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Molecular Mechanisms and Therapies of Colorectal Cancer 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 20977

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Dr. Donatella Delle Cave

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Institute of Genetics and Biophysics "A. Buzzati Traverso" (IGB-ABT), CNR, Via Pietro Castellino 111, 80131 Naples, Italy
Interests: pancreatic cancer; cancer stem cells; tumor microenvironment; cancer metabolism; fibrosis; TGF-β signaling; target therapy; drug delivery systems
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Dear Colleagues,

Colorectal cancer (CRC) is currently the third leading cause of cancer-related mortality. Transforming growth factor beta (TGF-β) signaling has been associated with CRC growth and metastasis due to its involvement in proliferation, epithelial-to-mesenchymal transition (EMT), and angiogenesis. The TGF-β superfamily contains over forty members, including TGF-βs, Nodal, Activin, and bone morphogenetic proteins (BMPs). Three types of TGF-β receptors (TGFβR) have been identified: types 1, 2, and 3. After ligand binding, TGF-βR2 recruits and phosphorylates TGF-βR1 that in turn phosphorylates downstream SMAD (small mother against decapentaplegic) proteins. Phosphorylated SMAD4 translocates into the nucleus, where it activates the transcription of numerous target genes (including SERPINE1, LTBP2, CDKN1A, ARID3B, ATXN1, PTPRK, RAB6A, SMAD7, EHBP1, etc.), acting predominantly as a tumor-suppressor gene. Interestingly, alterations of SMAD4 are frequent in metastatic CRC and, together with TGF-βR2 genes mutations, have been reported as late events able to promote CRC progression. The study of TGF-β pathway in metastatic CRC is challenging because of the great genetic heterogeneity of CRC. However, the increasing availability of targeted and whole-exome DNA sequencing techniques makes it possible to identify genes’ mutations in complex, dynamic, and heterogeneous clinical contexts and to make correlations with clinical outcome.

This Special Issue was established to prompt researchers to perform studies on:

Involvement of the TGF-β pathway in metastatic CRC;
Emerging methods to identify and correlate specific TGF-β pathway genes’ mutations with metastatic behavior;
Novel approaches to target the TGF-β pathway in metastatic CRC;
Novel studies to depict TGF-β pathway evolution from primary to metastatic lesions.

Articles consisting exclusively of bioinformatics or computational analyses of public databases or pure clinical studies will not be accepted. Basic studies or translational studies including molecular characterizations of patients from real practice are welcome. Reviews will also be appreciated.

Dr. Donatella Delle Cave
Guest Editor

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

transforming growth factor beta (TGF-β) signaling
genetic alterations
molecular targeted therapy
precision medicine

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Molecular Mechanisms and Therapies of Colorectal Cancer 3.0 in International Journal of Molecular Sciences (4 articles)
Molecular Mechanisms and Therapies of Colorectal Cancer in International Journal of Molecular Sciences (16 articles)

Published Papers (12 papers)

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Editorial

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4 pages, 173 KiB

Open AccessEditorial

Novel Therapeutic Approaches for Colorectal Cancer Treatment

by Athanasios G. Papavassiliou and Donatella Delle Cave

Int. J. Mol. Sci. 2024, 25(4), 2228; https://doi.org/10.3390/ijms25042228 - 13 Feb 2024

Cited by 1 | Viewed by 846

Abstract

According to GLOBOCAN 2020 data, colorectal cancer (CRC) represents the third most common malignancy and the second most deadly cancer worldwide [...] Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer 2.0)

Research

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18 pages, 1904 KiB

Open AccessArticle

Bafilomycin A1 Molecular Effect on ATPase Activity of Subcellular Fraction of Human Colorectal Cancer and Rat Liver

by Solomiia Bychkova, Mykola Bychkov, Dani Dordevic, Monika Vítězová, Simon K.-M. R. Rittmann and Ivan Kushkevych

