Colorectal cancer (CRC) represents a common type of carcinoma with significant mortality rates globally. A primary factor contributing to the unfavorable treatment outcomes and reduced survival rates in CRC patients is the occurrence of metastasis. Various intricate molecular mechanisms are implicated in the metastatic process, leading to mortality among individuals with CRC. In the realm of intercellular communication, exosomes, which are a form of extracellular vesicle (EV), play an essential role. These vesicles act as conduits for information exchange between cells and originate from multiple sources. By fostering a microenvironment conducive to CRC progression, exosomes and EVs significantly influence the advancement of the disease. They contain a diverse array of molecules, including messenger RNAs (mRNAs), non-coding RNAs (ncRNAs), proteins, lipids, and transcription factors. Notably, ncRNAs, such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are prominently featured within exosomes. These ncRNAs have the capacity to regulate various critical molecules or signaling pathways, particularly those associated with tumor metastasis, thereby playing a crucial role in tumorigenesis. Their presence indicates a substantial potential to affect vital aspects of tumor progression, including proliferation, metastasis, and resistance to treatment. This research aims to categorize exosomal ncRNAs and examine their functions in colorectal cancer. Furthermore, it investigates the clinical applicability of novel biomarkers and therapeutic strategies in CRC. Abbreviations: ncRNAs, non-coding RNAs; CRC, Colorectal cancer; EV, extracellular vesicle; mRNAs, messenger RNAs; miRNAs, microRNAs; lncRNAs, long non-coding RNAs; circRNAs, circular RNAs; HOTTIP, HOXA transcript at the distal tip; NSCLC, non-small cell lung cancer; 5-FU, 5-fluorouracil; OX, Oxaliplatin; PDCD4, programmed cell death factor 4; Tregs, regulatory T cells; EMT, epithelial-mesenchymal transition; PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3; USP2, ubiquitin carboxyl-terminal hydrolase 2; TNM, tumor node metastasis; TAMs, tumor-associated macrophages; RASA1, RAS p21 protein activator 1; PDCD4, programmed cell death 4; ZBTB2, zinc finger and BTB domain containing 2; SOCS1, suppressor of cytokine signaling 1; TUBB3, β-III tubulin; MSCs, mesenchymal stem cells.

Patient-derived organoids (PDO) have the potential to be used as preclinical cancer models for testing anti-cancer drug efficiency. Cancer-associated fibroblasts (CAFs), which have been closely linked with colorectal carcinoma (CRC) progression and drug resistance, however, are generally not included (or gradually lost during culture) in the PDO models, leading to a major limitation in this cancer model. In this study, we established a new in vitro model with CRC organoids and co-cultured with CAFs and compared it with the organoid-only model. Through testing with anti-cancer drug, we demonstrated a significant difference in drug sensitivity between the two models, and the co-culture model showed higher drug resistance. RNA and whole exome sequencing were performed to reveal gene expression profiles in organoids and organoids co-culture with CAFs to assess interactions between drug sensitivity and gene copy number variation. We found that the expression levels of several pathway protein genes, which are highly expressed in original surgical specimens of colorectal carcinomas, were downregulated in organoids but restored in organoids by co-culturing with CAFs. In summary, the PDO-CAF joint model for CRC can recapitulate a more biomimetic tumor microenvironment and the drug resistance lead by changes in multiple signaling pathways that we discovered; thus, it could be a suitable model for future usage in drug discovery and precision medicine research.

Acquired resistance poses a significant obstacle to the effectiveness of platinum-based treatment for cancers. As the most abundant antioxidant, glutathione (GSH) enables cancer cell survival and chemoresistance, by scavenging excessive reactive oxygen species (ROS) induced by platinum. Therapeutic strategy targeting GSH synthesis has been developed, however, failed to produce desirable effects in preventing cancer progression. Thus, uncovering mechanisms of rewired GSH metabolism may aid in the development of additional therapeutic strategies to overcome or delay resistance. Here, we identify upregulation of long noncoding RNA (lncRNA) GDIL (GSH Degradation Inhibiting LncRNA) in platinum resistant colorectal cancer (CRC) and ovarian cancer cells compared with parental ones. High expression of GDIL in resistant CRC is associated with poor survival and hyposensitivity to chemotherapy. We demonstrate that GDIL boosted GSH levels and enhances clearance of ROS induced by platinum. Metabolomic and metabolic flux analysis further reveals that GDIL promotes GSH accumulation by inhibiting GSH degradation. This is attributed by downregulation of CHAC1, an enzyme that specifically degrades intracellular GSH. Mechanistically, GDIL binds and re-localizes the nuclear protein XRN2 to the cytoplasm, where GDIL further serve as a scaffold for XRN2 to identify and degrade CHAC1 mRNA. Suppression of GDIL with selective antisense oligonucleotide, restored drug sensitivity in platinum resistant cell lines and delayed drug resistance in cell line- and patient-derived xenografts. Thus, lncRNA GDIL is a novel target to promote GSH degradation and augment platinum therapy.

Exosomes, as key mediators of intercellular communication, have been increasingly recognized for their role in the oncogenic processes, particularly in facilitating drug resistance. This article delves into the emerging evidence linking exosomal lncRNAs to the modulation of drug resistance mechanisms in cancers such as ovarian, cervical, and endometrial cancer. It synthesizes current research findings on how these lncRNAs influence cancer cell survival, tumor microenvironment, and chemotherapy efficacy. Additionally, the review highlights potential therapeutic strategies targeting exosomal lncRNAs, proposing a new frontier in overcoming drug resistance. By mapping the interface of exosomal lncRNAs and drug resistance, this article aims to provide a comprehensive understanding that could pave the way for innovative treatments and improved patient outcomes in female reproductive system cancers.

