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Molecular Mechanisms and Therapies of Colorectal Cancer 3.0

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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: 30 May 2024 | Viewed by 4909

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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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Keywords

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

Related Special Issues

Molecular Mechanisms and Therapies of Colorectal Cancer in International Journal of Molecular Sciences (16 articles)
Molecular Mechanisms and Therapies of Colorectal Cancer 2.0 in International Journal of Molecular Sciences (12 articles)

Published Papers (8 papers)

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Research

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16 pages, 5175 KiB

Open AccessArticle

Genetic Insights into Colorectal Cancer: Evaluating PI3K/AKT Signaling Pathway Genes Expression

by Rafał Świechowski, Jacek Pietrzak, Agnieszka Wosiak, Michał Mik and Ewa Balcerczak

Int. J. Mol. Sci. 2024, 25(11), 5806; https://doi.org/10.3390/ijms25115806 - 27 May 2024

Viewed by 255

Abstract

The PI3K/AKT pathway plays a pivotal role in cellular processes, and its dysregulation is implicated in various cancers, including colorectal cancer. The present study correlates the expression levels of critical genes (PIK3CA, PTEN, AKT1, FOXO1, and FRAP) in 60 tumor tissues with clinicopathological and demographic characteristics. The results indicate age-related variation in FOXO1 gene expression, with higher levels observed in patients aged 68 and above. In addition, tumors originating from the rectum exhibit higher FOXO1 expression compared to colon tumors, suggesting region-specific differences in expression. The results also identify the potential correlation between PTEN, PIK3CA gene expression, and parameters such as tumor grade and neuroinvasion. The bioinformatic comparative analysis found that PTEN and FOXO1 expressions were downregulated in colorectal cancer tissue compared to normal colon tissue. Relapse-free survival analysis based on gene expression identified significant correlations, highlighting PTEN and FRAP as potential indicators of favorable outcomes. Our findings provide a deeper understanding of the role of the PI3K/AKT pathway in colorectal cancer and the importance of understanding the molecular basis of colorectal cancer development and progression. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer 3.0)

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16 pages, 1923 KiB

Open AccessArticle

Erk Inhibition as a Promising Therapeutic Strategy for High IL-8-Secreting and Low SPTAN1-Expressing Colorectal Cancer

by Clara Meier, Gianluca La Rocca, Virginia Nawrot, Beate Fißlthaler, Sarah J. Overby, Kai Hourfar, Guido Plotz, Christian Seidl, Paul Ziegler, Peter Wild, Stefan Zeuzem, Jürgen Brieger, Elke Jäger, Achim Battmann and Angela Brieger

Int. J. Mol. Sci. 2024, 25(11), 5658; https://doi.org/10.3390/ijms25115658 - 23 May 2024

Viewed by 253

Abstract

Tumor recurrence and drug resistance are responsible for poor prognosis in colorectal cancer (CRC). DNA mismatch repair (MMR) deficiency or elevated interleukin-8 (IL-8) levels are characteristics of CRCs, which have been independently correlated with treatment resistance to common therapies. We recently demonstrated significantly impaired therapeutical response and increased IL-8 release of CRC cell lines with reduced expression of MMR protein MLH1 as well as cytoskeletal non-erythrocytic spectrin alpha II (SPTAN1). In the present study, decreased intratumoral MLH1 and SPTAN1 expression in CRCs could be significantly correlated with enhanced serum IL-8. Furthermore, using stably reduced SPTAN1-expressing SW480, SW620 or HT-29 cell lines, the RAS-mediated RAF/MEK/ERK pathway was analyzed. Here, a close connection between low SPTAN1 expression, increased IL-8 secretion, enhanced extracellular-signal-regulated kinase (ERK) phosphorylation and a mesenchymal phenotype were detected. The inhibition of ERK by U0126 led to a significant reduction in IL-8 secretion, and the combination therapy of U0126 with FOLFOX optimizes the response of corresponding cancer cell lines. Therefore, we hypothesize that the combination therapy of FOLFOX and U0126 may have great potential to improve drug efficacy on this subgroup of CRCs, showing decreased MLH1 and SPTAN1 accompanied with high serum IL-8 in affected patients. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer 3.0)

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16 pages, 2515 KiB

Open AccessArticle

Combination of FOLFOXIRI Drugs with Oncolytic Coxsackie B3 Virus PD-H Synergistically Induces Oncolysis in the Refractory Colorectal Cancer Cell Line Colo320

by Maxim Girod, Anja Geisler, Luisa Hinze, Leslie Elsner, Babette Dieringer, Antje Beling, Jens Kurreck and Henry Fechner

Int. J. Mol. Sci. 2024, 25(11), 5618; https://doi.org/10.3390/ijms25115618 - 22 May 2024

Viewed by 305

Abstract

FOLFOXIRI chemotherapy is a first-line therapy for advanced or metastatic colorectal cancer (CRC), yet its therapeutic efficacy remains limited. Immunostimulatory therapies like oncolytic viruses can complement chemotherapies by fostering the infiltration of the tumor by immune cells and enhancing drug cytotoxicity. In this study, we explored the effect of combining the FOLFOXIRI chemotherapeutic agents with the oncolytic coxsackievirus B3 (CVB3) PD-H in the CRC cell line Colo320. Additionally, we examined the impact of the drugs on the expression of microRNAs (miRs), which could be used to increase the safety of oncolytic CVB3 containing corresponding miR target sites (miR-TS). The measurement of cytotoxic activity using the Chou–Talalay combination index approach revealed that PD-H synergistically enhanced the cytotoxic activity of oxaliplatin (OX), 5-fluorouracil (5-FU) and SN-38. PD-H replication was not affected by OX and SN-38 but inhibited by high concentrations of 5-FU. MiR expression levels were not or only slightly elevated by the drugs or with drug/PD-H combinations on Colo320 cells. Moreover, the drug treatment did not increase the mutation rate of the miR-TS inserted into the PD-H genome. The results demonstrate that the combination of FOLFOXIRI drugs and PD-H may be a promising approach to enhance the therapeutic effect of FOLFOXIRI therapy in CRC. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer 3.0)