Int. J. Mol. Sci. 2024, 25(3), 1657; https://doi.org/10.3390/ijms25031657 - 29 Jan 2024

Viewed by 910

Abstract

Bafilomycin A1 inhibits V-type H⁺ ATPases on the molecular level, which acidifies endo-lysosomes. The main objective of the study was to assess the effect of bafilomycin A1 on Ca²⁺ content, NAADP-induced Ca²⁺ release, and ATPase activity in rat hepatocytes and human colon cancer samples. Chlortetracycline (CTC) was used for a quantitative measure of stored calcium in permeabilized rat hepatocytes. ATPase activity was determined by orthophosphate content released after ATP hydrolysis in subcellular post-mitochondrial fraction obtained from rat liver as well as from patients’ samples of colon mucosa and colorectal cancer samples. In rat hepatocytes, bafilomycin A1 decreased stored Ca²⁺ and prevented the effect of NAADP on stored Ca²⁺. This effect was dependent on EGTA–Ca²⁺ buffers in the medium. Bafilomycin A1 significantly increased the activity of Ca²⁺ ATPases of endoplasmic reticulum (EPR), but not plasma membrane (PM) Ca²⁺ ATPases in rat liver. Bafilomycin A1 also prevented the effect of NAADP on these pumps. In addition, bafilomycin A1 reduced Na⁺/K⁺ ATPase activity and increased basal Mg²⁺ ATPase activity in the subcellular fraction of rat liver. Concomitant administration of bafilomycin A1 and NAADP enhanced these effects. Bafilomycin A1 increased the activity of the Ca²⁺ ATPase of EPR in the subcellular fraction of normal human colon mucosa and also in colon cancer tissue samples. In contrast, it decreased Ca²⁺ ATPase PM activity in samples of normal human colon mucosa and caused no changes in colon cancer. Bafilomycin A1 decreased Na⁺/K⁺ ATPase activity and increased basal Mg²⁺ ATPase activity in normal colon mucosa samples and in human colon cancer samples. It can be concluded that bafilomycin A1 targets NAADP-sensitive acidic Ca²⁺ stores, effectively modulates ATPase activity, and assumes the link between acidic stores and EPR. Bafilomycin A1 may be useful for cancer therapy. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer 2.0)

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14 pages, 2791 KiB

Open AccessArticle

Pictilisib-Induced Resistance Is Mediated through FOXO1-Dependent Activation of Receptor Tyrosine Kinases in Mucinous Colorectal Adenocarcinoma Cells

by Murali R. Kuracha, Venkatesh Govindarajan, Brian W. Loggie, Martin Tobi and Benita L. McVicker

Int. J. Mol. Sci. 2023, 24(15), 12331; https://doi.org/10.3390/ijms241512331 - 02 Aug 2023

Cited by 3 | Viewed by 1000

Abstract

The phosphatidylinositol (PI3K)/AKT/mTOR axis represents an important therapeutic target to treat human cancers. A well-described downstream target of the PI3K pathway is the forkhead box O (FOXO) transcription factor family. FOXOs have been implicated in many cellular responses, including drug-induced resistance in cancer cells. However, FOXO-dependent acute phase resistance mediated by pictilisib, a potent small molecule PI3K inhibitor (PI3Ki), has not been studied. Here, we report that pictilisib-induced adaptive resistance is regulated by the FOXO-dependent rebound activity of receptor tyrosine kinases (RTKs) in mucinous colorectal adenocarcinoma (MCA) cells. The resistance mediated by PI3K inhibition involves the nuclear localization of FOXO and the altered expression of RTKs, including ErbB2, ErbB3, EphA7, EphA10, IR, and IGF-R1 in MCA cells. Further, in the presence of FOXO siRNA, the pictilisib-induced feedback activation of RTK regulators (pERK and pAKT) was altered in MCA cells. Interestingly, the combinational treatment of pictilisib (Pi3Ki) and FOXO1i (AS1842856) synergistically reduced MCA cell viability and increased apoptosis. These results demonstrate that pictilisib used as a single agent induces acute resistance, partly through FOXO1 inhibition. Therefore, overcoming PI3Ki single-agent adaptive resistance by rational design of FOXO1 and PI3K inhibitor combinations could significantly enhance the therapeutic efficacy of PI3K-targeting drugs in MCA cells. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer 2.0)