Extracellular vesicles (EVs) are key mediators in the communication between cancer cells and their microenvironment, significantly influencing drug resistance. This review provides a comprehensive analysis of the roles of EVs in promoting drug resistance through mechanisms such as drug efflux, apoptosis resistance, autophagy imbalance, and tumor microenvironment modulation. Despite extensive research, details of EVs biogenesis, cargo selection, and specific pathways in EVs-mediated drug resistance are not fully understood. This review critically examines recent advancements, highlighting key studies that elucidate the molecular mechanisms of EVs functions. Additionally, innovative therapeutic strategies targeting EVs are explored, including inhibiting EVs biogenesis, engineering EVs for drug delivery, and identifying resistance-inhibiting molecules within EVs. By integrating insights from primary research and proposing new directions for future studies, this review aims to advance the understanding of EVs in cancer biology and foster effective interventions to mitigate drug resistance in cancer therapy.

Liver metastasis from colorectal cancer (CRC) is a major clinical challenge that severely affects patient survival. myofibroblastic cancer-associated fibroblasts (myCAFs) are a major component of the CRC tumor microenvironment, where they contribute to tumor progression and metastasis through exosomes.

Single-cell analysis highlighted a notable increase in myCAFs in colorectal cancer liver metastases (CRLM). Exosomal sequencing identified PWAR6 as the most significantly elevated lncRNA in these metastatic tissues. In vivo and in vitro assays confirmed PWAR6's roles in CRC cell stemness, migration, and glutamine uptake. RNA pulldown, RIP, and Co-IP assays investigated the molecular mechanisms of the PWAR6/NRF2/SLC38A2 signaling axis in CRC progression, flow cytometry was used to assess NK cell activity and cytotoxicity.

Clinically, higher PWAR6 expression levels are strongly associated with increased 68Ga FAPI-PET/CT SUVmax values, particularly in CRLM patients, where expression significantly exceeds that of non-LM cases and normal colon tissues. Regression analysis and survival data further support PWAR6 as a negative prognostic marker, with elevated levels correlating with worse patient outcomes. Mechanistically, PWAR6 promotes immune evasion by inhibiting NRF2 degradation through competitive binding with Keap1, thereby upregulating SLC38A2 expression, which enhances glutamine uptake in CRC cells and depletes glutamine availability for NK cells.

myCAFs derived exosomes PWAR6 represents a pivotal marker for CRC liver metastasis, and its targeted inhibition with ASO-PWAR6, in combination with FAPI treatment, effectively curtails metastasis in preclinical models, offering promising therapeutic potential for clinical management.

Within the intricate milieu of colorectal cancer (CRC) tissues, cancer-associated fibroblasts (CAFs) act as pivotal orchestrators, wielding considerable influence over tumor progression. This review endeavors to dissect the multifaceted functions of CAFs within the realm of CRC, thereby highlighting their indispensability in fostering CRC malignant microenvironment and indicating the development of CAFs-targeted therapeutic interventions. Through a comprehensive synthesis of current knowledge, this review delineates insights into CAFs-mediated modulation of cancer cell proliferation, invasiveness, immune evasion, and neovascularization, elucidating the intricate web of interactions that sustain the pro-tumor metabolism and secretion of multiple factors. Additionally, recognizing the high level of heterogeneity within CAFs is crucial, as they encompass a range of subtypes, including myofibroblastic CAFs, inflammatory CAFs, antigen-presenting CAFs, and vessel-associated CAFs. Innovatively, the symbiotic relationship between CAFs and the intestinal microbiota is explored, shedding light on a novel dimension of CRC pathogenesis. Despite remarkable progress, the orchestrated dynamic functions of CAFs remain incompletely deciphered, underscoring the need for continued research endeavors for therapeutic advancements in CRC management.

Lung Cancer (LC) is characterized by chemoresistance, which poses a significant clinical challenge and results in a poor prognosis for patients. Long non-coding RNAs (lncRNAs) have recently gained recognition as crucial mediators of chemoresistance in LC. Through the regulation of key cellular processes, these molecules play important roles in the progression of LC and response to therapy. The mechanisms by which lncRNAs affect chemoresistance include the modulation of gene expression, chromatin structure, microRNA interactions, and signaling pathways. Exosomes have emerged as key mediators of lncRNA-driven chemoresistance, facilitating the transfer of resistance-associated lncRNAs between cancer cells and contributing to tumor development. Consequently, exosomal lncRNAs may serve as biomarkers and therapeutic targets for the treatment of LC. Therapeutic strategies targeting lncRNAs offer novel approaches to circumvent chemoresistance. Different approaches, including RNA interference (RNAi) and antisense oligonucleotides (ASOs), are available to degrade lncRNAs or alter their function. ASO-based therapies are effective at reducing lncRNA expression levels, increasing chemotherapy sensitivity, and improving clinical outcomes. The use of these strategies can facilitate the development of targeted interventions designed to disrupt lncRNA-mediated mechanisms of chemoresistance. An important aspect of this review is the discussion of the complex relationship between lncRNAs and drug resistance in LC, particularly through exosomal pathways, and the development of innovative therapeutic strategies to enhance drug efficacy by targeting lncRNAs. The development of new pathways and interventions for treating LC holds promise in overcoming this resistance.

