investigations of OMV-mediated bacteria-host interactions and offers great insights into the underlying mechanism of probiotic-assisted colorectal cancer therapy.

Overcoming the Tumor Collagen Barriers: A Multistage Drug Delivery Strategy for DDR1-Mediated Resistant Colorectal Cancer Therapy.

The extracellular matrix (ECM) is critical for drug resistance in colorectal cancer (CRC). The abundant collagen within the ECM significantly influences tumor progression and matrix-mediated drug resistance (MMDR) by binding to discoidin domain receptor 1 (DDR1), but the specific mechanisms by which tumor cells modulate ECM via DDR1 and ultimately regulate TME remain poorly understand. Furthermore, overcoming drug resistance by modulating the tumor ECM remains a challenge in CRC treatment. In this study, a novel mechanism is elucidated by which DDR1 mediates the interactions between tumor cells and collagen, enhances collagen barriers, inhibits immune infiltration, promotes drug efflux, and leads to MMDR in CRC. To address this issue, a multistage drug delivery system carrying DDR1-siRNA and chemotherapeutic agents is employed to disrupt collagen barriers by silencing DDR1 in tumor, enhancing chemotherapy drugs diffusion and facilitating immune infiltration. These findings not only revealed a novel role for collagen-rich matrix mediated by DDR1 in tumor resistance, but also introduced a promising CRC treatment strategy.

Molecular subtypes of colorectal cancer in the era of precision oncotherapy: Current inspirations and future challenges.

Colorectal cancer (CRC) is among the most hackneyed malignancies. Even patients with identical clinical symptoms and the same TNM stage still exhibit radically different clinical outcomes after receiving equivalent treatment regimens, indicating extensive heterogeneity of CRC. Myriad molecular subtypes of CRC have been exploited for decades, including the most compelling consensus molecular subtype (CMS) classification that has been broadly applied for patient stratification and biomarker-drug combination formulation. Encountering barriers to clinical translation, however, CMS classification fails to fully reflect inter- or intra-tumor heterogeneity of CRC. As a consequence, addressing heterogeneity and precisely managing CRC patients with unique characteristics remain arduous tasks for clinicians. In this review, we systematically summarize molecular subtypes of CRC and further elaborate on their clinical applications, limitations, and future orientations. In recent years, exploration of subtypes through cell lines, animal models, patient-derived xenografts (PDXs), organoids, and clinical trials contributes to refining biological insights and unraveling subtype-specific therapies in CRC. Therapeutic interventions including nanotechnology, clustered regulatory interspaced short palindromic repeat/CRISPR-associated nuclease 9 (CRISPR/Cas9), gut microbiome, and liquid biopsy are powerful tools with the possibility to shift the immunologic landscape and outlook for CRC precise medicine.

Research Advances of Lipid Nanoparticles in the Treatment of Colorectal Cancer.

Colorectal cancer (CRC) is a common type of gastrointestinal tract (GIT) cancer and poses an enormous threat to human health. Current strategies for metastatic colorectal cancer (mCRC) therapy primarily focus on chemotherapy, targeted therapy, immunotherapy, and radiotherapy; however, their adverse reactions and drug resistance limit their clinical application. Advances in nanotechnology have rendered lipid nanoparticles (LNPs) a promising nanomaterial-based drug delivery system for CRC therapy. LNPs can adapt to the biological characteristics of CRC by modifying their formulation, enabling the selective delivery of drugs to cancer tissues. They overcome the limitations of traditional therapies, such as poor water solubility, nonspecific biodistribution, and limited bioavailability. Herein, we review the composition and targeting strategies of LNPs for CRC therapy. Subsequently, the applications of these nanoparticles in CRC treatment including drug delivery, thermal therapy, and nucleic acid-based gene therapy are summarized with examples provided. The last section provides a glimpse into the advantages, current limitations, and prospects of LNPs in the treatment of CRC.