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37 pages, 14563 KiB

Open AccessArticle

ABCG2 Gene and ABCG2 Protein Expression in Colorectal Cancer—In Silico and Wet Analysis

by Aleksandra Sałagacka-Kubiak, Dawid Zawada, Lias Saed, Radzisław Kordek, Agnieszka Jeleń and Ewa Balcerczak

Int. J. Mol. Sci. 2023, 24(13), 10539; https://doi.org/10.3390/ijms241310539 - 23 Jun 2023

Cited by 2 | Viewed by 1751

Abstract

ABCG2 (ATP-binding cassette superfamily G member 2) is a cell membrane pump encoded by the ABCG2 gene. ABCG2 can protect cells against compounds initiating and/or intensifying neoplasia and is considered a marker of stem cells responsible for cancer growth, drug resistance and recurrence. Expression of the ABCG2 gene or its protein has been shown to be a negative prognostic factor in various malignancies. However, its prognostic significance in colorectal cancer remains unclear. Using publicly available data, ABCG2 was shown to be underexpressed in colon and rectum adenocarcinomas, with lower expression compared to both the adjacent nonmalignant lung tissues and non-tumour lung tissues of healthy individuals. This downregulation could result from the methylation level of some sites of the ABCG2 gene. This was connected with microsatellite instability, weight and age among patients with colon adenocarcinoma, and with tumour localization, population type and age of patients for rectum adenocarcinoma. No association was found between ABCG2 expression level and survival of colorectal cancer patients. In wet analysis of colorectal cancer samples, neither ABCG2 gene expression, analysed by RT-PCR, nor ABCG2 protein level, assessed by immunohistochemistry, was associated with any clinicopathological factors or overall survival. An ABCG2-centered protein–protein interaction network build by STRING showed proteins were found to be involved in leukotriene, organic anion and xenobiotic transport, endodermal cell fate specification, and histone methylation and ubiquitination. Hence, ABCG2 underexpression could be an indicator of the activity of certain signalling pathways or protein interactors essential for colorectal carcinogenesis. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer 2.0)

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11 pages, 906 KiB

Open AccessCommunication

Analysis of Circulating Tumor DNA in Synchronous Metastatic Colorectal Cancer at Diagnosis Predicts Overall Patient Survival

by José María Sayagués, Juan Carlos Montero, Andrea Jiménez-Pérez, Sofía del Carmen, Marta Rodríguez, Rosario Vidal Tocino, Enrique Montero, Julia Sanz and Mar Abad

Int. J. Mol. Sci. 2023, 24(9), 8438; https://doi.org/10.3390/ijms24098438 - 08 May 2023

Viewed by 1554

Abstract

Sporadic colorectal cancer (sCRC) initially presents as metastatic tumors in 25–30% of patients. The 5-year overall survival (OS) in patients with metastatic sCRC is 50%, falling to 10% in patients presenting with synchronous metastatic disease (stage IV). In this study, we systematically analyzed the mutations of RAS, PIK3CA and BRAF genes in circulating tumor DNA (ctDNA) and tumoral tissue DNA (ttDNA) from 51 synchronous metastatic colorectal carcinoma (SMCC) patients by real-time PCR, and their relationship with the clinical, biological and histological features of disease at diagnosis. The highest frequency of mutations detected was in the KRAS gene, in tumor biopsies and plasma samples, followed by mutations of the PIK3CA, NRAS and BRAF genes. Overall, plasma systematically contained those genetic abnormalities observed in the tumor biopsy sample from the same subject, the largest discrepancies detected between the tumor biopsy and plasma from the same patient being for mutations in the KRAS and PIK3CA genes, with concordances of genotyping results between ttDNA and ctDNA at diagnosis of 75% and 84%, respectively. Of the 51 SMCC patients in the study, 25 (49%) showed mutations in at least 1 of the 4 genes analyzed in patient plasma. From the prognostic point of view, the presence and number of the most common mutations in the RAS, PIK3CA and BRAF genes in plasma from SMCC patients are independent prognostic factors for OS. Determination of the mutational status of ctDNA in SMCC could be a key tool for the clinical management of patients. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer 2.0)