Although the pulse electric field (PEF) has been used in electrochemotherapy (ECT) for many years, the kinetics and profile of extracellular particles (EPs) released as a result of reversible electroporation have yet to be studied. It also needs to be clarified whether and how the profile of released EPs depends on the parameters of the applied PEF. The presented studies investigated the effect of EPs released from human melanoma cells after various parameters of reversible electroporation on markers indicating EP-mediated transformation of normal fibroblasts into tumor-associated fibroblasts. The expression levels of the vascular cell adhesion molecule-1 (VCAM-1) and changes in the expression of phosphor-histone H3 (pHH3), a biomarker specific for cells in mitosis, cell viability, and the migration capacity of the studied fibroblast cells, were analyzed. EPs were isolated from two commercial malignant melanoma cell lines previously subjected to reversible electroporation. Human primary fibroblasts (HPFs) were selected for EPs exposure. It was observed that after incubation with melanoma-derived EPs, HPFs showed differences in cell viability, migration capacity, VCAM-1, pHH3, and N-cadherin expression, depending on PEF parameters and the grade of melanoma cells. This study highlights that small extracellular particles (sEPs) from cancer cells can promote metastasis by carrying specific signals that lead to the upregulation of molecules like FAK, MMP-9, and N-cadherin in recipient cells.

Tumor-secreted exosomes are heterogeneous multi-signal messengers that support cancer growth and dissemination by mediating intercellular crosstalk and activating signaling pathways. Distinct from previous reviews, we focus intently on exosome-therapeutic resistance dynamics and summarize the new findings about the regulation of cancer treatment resistance by exosomes, shedding light on the complex processes via which these nanovesicles facilitate therapeutic refractoriness across various malignancies. Future research in exosome biology can potentially transform diagnostic paradigms and therapeutic interventions for cancer management. This review synthesizes recent insights into the exosome-driven regulation of cancer drug resistance, illuminates the sophisticated mechanisms by which these nanovesicles facilitate therapeutic refractoriness across various malignancies, and summarizes some strategies to overcome drug resistance.

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Platinum-based drugs, such as cisplatin and oxaliplatin, are frontline chemotherapy for CRC, effective in both monotherapy and combination regimens. However, the clinical efficacy of these treatments is often undermined by the development of drug resistance, a significant obstacle in cancer therapy. In recent years, epigenetic alterations have been recognized as key players in the acquisition of resistance to platinum drugs. Targeting these dysregulated epigenetic mechanisms with small molecules represents a promising therapeutic strategy. This review explores the complex relationship between epigenetic changes and platinum resistance in CRC, highlighting current epigenetic therapies and their effectiveness in countering resistance mechanisms. By elucidating the epigenetic underpinnings of platinum resistance, this review aims to contribute to ongoing efforts to improve treatment outcomes for CRC patients.

One of the critical challenges in managing colorectal cancer (CRC) is the development of oxaliplatin (OXP) resistance. Long non-coding RNAs (lncRNAs) have a crucial role in CRC progression and chemotherapy resistance, with exosomal lncRNAs emerging as potential biomarkers. This study aimed to predict key lncRNAs involved in OXP-resistance using in-silico methods and validate them using RT-qPCR methods in CRC cells and their isolated exosomes. Two public datasets, GSE42387 and GSE119481, were downloaded from the GEO database to identify differentially expressed genes (DEGs) and miRNAs (DEmiRNAs) associated with OXP-resistance in the HCT116 cell line. The analysis of GSE42387 revealed 210 DEGs, and GSE119481 identified 73 DEmiRNAs. A protein-protein interaction (PPI) network analysis of the DEGs identified 133 interconnected genes, from which the top ten genes with the highest degree scores were selected. By intersecting predicted miRNAs targeting these genes with the DEmiRNAs, 38 common miRNAs were found. Subsequently, 224 lncRNAs targeting these common miRNAs were predicted. LncRNA-miRNA-mRNA network were constructed and the top five lncRNAs with the highest degree scores were identified. Analysis using the Kaplan-Meier plotter database revealed that the key lncRNAs NEAT1, OIP5-AS1, and MALAT1 are significantly associated with the overall survival of CRC patients. To validate these lncRNAs, OXP-resistant HCT116 sub-cell line (HCT116/OXR) was developed by exposing parental HCT116 cells to gradually increasing concentrations of OXP. Exosomes derived from both HCT116 and HCT116/OXR cells were isolated and characterized utilizing dynamic light scattering (DLS), transmission electron microscopy (TEM), and Western blotting. RT-qPCR confirmed elevated levels of NEAT1, OIP5-AS1, and MALAT1 in HCT116/OXR cells and their exosomes compared to parental HCT116 cells and their exosomes. This study concludes that NEAT1, OIP5-AS1, and MALAT1 are associated with the OXP-resistance in CRC. The high levels of these lncRNAs in exosomes of resistant cells suggest their involvement in intercellular communication and resistance propagation. This positioning makes them promising biomarkers for OXP-resistance in CRC.

Cancer-associated fibroblasts are the most important cellular component of the tumor microenvironment, controlling cancer progression and therapeutic response. These cells in the tumor microenvironment regulate tumor progression and development as oncogenic or tumor suppressor agents. However, the mechanisms by which CAFs communicate with cancer cells remain to investigate. Here, we review evidence that extracellular vesicles, particularly exosomes, serve as vehicles for the intercellular transfer of bioactive cargos, notably microRNAs and long non-coding RNAs, from CAFs to cancer cells. We try to highlight molecular pathways of non-coding RNAs and the interaction among these molecules. Together, these findings elucidate a critical exosome-based communication axis by which CAFs create mostly a supportive pro-tumorigenic microenvironment and highlight therapeutic opportunities for disrupting this intercellular crosstalk.