The application of graphene oxide and ferroptosis in the diagnosis and treatment of colorectal cancer: a narrative review.

Colorectal cancer (CRC), a leading global malignancy, continues to challenge the medical community. Despite advancements in surgical, chemotherapeutic, radiation, targeted, and immunotherapeutic strategies, issues like resistance and side effects persist. This review illuminates the potential of ferroptosis, an emerging non-apoptotic cell death form, and graphene oxide (GO), with its distinctive physicochemical properties, in CRC therapy. The databases search included PubMed, Medline and Web of Science. Search terms focused on CRC, graphene, GO, ferroptosis, and related aspects in therapy and drug delivery. The time frame for literature retrieval was up to April 2024. Studies in languages other than English were excluded. Ferroptosis has been recognized for its role in addressing treatment resistance, a notable hurdle in effective CRC management. This form of cell death offers a promising avenue for enhancing the effectiveness of existing treatments. However, understanding its mechanisms and clinical implications in CRC remains an area of active research, with significant progress required for its practical application. Simultaneously, GO, a versatile two-dimensional material, has demonstrated substantial potential in biomedical applications, especially in cancer therapy. Its high specific surface area and unique π-electron domains facilitate the effective binding of chemotherapy drugs, target genes, and photosensitizers. This makes GO a promising candidate in cancer diagnosis and treatment, particularly through tumor photothermal and photodynamic therapy (PDT). Despite these advancements, GO's clinical application faces challenges, including in vitro cytotoxicity and decreased biodegradability, necessitating further research. This review focuses on the characteristics of GO and ferroptosis, as well as their applications in tumor diagnosis and treatment, with a particular emphasis on their potential in CRC.

Circulating Tumor DNA Predicts Early Recurrence Following Locoregional Therapy for Oligometastatic Colorectal Cancer.

(1) Background: Local therapies offer a potentially curative approach for patients with oligometastatic colorectal cancer (CRC). An evidence-based consensus recommendation for systemic therapy following definitive locoregional therapy is lacking. Tumor-informed circulating tumor DNA (ctDNA) might provide information to help guide management in this setting. (2) Methods: A multi-institutional retrospective study was conducted, including patients with CRC that underwent curative-intent locoregional therapy to an isolated site of metastatic disease, followed by tumor-informed ctDNA assessment. The Kaplan-Meier method and log-rank tests were used to compare disease-free survival based on ctDNA results. ctDNA test performance was compared to carcinoembryonic antigen (CEA) test results using McNemar's test. (3) Results: Our study cohort consisted of 87 patients treated with locoregional interventions who underwent ctDNA testing. The initial ctDNA test post-intervention was positive in 28 patients and negative in 59 patients. The median follow-up time was 14.0 months. Detectable ctDNA post-intervention was significantly associated with early disease recurrence, with a median disease-free survival (DFS) of 6.63 months compared to 21.30 months in ctDNA-negative patients (p < 0.001). ctDNA detected a numerically higher proportion of recurrences than CEA (p < 0.097). Post-intervention systemic therapy was not associated with improved DFS (p = 0.745). (4) Conclusions: ctDNA results are prognostically important in oligometastatic CRC, and further prospective studies are urgently needed to define its role in guiding clinical decisions.

The Old: Is There Any Role for Screening Colonoscopy after the Age of 75? The Surgeon's Perspective

AbstractGuidelines recommend individualized decision making for screening colonoscopy for colorectal cancer (CRC) in patients after the age of 75 years due to low additional benefits. That should be taken with a grain of salt, as these recommendations are based on expert opinion and simulation models which do not consider (1) the differences in pathogenesis and cancer biology of CRC in elderly; (2) the risks of colonoscopy in this patient population; (3) and the impact of new surgical and nonsurgical therapies for CRC. In this review, our goal is to bring a surgeon's perspective to understand the role of screening colonoscopy in patients older than 75 years.