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14 pages, 1161 KiB

Open AccessArticle

Muscarinic Acetylcholine Receptor M3 Expression and Survival in Human Colorectal Carcinoma—An Unexpected Correlation to Guide Future Treatment?

by Leonard A. Lobbes, Marcel A. Schütze, Raoul Droeser, Marco Arndt, Ioannis Pozios, Johannes C. Lauscher, Nina A. Hering and Benjamin Weixler

Int. J. Mol. Sci. 2023, 24(9), 8198; https://doi.org/10.3390/ijms24098198 - 03 May 2023

Cited by 3 | Viewed by 1568

Abstract

Muscarinic acetylcholine receptor M3 (M3R) has repeatedly been shown to be prominently expressed in human colorectal cancer (CRC), playing roles in proliferation and cell invasion. Its therapeutic targetability has been suggested in vitro and in animal models. We aimed to investigate the clinical role of MR3 expression in CRC for human survival. Surgical tissue samples from 754 CRC patients were analyzed for high or low immunohistochemical M3R expression on a clinically annotated tissue microarray (TMA). Immunohistochemical analysis was performed for established immune cell markers (CD8, TIA-1, FOXP3, IL 17, CD16 and OX 40). We used Kaplan–Meier curves to evaluate patients’ survival and multivariate Cox regression analysis to evaluate prognostic significance. High M3R expression was associated with increased survival in multivariate (hazard ratio (HR) = 0.52; 95% CI = 0.35–0.78; p = 0.001) analysis, as was TIA-1 expression (HR = 0.99; 95% CI = 0.94–0.99; p = 0.014). Tumors with high M3R expression were significantly more likely to be grade 2 compared to tumors with low M3R expression (85.7% vs. 67.1%, p = 0.002). The 5-year survival analysis showed a trend of a higher survival rate in patients with high M3R expression (46%) than patients with low M3R expression CRC (42%) (p = 0.073). In contrast to previous in vitro and animal model findings, this study demonstrates an increased survival for CRC patients with high M3R expression. This evidence is highly relevant for translation of basic research findings into clinically efficient treatments. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer 2.0)

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10 pages, 1991 KiB

Open AccessArticle

KRAS, NRAS, BRAF, HER2 and MSI Status in a Large Consecutive Series of Colorectal Carcinomas

by Aleksandr S. Martianov, Natalia V. Mitiushkina, Anastasia N. Ershova, Darya E. Martynenko, Mikhail G. Bubnov, Priscilla Amankwah, Grigory A. Yanus, Svetlana N. Aleksakhina, Vladislav I. Tiurin, Aigul R. Venina, Aleksandra A. Anuskina, Yuliy A. Gorgul, Anna D. Shestakova, Mikhail A. Maidin, Alexey M. Belyaev, Liliya S. Baboshkina, Aglaya G. Iyevleva and Evgeny N. Imyanitov

Int. J. Mol. Sci. 2023, 24(5), 4868; https://doi.org/10.3390/ijms24054868 - 02 Mar 2023