Cancer-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in the tumor microenvironment, which play important roles in regulating tumor progression and therapy resistance by transferring exosomes to cancer cells. However, how CAFs modulate esophageal squamous cell carcinoma (ESCC) progression and radioresistance remains incompletely understood. The expression of fibroblast activation protein (FAP) in CAFs was evaluated by immunohistochemistry in 174 ESCC patients who underwent surgery and 78 pretreatment biopsy specimens of ESCC patients who underwent definitive chemoradiotherapy. We sorted CAFs according to FAP expression, and the conditioned medium (CM) was collected to culture ESCC cells. The expression levels of several lncRNAs that were considered to regulate ESCC progression and/or radioresistance were measured in exosomes derived from FAP+ CAFs and FAP- CAFs. Subsequently, cell counting kit-8, 5-ethynyl-2'-deoxyuridine, transwell, colony formation, and xenograft assays were performed to investigate the functional differences between FAP+ CAFs and FAP- CAFs. Finally, a series of in vitro and in vivo assays were used to evaluate the effect of AFAP1-AS1 on radiosensitivity of ESCC cells. FAP expression in stromal CAFs was positively correlated with nerve invasion, vascular invasion, depth of invasion, lymph node metastasis, lack of clinical complete response and poor survival. Culture of ESCC cells with CM/FAP+ CAFs significantly increased cancer proliferation, migration, invasion and radioresistance, compared with culture with CM/FAP- CAFs. Importantly, FAP+ CAFs exert their roles by directly transferring the functional lncRNA AFAP1-AS1 to ESCC cells via exosomes. Functional studies showed that AFAP1-AS1 promoted radioresistance by enhancing DNA damage repair in ESCC cells. Clinically, high levels of plasma AFAP1-AS1 correlated with poor responses to dCRT in ESCC patients. Our findings demonstrated that FAP+ CAFs promoted radioresistance in ESCC cells through transferring exosomal lncRNA AFAP1-AS1; and may be a potential therapeutic target for ESCC treatment.

Cancer is one of the most serious diseases that threaten human life and health. Among all kinds of diseases, the mortality rate of malignant tumors is the second highest, second only to cardio-cerebrovascular diseases. Cancer treatment typically involves imaging, surgery, and pathological analysis. When patients are identified as carcinoma by the above means, there are often problems of distant metastasis, delayed treatment, and drug tolerance, indicating that patients have some poor prognosis and overall survival. Hence, the development of novel molecular biomarkers is of great clinical importance. In recent years, as an important mediator of material and information exchange between cells in the tumor microenvironment, lncRNA have attracted widespread attention for their roles in tumor development. In this review, we comprehensively summarize the up-to-date knowledge of lncARSR on diverse cancer types which mainly focuses on tumor proliferation, drug tolerance, and lipid and cholesterol metabolism, highlighting the potential of lncARSR as a diagnostic and prognostic biomarker and even a therapeutic target. In our final analysis, we provide a synthesized overview of the directions for future inquiry into lncARSR, and we are eager to witness the advancement of research that will elucidate the multifaceted nature of this lncRNA.

Cancer-associated fibroblasts (CAFs) are a diverse stromal cell population within the tumour microenvironment, where they play fundamental roles in cancer progression and patient prognosis. Multiple lines of evidence have identified that CAFs are critically involved in shaping the structure and function of the tumour microenvironment with numerous functions in regulating tumour behaviours, such as metastasis, invasion, and epithelial-mesenchymal transition (EMT). CAFs can interact extensively with cancer cells by producing extracellular vesicles (EVs), multiple secreted factors, and metabolites. Notably, CAF-derived EVs have been identified as critical mediators of cancer therapy resistance, and constitute novel therapy targets and biomarkers in cancer management. This review aimed to summarize the biological roles and detailed molecular mechanisms of CAF-derived EVs in mediating cancer resistance to chemotherapy, targeted therapy agents, radiotherapy, and immunotherapy. We also discussed the therapeutic potential of CAF-derived EVs as novel targets and clinical biomarkers in cancer clinical management, thereby providing a novel therapeutic strategy for enhancing cancer therapy efficacy and improving patient prognosis.

As global population ageing accelerates, cancer emerges as a predominant cause of mortality. Long non-coding RNAs (lncRNAs) play crucial roles in cancer cell growth and death, given their involvement in regulating downstream gene expression levels and numerous cellular processes. Cell death, especially non-apoptotic regulated cell death (RCD), such as ferroptosis, pyroptosis and necroptosis, significantly impacts cancer proliferation, invasion and metastasis. Understanding the interplay between lncRNAs and the diverse forms of cell death in cancer is imperative. Modulating lncRNA expression can regulate cancer onset and progression, offering promising therapeutic avenues. This review discusses the mechanisms by which lncRNAs modulate non-apoptotic RCDs in cancer, highlighting their potential as biomarkers for various cancer types. Elucidating the role of lncRNAs in cell death pathways provides valuable insights for personalised cancer interventions.

Drug resistance remains a significant challenge in cancer treatment. Recently, the interactions among various cell types within the tumor microenvironment (TME) have deepened our understanding of the mechanisms behind treatment resistance. Therefore, this review aims to synthesize current research focusing on infiltrating cells and drug resistance suggesting that targeting the TME could be a viable strategy to combat this issue. Numerous factors, including inflammation, metabolism, senescence, hypoxia, and angiogenesis, contribute to drug resistance could be a viable strategy to combat this issue. Overexpression of STAT3 is commonly associated with drug-resistant cancer cells or stromal cells. Current research often generalizes the impact of stromal cells on resistance, lacking specificity and statistical robustness. Thus, future research should take notice of this issue and aim to provide high-quality evidence. Despite the existing limitations, targeting the TME to overcome therapy resistance hold promising and valuable potential.

Long non-coding RNAs (lncRNAs), with transcript lengths exceeding 200 nucleotides and little or no protein-coding capacity, have been found to impact colorectal cancer (CRC) through various biological processes. LncRNA expression can regulate autophagy, which plays dual roles in the initiation and progression of cancers, including CRC. Abnormal expression of lncRNAs is associated with the emergence of chemoresistance. Moreover, it has been confirmed that targeting autophagy through lncRNA regulation could be a viable approach for combating chemoresistance. Two recent studies titled "Human β-defensin-1 affects the mammalian target of rapamycin pathway and autophagy in colon cancer cells through long non-coding RNA TCONS_00014506" and "Upregulated lncRNA PRNT promotes progression and oxaliplatin resistance of colorectal cancer cells by regulating HIPK2 transcription" revealed novel insights into lncRNAs associated with autophagy and oxaliplatin resistance in CRC, respectively. In this editorial, we particularly focus on the regulatory role of lncRNAs in CRC-related autophagy and chemoresistance since the regulation of chemotherapeutic sensitivity by intervening with the lncRNAs involved in the autophagy process has become a promising new approach for cancer treatment.