Cited by 9 | Viewed by 2249

Abstract

This study aimed to analyze clinical and regional factors influencing the distribution of actionable genetic alterations in a large consecutive series of colorectal carcinomas (CRCs). KRAS, NRAS and BRAF mutations, HER2 amplification and overexpression, and microsatellite instability (MSI) were tested in 8355 CRC samples. KRAS mutations were detected in 4137/8355 (49.5%) CRCs, with 3913 belonging to 10 common substitutions affecting codons 12/13/61/146, 174 being represented by 21 rare hot-spot variants, and 35 located outside the “hot” codons. KRAS Q61K substitution, which leads to the aberrant splicing of the gene, was accompanied by the second function-rescuing mutation in all 19 tumors analyzed. NRAS mutations were detected in 389/8355 (4.7%) CRCs (379 hot-spot and 10 non-hot-spot substitutions). BRAF mutations were identified in 556/8355 (6.7%) CRCs (codon 600: 510; codons 594–596: 38; codons 597–602: 8). The frequency of HER2 activation and MSI was 99/8008 (1.2%) and 432/8355 (5.2%), respectively. Some of the above events demonstrated differences in distribution according to patients’ age and gender. In contrast to other genetic alterations, BRAF mutation frequencies were subject to geographic variation, with a relatively low incidence in areas with an apparently warmer climate (83/1726 (4.8%) in Southern Russia and North Caucasus vs. 473/6629 (7.1%) in other regions of Russia, p = 0.0007). The simultaneous presence of two drug targets, BRAF mutation and MSI, was observed in 117/8355 cases (1.4%). Combined alterations of two driver genes were detected in 28/8355 (0.3%) tumors (KRAS/NRAS: 8; KRAS/BRAF: 4; KRAS/HER2: 12; NRAS/HER2: 4). This study demonstrates that a substantial portion of RAS alterations is represented by atypical mutations, KRAS Q61K substitution is always accompanied by the second gene-rescuing mutation, BRAF mutation frequency is a subject to geographical variations, and a small fraction of CRCs has simultaneous alterations in more than one driver gene. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer 2.0)

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9 pages, 1453 KiB

Open AccessArticle

Sleep Fragmentation Accelerates Carcinogenesis in a Chemical-Induced Colon Cancer Model

by Da-Been Lee, Seo-Yeon An, Sang-Shin Pyo, Jinkwan Kim, Suhng-Wook Kim and Dae-Wui Yoon

Int. J. Mol. Sci. 2023, 24(5), 4547; https://doi.org/10.3390/ijms24054547 - 25 Feb 2023

Cited by 3 | Viewed by 1751

Abstract

Aims of this study were to test whether sleep fragmentation (SF) increased carcinogenesis and to investigate the possible mechanisms of carcinogenesis in a chemical-induced colon cancer model. In this study, eight-week-old C57BL/6 mice were divided into Home cage (HC) and SF groups. After the azoxymethane (AOM) injection, the mice in the SF group were subjected to SF for 77 days. SF was accomplished in a sleep fragmentation chamber. In the second protocol, mice were divided into 2% dextran sodium sulfate (DSS)-treated, HC, and SF groups and were exposed to the HC or SF procedures. Immunohistochemical and immunofluorescent stainings were conducted to determine the level of 8-OHdG and reactive oxygen species (ROS), respectively. Quantitative real-time polymerase chain reaction was used to assess the relative expression of inflammatory and ROS-generating genes. The number of tumors and average tumor size were significantly higher in the SF group than in the HC group. The intensity (%) of the 8-OHdG stained area was significantly higher in the SF group than in the HC group. The fluorescence intensity of ROS was significantly higher in the SF group than the HC group. SF accelerated cancer development in a murine AOM/DSS-induced model of colon cancer, and the increased carcinogenesis was associated with ROS- and oxidative stress-induced DNA damage. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer 2.0)

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16 pages, 2982 KiB

Open AccessArticle

Development of a Novel Anti-CD44 Variant 6 Monoclonal Antibody C₄₄Mab-9 for Multiple Applications against Colorectal Carcinomas

by Ryo Ejima, Hiroyuki Suzuki, Tomohiro Tanaka, Teizo Asano, Mika K. Kaneko and Yukinari Kato

Int. J. Mol. Sci. 2023, 24(4), 4007; https://doi.org/10.3390/ijms24044007 - 16 Feb 2023