Gastrointestinal (GI) cancers account for one-fourth of the global cancer incidence and are incriminated to cause one-third of cancer-related deaths. GI cancer includes esophageal, gastric, liver, pancreatic, and colorectal cancers, mostly diagnosed at advanced stages due to a lack of accurate markers for early stages. The invasiveness of diagnostic methods like colonoscopy for solid biopsy reduces patient compliance as it cannot be frequently used to screen patients. Therefore, minimally invasive approaches like liquid biopsy may be explored for screening and early identification of gastrointestinal cancers. Liquid biopsy involves the qualitative and quantitative determination of certain cancer-specific biomarkers in body fluids such as blood, serum, saliva, and urine to predict disease progression, therapeutic tolerance, toxicities, and recurrence by evaluating minimal residual disease and its correlation with other clinical features. In this review, we deliberate upon various tumor-specific cellular and molecular entities such as circulating tumor cells (CTCs), tumor-educated platelets (TEPs), circulating tumor DNA (ctDNA), cell-free DNA (cfDNA), exosomes, and exosome-derived biomolecules and cite recent advances pertaining to their use in predicting disease progression, therapy response, or risk of relapse. We also discuss the technical challenges associated with translating liquid biopsy into clinical settings for various clinical applications in gastrointestinal cancers.

Colorectal cancer (CRC) ranks as the second leading cause of cancer-related mortality, with metastasis being the primary determinant of poor prognosis in patients. Investigating the molecular mechanisms underlying CRC metastasis is currently a prominent and challenging area of research. Exosomes, as crucial intercellular communication mediators, facilitate the transfer of metabolic and genetic information from cells of origin to recipient cells. Their roles in mediating information exchange between CRC cells and immune cells, fibroblasts, and other cell types are pivotal in reshaping the tumor microenvironment, regulating key biological processes such as invasion, migration, and formation of pre-metastatic niche. This article comprehensively examines the communication function and mechanism of exosomes derived from different cells in cancer metastasis, while also presenting an outlook on current research advancements and future application prospects. The aim is to offer a distinctive perspective that contributes to accurate diagnosis and rational treatment strategies for CRC.

Exosomes are indispensable for intercellular communications. Tumor microenvironment (TME) is the living environment of tumor cells, which is composed of various components, including immune cells. Based on TME, immunotherapy has been recently developed for eradicating cancer cells by reactivating antitumor effect of immune cells. The communications between tumor cells and TME are crucial for tumor development, metastasis, and drug resistance. Exosomes play an important role in mediating these communications and regulating the reprogramming of TME, which affects the sensitivity of immunotherapy. Therefore, it is imperative to investigate the role of exosomes in TME reprogramming and the impact of exosomes on immunotherapy. Here, we review the communication role of exosomes in regulating TME remodeling and the efficacy of immunotherapy, as well as summarize the underlying mechanisms. Furthermore, we also introduce the potential application of the artificially modified exosomes as the delivery systems of antitumor drugs. Further efforts in this field will provide new insights on the roles of exosomes in intercellular communications of TME and cancer progression, thus helping us to uncover effective strategies for cancer treatment.

Colorectal cancer (CRC) is a multifaceted disease characterized by a complex interaction between tumor cells and the surrounding microenvironment. Within this intricate landscape, exosomes have emerged as pivotal players in the tumor-stroma crosstalk, influencing the immune microenvironment of CRC. These nano-sized vesicles, secreted by both tumoral and stromal cells, serve as molecular transporters, delivering a heterogeneous mix of biomolecules such as RNAs, proteins, and lipids. In the CRC context, exosomes exert dual roles: they promote tumor growth, metastasis, and immune escape by altering immune cell functions and activating oncogenic signaling pathways and offer potential as biomarkers for early CRC detection and treatment targets. This review delves into the multifunctional roles of exosomes in the CRC immune microenvironment, highlighting their potential implications for future therapeutic strategies and clinical outcomes.

Gastrointestinal (GI) tumors are a significant global health threat, with high rates of morbidity and mortality. Exosomes contain various biologically active molecules like nucleic acids, proteins, and lipids and can serve as messengers for intercellular communication. They play critical roles in the exchange of information between tumor cells and the tumor microenvironment (TME). The TME consists of mesenchymal cells and components of the extracellular matrix (ECM), with fibroblasts being the most abundant cell type in the tumor mesenchyme. Cancer-associated fibroblasts (CAFs) are derived from normal fibroblasts and mesenchymal stem cells that are activated in the TME. CAFs can secrete exosomes to modulate cell proliferation, invasion, migration, drug resistance, and other biological processes in tumors. Additionally, tumor cells can manipulate the function and behavior of fibroblasts through direct cell-cell interactions. This review provides a summary of the intercellular crosstalk between GI tumor cells and CAFs through exosomes, along with potential underlying mechanisms.

In recent decades, emerging data have highlighted the critical role of extracellular vesicles (EVs), especially (exosomes) Exos, in the progression and development of several cancer types. These nano-sized vesicles are released by different cell lineages within the cancer niche and maintain a suitable platform for the interchange of various signaling molecules in a paracrine manner. Based on several studies, Exos can transfer oncogenic factors to other cells, and alter the activity of immune cells, and tumor microenvironment, leading to the expansion of tumor cells and metastasis to the remote sites. It has been indicated that the cell-to-cell crosstalk is so complicated and a wide array of factors are involved in this process. How and by which mechanisms Exos can regulate the behavior of tumor cells and non-cancer cells is at the center of debate. Here, we scrutinize the molecular mechanisms involved in the oncogenic behavior of Exos released by different cell lineages of tumor parenchyma. Besides, tumoricidal properties of Exos from various stem cell (SC) types are discussed in detail.

Colorectal cancer (CRC) remains a leading cause of cancer-related deaths worldwide. In recent years, liquid biopsy has emerged as one of the most interesting areas of research in oncology, leading to innovative trials and practical changes in all aspects of CRC management. RNAs and cell free DNA (cfDNA) methylation are emerging as promising biomarkers for early diagnosis. Post-surgical circulating tumour DNA (ctDNA) can aid in evaluating minimal residual disease and personalising adjuvant treatment. In rectal cancer, ctDNA could improve response assessment to neoadjuvant therapy and risk stratification, especially in the era of organ-preservation trials. In the advanced setting, ctDNA analysis offers the opportunity to monitor treatment response and identify driver and resistance mutations more comprehensively than traditional tissue analysis, providing prognostic and predictive information. The aim of this review is to provide a detailed overview of the clinical applications and future perspectives of liquid biopsy in CRC.

Oxaliplatin is a widely applied anti-cancer drug in clinics for colorectal cancer (CRC) treatment. Nonetheless, the treatment efficacy is always limited by the acquisition of chemoresistance in cancer cells. The deregulation of long non-coding RNA (lncRNA) FAL1 has been implicated in the tumorigenesis and progression of different malignancies. Nevertheless, the possible contribution of lnc-FAL1 in drug resistance development of CRC has not been investigated. Here, we reported the overexpression of lnc-FAL1 in CRC samples, and elevated lnc-FAL1 levels seemed to be associated with the poor survival in CRC patients. We further demonstrated that lnc-FAL1 promoted oxaliplatin chemoresistance in both cell and animal model. Additionally, lnc-FAL1 was mainly derived from exosomes secreted by cancer associated fibroblasts (CAFs), and lnc-FAL1-containing exosomes or lnc-FAL1 overexpression significantly inhibited oxaliplatin-induced autophagy in CRC cells. Mechanistically, lnc-FAL1 acted as a scaffold for the interaction between Beclin1 and TRIM3 to promote TRIM3-dependent Beclin1 polyubiquitination and degradation, thereby suppressing oxaliplatin-induced autophagic cell death. In summary, these data imply a molecular mechanism through which CAF-derived exosomal lnc-FAL1 contributes to the acquisition of oxaliplatin resistance in CRC.

Gastrointestinal (GI) cancers, including colorectal, gastric, esophageal, pancreatic, and liver, are associated with high mortality and morbidity rates worldwide. One of the underlying reasons for the poor survival outcomes in patients with these malignancies is late disease detection, typically when the tumor has already advanced and potentially spread to distant organs. Increasing evidence indicates that earlier detection of these cancers is associated with improved survival outcomes and, in some cases, allows curative treatments. Consequently, there is a growing interest in the development of molecular biomarkers that offer promise for screening, diagnosis, treatment selection, response assessment, and predicting the prognosis of these cancers. Extracellular vesicles (EVs) are membranous vesicles released from cells containing a repertoire of biological molecules, including nucleic acids, proteins, lipids, and carbohydrates. MicroRNAs (miRNAs) are the most extensively studied non-coding RNAs, and the deregulation of miRNA levels is a feature of cancer cells. EVs miRNAs can serve as messengers for facilitating interactions between tumor cells and the cellular milieu, including immune cells, endothelial cells, and other tumor cells. Furthermore, recent years have witnessed considerable technological advances that have permitted in-depth sequence profiling of these small non-coding RNAs within EVs for their development as promising cancer biomarkers -particularly non-invasive, liquid biopsy markers in various cancers, including GI cancers. Herein, we summarize and discuss the roles of EV-associated miRNAs as they play a seminal role in GI cancer progression, as well as their promising translational and clinical potential as cancer biomarkers as we usher into the area of precision oncology.

Drug resistance has been a major obstacle in the quest for a cancer cure. Many chemotherapeutic treatments fail to overcome chemoresistance, resulting in tumor remission. The exact process that leads to drug resistance in many cancers has not been fully explored or understood. However, the discovery of RNA binding proteins (RBPs) has provided insight into various pathways and post-transcriptional gene modifications involved in drug tolerance. RBPs are evolutionarily conserved proteins, and their abnormal gene expression has been associated with cancer progression. Additionally, RBPs are aberrantly expressed in numerous neoplasms. RBPs have also been implicated in maintaining cancer stemness, epithelial-to-mesenchymal transition, and other processes. In this review, we aim to provide an overview of RBP-mediated mechanisms of drug resistance and their implications in cancer malignancy. We discuss in detail the role of major RBPs and their correlation with noncoding RNAs (ncRNAs) that are associated with the inhibition of chemosensitivity. Understanding and exploring the pathways of RBP-mediated chemoresistance will contribute to the development of improved cancer diagnosis and treatment strategies.

In 2023, colorectal cancer (CRC) is the third most diagnosed malignancy and the third leading cause of cancer death worldwide. At the time of the initial visit, 20% of patients diagnosed with CRC have metastatic CRC (mCRC), and another 25% who present with localized disease will later develop metastases. Despite the improvement in response rates with various modulation strategies such as chemotherapy combined with targeted therapy, radiotherapy, and immunotherapy, the prognosis of mCRC is poor, with a 5-year survival rate of 14%, and the primary reason for treatment failure is believed to be the development of resistance to therapies. Herein, we provide an overview of the main mechanisms of resistance in mCRC and specifically highlight the role of drug transports, EGFR, and HGF/c-MET signaling pathway in mediating mCRC resistance, as well as discuss recent therapeutic approaches to reverse resistance caused by drug transports and resistance to anti-EGFR blockade caused by mutations in EGFR and alteration in HGF/c-MET signaling pathway.