Cited by 13 | Viewed by 2741

Abstract

CD44 is a cell surface glycoprotein, and its isoforms are produced by the alternative splicing with the standard and variant exons. The CD44 variant exon-containing isoforms (CD44v) are overexpressed in carcinomas. CD44v6 is one of the CD44v, and its overexpression predicts poor prognosis in colorectal cancer (CRC) patients. CD44v6 plays critical roles in CRC adhesion, proliferation, stemness, invasiveness, and chemoresistance. Therefore, CD44v6 is a promising target for cancer diagnosis and therapy for CRC. In this study, we established anti-CD44 monoclonal antibodies (mAbs) by immunizing mice with CD44v3-10-overexpressed Chinese hamster ovary (CHO)-K1 cells. We then characterized them using enzyme-linked immunosorbent assay, flow cytometry, western blotting, and immunohistochemistry. One of the established clones (C₄₄Mab-9; IgG₁, kappa) reacted with a peptide of the variant 6-encoded region, indicating that C₄₄Mab-9 recognizes CD44v6. Furthermore, C₄₄Mab-9 reacted with CHO/CD44v3-10 cells or CRC cell lines (COLO201 and COLO205) by flow cytometry. The apparent dissociation constant (K_D) of C₄₄Mab-9 for CHO/CD44v3-10, COLO201, and COLO205 was 8.1 × 10⁻⁹ M, 1.7 × 10⁻⁸ M, and 2.3 × 10⁻⁸ M, respectively. C₄₄Mab-9 detected the CD44v3-10 in western blotting, and partially stained the formalin-fixed paraffin-embedded CRC tissues in immunohistochemistry. Collectively, C₄₄Mab-9 is useful for detecting CD44v6 in various applications. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer 2.0)

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19 pages, 1348 KiB

Open AccessReview

Targeting KRAS G12C Mutation in Colorectal Cancer, A Review: New Arrows in the Quiver

by Javier Ros, Caterina Vaghi, Iosune Baraibar, Nadia Saoudi González, Marta Rodríguez-Castells, Ariadna García, Adriana Alcaraz, Francesc Salva, Josep Tabernero and Elena Elez

Int. J. Mol. Sci. 2024, 25(6), 3304; https://doi.org/10.3390/ijms25063304 - 14 Mar 2024

Viewed by 1134

Abstract

Kirsten rat sarcoma virus oncogene homolog (KRAS) is the most frequently mutated oncogene in human cancer. In colorectal cancer (CRC), KRAS mutations are present in more than 50% of cases, and the KRAS glycine-to-cysteine mutation at codon 12 (KRAS G12C) occurs in up to 4% of patients. This mutation is associated with short responses to standard chemotherapy and worse overall survival compared to non-G12C mutations. In recent years, several KRAS G12C inhibitors have demonstrated clinical activity, although all patients eventually progressed. The identification of negative feedback through the EGFR receptor has led to the development of KRAS inhibitors plus an anti-EGFR combination, thus boosting antitumor activity. Currently, several KRAS G12C inhibitors are under development, and results from phase I and phase II clinical trials are promising. Moreover, the phase III CodeBreaK 300 trial demonstrates the superiority of sotorasib-panitumumab over trifluridine/tipiracil, establishing a new standard of care for patients with colorectal cancer harboring KRAS G12C mutations. Other combinations such as adagrasib-cetuximab, divarasib-cetuximab, or FOLFIRI-panitumumab-sotorasib have also shown a meaningful response rate and are currently under evaluation. Nonetheless, most of these patients will eventually relapse. In this setting, liquid biopsy emerges as a critical tool to characterize the mechanisms of resistance, consisting mainly of acquired genomic alterations in the MAPK and PI3K pathways and tyrosine kinase receptor alterations, but gene fusions, histological changes, or conformational changes in the kinase have also been described. In this paper, we review the development of KRAS G12C inhibitors in colorectal cancer as well as the main mechanisms of resistance. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer 2.0)

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13 pages, 1201 KiB

Open AccessReview

Exosomes in Colorectal Cancer: From Physiology to Clinical Applications

by Stefan Titu, Vlad Alexandru Gata, Roxana Maria Decea, Teodora Mocan, Constantin Dina, Alexandru Irimie and Cosmin Ioan Lisencu

Int. J. Mol. Sci. 2023, 24(5), 4382; https://doi.org/10.3390/ijms24054382 - 23 Feb 2023

Cited by 6 | Viewed by 2571

Abstract

Exosomes are nanosized vesicles that have been found to be involved in many diseases. Exosomes can mediate communication between cells in a variety of ways. Certain types of mediators derived from cancer cells can play a crucial role in the development of this pathology, promoting tumor growth, invasion, metastasis, angiogenesis, and immunomodulation. Exosomes in the bloodstream show promise as a future tool for detecting cancer at an early stage. The sensitivity and specificity of clinical exosome biomarkers need to be enhanced. Knowledge of exosomes is not only important for understanding the significance of cancer progression but also for providing clinicians with useful information for the diagnosis, treatment, and discovery of methods to prevent cancer from recurring. The widespread adoption of diagnostic tools based on exosomes may revolutionize cancer diagnosis and treatment. Tumor metastasis, chemoresistance, and immunity are all aided by exosomes. A potential new approach to cancer therapy involves preventing metastasis by inhibiting miRNA intracellular signaling and blocking the formation of pre-metastatic niches. For colorectal patients, exosomes represent a promising area of investigation for improving the diagnosis, treatment, and management. Reported data demonstrate that the serum expression level of certain exosomal miRNA is significantly higher in primary colorectal cancer patients. The present review discusses mechanisms and clinical implications of exosomes in colorectal cancer. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer 2.0)

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12 pages, 2790 KiB

Open AccessCase Report

Complete Metabolic Response to Combined Immune Checkpoint Inhibition after Progression of Metastatic Colorectal Cancer on Pembrolizumab: A Case Report

by Carolin Krekeler, Klaus Wethmar, Jan-Henrik Mikesch, Andrea Kerkhoff, Kerstin Menck, Georg Lenz, Hans-Ulrich Schildhaus, Michael Wessolly, Matthias W. Hoffmann, Andreas Pascher, Inga Asmus, Eva Wardelmann and Annalen Bleckmann

Int. J. Mol. Sci. 2023, 24(15), 12056; https://doi.org/10.3390/ijms241512056 - 27 Jul 2023

Cited by 1 | Viewed by 1776

Abstract

DNA mismatch repair deficient (dMMR) and microsatellite instable (MSI) metastatic colorectal cancer (mCRC) can be successfully treated with FDA- and EMA-approved immune checkpoint inhibitors (ICI) pembrolizumab and nivolumab (as single agents targeting the anti-programmed cell death protein-1 (PD-1)) or combinations of a PD-1 inhibitor with ipilimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)-targeting antibody. The best treatment strategy beyond progression on single-agent ICI therapy remains unclear. Here, we present the case of a 63-year-old male with Lynch-syndrome-associated, microsatellite instability-high (MSI-H) mCRC who achieved a rapid normalization of his tumor markers and a complete metabolic remission (CMR), currently lasting for ten months, on sequential ICI treatment with the combination of nivolumab and ipilimumab followed by nivolumab maintenance therapy after progression on single-agent anti-PD-1 ICI therapy. The therapy was well-tolerated, and no immune-related adverse events occurred. To the best of our knowledge, this is the first case of a sustained metabolic complete remission in an MSI-H mCRC patient initially progressing on single-agent anti-PD-1 therapy. Thus, dMMR mCRC patients might benefit from sequential immune checkpoint regimens even with long-term responses. However, further sophistication of clinical algorithms for treatment beyond progression on single-agent ICI therapy in MSI-mCRC is urgently needed. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer 2.0)

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