Cancer heterogeneity and drug resistance remain pivotal obstacles in effective cancer treatment and management. One major contributor to these challenges is epigenetic modifications - gene regulation that does not involve changes to the DNA sequence itself but significantly impacts gene expression. As we elucidate these phenomena, we underscore the pivotal role of epigenetic modifications in regulating gene expression, contributing to cellular diversity, and driving adaptive changes that can instigate therapeutic resistance. This review dissects essential epigenetic modifications - DNA methylation, histone modifications, and chromatin remodeling - illustrating their significant yet complex contributions to cancer biology. While these changes offer potential avenues for therapeutic intervention due to their reversible nature, the interplay of epigenetic and genetic changes in cancer cells presents unique challenges that must be addressed to harness their full potential. By critically analyzing the current research landscape, we identify knowledge gaps and propose future research directions, exploring the potential of epigenetic therapies and discussing the obstacles in translating these concepts into effective treatments. This comprehensive review aims to stimulate further research and aid in developing innovative, patient-centered cancer therapies. Understanding the role of epigenetic modifications in cancer heterogeneity and drug resistance is critical for scientific advancement and paves the way towards improving patient outcomes in the fight against this formidable disease.

Drug resistance is one of the main challenges in cancer treatment. Long non coding RNAs (lncRNAs) play a complex and precise regulatory role in regulating drug resistance of cancer. The common ways of lncRNA regulating drug resistance of cancer involve ATP binding transporter overexpression, abnormal DNA damage response, tumor cell apoptosis, accumulation of epithelial mesenchymal transformation and cancer stem cell formation. Moreover, studies on exosomal lncRNAs regulating cancer drug resistance are developed in recent years. Further study on the role and mechanism of lncRNAs drug resistance in cancer will help clinical cancer treatment program and explore new treatment methods. This paper reviews recent advances in lncRNAs regulating drug resistance of cancer, especially the role of exosomal lncRNAs.

Extracellular vesicles (EVs) are membrane-bound nanoparticles with different types of cargo released by cells and postulated to mediate functions such as intercellular communications. Recent studies have shown that long non-coding RNAs (lncRNAs) or their fragments are present as cargo within EVs. LncRNAs are a heterogeneous group of RNA species with a length exceeding 200 nucleotides with diverse functions in cells based on their localization. While lncRNAs are known for their important functions in cellular regulation, their presence and role in EVs have only recently been explored. While certain studies have observed EV-lncRNAs to be tissue-and disease-specific, it remains to be determined whether or not this is a global observation. Nonetheless, these molecules have demonstrated promising potential to serve as new diagnostic and prognostic biomarkers. In this review, we critically evaluate the role of EV-derived lncRNAs in several prevalent diseases, including cancer, cardiovascular diseases, and neurodegenerative diseases, with a specific focus on their role as biomarkers.

Cancer-associated fibroblasts (CAFs) are mesenchymal cells in the tumor microenvironment (TME). CAFs are the most abundant cellular components in the TME of solid tumors. They affect the progression and course of chemotherapy and radiotherapy in various types of tumors including colorectal cancer (CRC). CAFs can promote tumor proliferation, invasion, and metastasis; protect tumor cells from immune surveillance; and resist tumor cell apoptosis caused by chemotherapy, resulting in drug resistance to chemotherapy. In recent years, researchers have become increasingly interested CAF functions and have conducted extensive research. However, compared to other types of malignancies, our understanding of the interaction between CRC cells and CAFs remains limited. Therefore, we searched the relevant literature published in the past 10 years, and reviewed the origin, biological characteristics, heterogeneity, role in the TME, and potential therapeutic targets of CAFs, to aid future research on CAFs and tumors.

Adenocarcinoma is a common type of malignant tumor, originating from glandular epithelial cells in various organs, such as pancreas, breast, lung, stomach, colon, rectus, and prostate. For patients who lose the opportunity for radical surgery, medication is available to provide potential clinical benefits. However, drug resistance is a big obstacle to obtain desired clinical prognosis. In this review, we provide a summary of treatment strategies and drug resistance mechanisms in adenocarcinoma of different organs, including pancreatic cancer, gastric adenocarcinoma, colorectal adenocarcinoma, lung adenocarcinoma, and prostate cancer. Although the underlying molecular mechanisms involved in drug resistance of adenocarcinoma vary from one organ to the other, there are several targets that are universal for drug resistance in adenocarcinoma, and targeting these molecules could potentially reverse drug resistance in the treatment of adenocarcinomas.

The intricate mechanisms underlying intercellular communication within the tumor microenvironment remain largely elusive. Recently, attention has shifted towards exploring the intercellular signaling mediated by exosomal long non-coding RNAs (lncRNAs) within this context. This comprehensive systematic review aims to elucidate the functional paradigm of exosome-derived lncRNAs in cancer.

The review provides a comprehensive narrative of lncRNA definition, characteristics, as well as the formation, sorting, and uptake processes of exosome-derived lncRNAs. Additionally, it describes comprehensive technology for exosome research and nucleic acid drug loading. This review further systematically examines the cellular origins, functional roles, and underlying mechanisms of exosome-derived lncRNAs in recipient cells within the cancer setting.

The functional paradigm of exosome-derived lncRNAs in cancer mainly depends on the source cells and sorting mechanism of exosomal lncRNAs, the recipient cells and uptake mechanisms of exosomal lncRNAs, and the specific molecular mechanisms of lncRNAs in recipient cells. The source cells of exosomal lncRNAs mainly involved in the current review included tumor cells, cancer stem cells, normal cells, macrophages, and cancer-associated fibroblasts.

This synthesis of knowledge offers valuable insights for accurately identifying exosomal lncRNAs with potential as tumor biomarkers. Moreover, it aids in the selection of appropriate targeting strategies and preclinical models, thereby facilitating the clinical translation of exosomal lncRNAs as promising therapeutic targets against cancer. Through a comprehensive understanding of the functional role of exosome-derived lncRNAs in cancer, this review paves the way for advancements in personalized medicine and improved treatment outcomes.

Small extracellular vesicles (sEVs) are a type of membranous vesicles that can be released by cells into the extracellular space. The relationship between sEVs and non-coding RNAs (ncRNAs) is highly intricate and interdependent. This symbiotic relationship plays a pivotal role in facilitating intercellular communication and holds profound implications for a myriad of biological processes. The concept of sEVs and their ncRNA cargo as a "Trojan Horse" highlights their remarkable capacity to traverse biological barriers and surreptitiously deliver their cargo to target cells, evading detection by the host-immune system. Accumulating evidence suggests that sEVs may be harnessed as carriers to ferry therapeutic ncRNAs capable of selectively silencing disease-driving genes, particularly in conditions such as cancer. This approach presents several advantages over conventional drug delivery methods, opening up new possibilities for targeted therapy and improved treatment outcomes. However, the utilization of sEVs and ncRNAs as therapeutic agents raises valid concerns regarding the possibility of unforeseen consequences and unintended impacts that may emerge from their application. It is important to consider the fundamental attributes of sEVs and ncRNAs, including by an in-depth analysis of the practical and clinical potentials of exosomes, serving as a representative model for sEVs encapsulating ncRNAs.

Colorectal cancer (CRC) as the second leading cause of global cancer deaths poses critical challenges in clinical settings. Cancer-derived small extracellular vesicles (sEVs), which are secreted by cancer cells, have been shown to mediate tumor development, invasion, and even metastasis, and have thus received increasing attention for the development of cancer diagnostic or therapeutic platforms. In the present study, the sEV-targeted systematic evolution of ligands by exponential enrichment (E-SELEX) is developed to generate a high-quality aptamer (CCE-10F) that recognizes and binds to CRC-derived sEVs. Via an in-depth investigation, it is confirmed that this novel aptamer possesses high affinity (Kd = 3.41 nm) for CRC-derived sEVs and exhibits a wide linear range (2.0 × 104 -1.0 × 106 particles µL-1 ) with a limit of detection (LOD) of 1.0 × 103 particles µL-1 . Furthermore, the aptamer discriminates CRC cell-derived sEVs from those derived from normal colon cell, human serum, and other cancer cells, showing high specificity for CRC cell-derived sEVs and significantly suppresses the critical processes of metastasis, including cellular migration, invasion, and angiogenesis, which are originally induced by sEVs themselves. These findings are highly encouraging for the potential use of the aptamer in sEV-based diagnostic and therapeutic applications.

Despite continuous improvements in research and new cancer therapeutics, the goal of eradicating cancer remains elusive because of drug resistance. For a long time, drug resistance research has been focused on tumor cells themselves; however, recent studies have found that the tumor microenvironment also plays an important role in inducing drug resistance. Cancer-associated fibroblasts (CAFs) are a main component of the tumor microenvironment. They cross-talk with cancer cells to support their survival in the presence of anticancer drugs. This review summarizes the current knowledge of the role of CAFs in tumor drug resistance. An in-depth understanding of the mechanisms underlying the cross-talk between CAFs and cancer cells and insight into the importance of CAFs in drug resistance can guide the development of new anticancer strategies.

Gastrointestinal cancer remains a significant global health burden. The pursuit of advancing the comprehension of tumorigenesis, along with the identification of reliable biomarkers and the development of precise therapeutic strategies, represents imperative objectives in this field. Exosomes, small membranous vesicles released by most cells, commonly carry functional biomolecules, including noncoding RNAs (ncRNAs), which are specifically sorted and encapsulated by exosomes. Exosome-mediated communication involves the release of exosomes from tumor or stromal cells and the uptake by nearby or remote recipient cells. The bioactive cargoes contained within these exosomes exert profound effects on the recipient cells, resulting in significant modifications in the tumor microenvironment (TME) and distinct alterations in gastrointestinal tumor behaviors. Due to the feasibility of isolating exosomes from various bodily fluids, exosomal ncRNAs have shown great potential as liquid biopsy-based indicators for different gastrointestinal cancers, using blood, ascites, saliva, or bile samples. Moreover, exosomes are increasingly recognized as natural delivery vehicles for ncRNA-based therapeutic interventions. In this review, we elucidate the processes of ncRNA-enriched exosome biogenesis and uptake, examine the regulatory and functional roles of exosomal ncRNA-mediated intercellular crosstalk in gastrointestinal TME and tumor behaviors, and explore their potential clinical utility in diagnostics, prognostics, and therapeutics.

Colorectal cancer (CRC) is the second most common malignant tumor of the gastrointestinal tract with the second highest mortality rate and the third highest incidence rate. Early diagnosis and treatment are important measures to reduce CRC mortality. Small extracellular vesicles (sEVs) have emerged as key mediators that facilitate communication between tumor cells and various other cells, playing a significant role in the growth, invasion, and metastasis of cancer cells. Regulatory RNAs have been identified as potential biomarkers for early diagnosis and prognosis of CRC, serving as crucial factors in promoting CRC cell proliferation, invasion and metastasis, angiogenesis, drug resistance, and immune cell differentiation. This review provides a comprehensive summary of the vital role of sEVs as biomarkers in CRC diagnosis and their potential application in CRC treatment, highlighting their importance as a promising avenue for further research and clinical translation.