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15 pages, 4045 KiB

Open AccessArticle

Additive Cytotoxic and Colony-Formation Inhibitory Effects of Aspirin and Metformin on PI3KCA-Mutant Colorectal Cancer Cells

by Joana Gonçalves, Sara Pinto, Francisca Carmo, Cláudia Silva, Nelson Andrade and Fátima Martel

Int. J. Mol. Sci. 2024, 25(10), 5381; https://doi.org/10.3390/ijms25105381 - 15 May 2024

Viewed by 382

Abstract

Human malignancies are one of the major health-related issues throughout the world and are anticipated to rise in the future. Despite huge investments made in anticancer drug development, limited success has been obtained and the average number of FDA approvals per year is declining. So, an increasing interest in drug repurposing exists. Metformin (MET) and aspirin (ASP) possess anticancer properties. This work aims to test the effect of these two drugs in combination on colorectal cancer (CRC) cells in vitro. The effects of MET and/or ASP on cell proliferation, viability, migratory ability, anchorage-independent growth ability (colony formation), and nutrient uptake were determined in two (HT-29 and Caco-2) human CRC cell lines. Individually, MET and ASP possessed antiproliferative, cytotoxic, and antimigratory effects and reduced colony formation in HT-29 cells (BRAF- and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PI3KCA)-mutant), although MET did not affect either ³H-deoxy-D-glucose or ¹⁴C-butyrate uptake and lactate production, and ASP caused only a small decrease in ¹⁴C-butyrate uptake. Moreover, in these cells, the combination of MET and ASP resulted in a tendency to an increase in the cytotoxic effect and in a potentiation of the inhibitory effect on colony formation, although no additive antiproliferative and antimigratory effects, and no effect on nutrient uptake and lactate production were observed. In contrast, MET and ASP, both individually and in combination, were almost devoid of effects on Caco-2 cells (BRAF- and PI3KCA-wild type). We suggest that inhibition of PI3K is the common mechanism involved in the anti-CRC effect of both MET, ASP and their combination and, therefore, that the combination of MET + ASP may especially benefit PI3KCA-mutant CRC cases, which currently have a poor prognostic. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer 3.0)

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10 pages, 1277 KiB

Open AccessCommunication

TGFβ-Responsive Stromal Activation Occurs Early in Serrated Colorectal Carcinogenesis

by Hideaki Tsumuraya, Hirokazu Okayama, Masanori Katagata, Akira Matsuishi, Satoshi Fukai, Misato Ito, Wataru Sakamoto, Motonobu Saito, Tomoyuki Momma, Shotaro Nakajima, Kosaku Mimura and Koji Kono

Int. J. Mol. Sci. 2024, 25(9), 4626; https://doi.org/10.3390/ijms25094626 - 24 Apr 2024

Viewed by 509

Abstract

Activated TGFβ signaling in the tumor microenvironment, which occurs independently of epithelial cancer cells, has emerged as a key driver of tumor progression in late-stage colorectal cancer (CRC). This study aimed to elucidate the contribution of TGFβ-activated stroma to serrated carcinogenesis, representing approximately 25% of CRCs and often characterized by oncogenic BRAF mutations. We used a transcriptional signature developed based on TGFβ-responsive, stroma-specific genes to infer TGFβ-dependent stromal activation and conducted in silico analyses in 3 single-cell RNA-seq datasets from a total of 39 CRC samples and 12 bulk transcriptomic datasets consisting of 2014 CRC and 416 precursor samples, of which 33 were serrated lesions. Single-cell analyses validated that the signature was expressed specifically by stromal cells, effectively excluding transcriptional signals derived from epithelial cells. We found that the signature was upregulated during malignant transformation and cancer progression, and it was particularly enriched in CRCs with mutant BRAF compared to wild-type counterparts. Furthermore, across four independent precursor datasets, serrated lesions exhibited significantly higher levels of TGFβ-responsive stromal activation compared to conventional adenomas. This large-scale analysis suggests that TGFβ-dependent stromal activation occurs early in serrated carcinogenesis. Our study provides novel insights into the molecular mechanisms underlying CRC development via the serrated pathway. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer 3.0)

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11 pages, 965 KiB

Open AccessArticle

Breath Fingerprint of Colorectal Cancer Patients Based on the Gas Chromatography–Mass Spectrometry Analysis

by Elīna Kononova, Linda Mežmale, Inese Poļaka, Viktors Veliks, Linda Anarkulova, Ilona Vilkoite, Ivars Tolmanis, Anna Marija Ļeščinska, Ilmārs Stonāns, Andrejs Pčolkins, Pawel Mochalski and Mārcis Leja

Int. J. Mol. Sci. 2024, 25(3), 1632; https://doi.org/10.3390/ijms25031632 - 29 Jan 2024

Viewed by 1043

Abstract

The human body emits a multitude of volatile organic compounds (VOCs) via tissues and various bodily fluids or exhaled breath. These compounds collectively create a distinctive chemical profile, which can potentially be employed to identify changes in human metabolism associated with colorectal cancer (CRC) and, consequently, facilitate the diagnosis of this disease. The main goal of this study was to investigate and characterize the VOCs’ chemical patterns associated with the breath of CRC patients and controls and identify potential expiratory markers of this disease. For this purpose, gas chromatography–mass spectrometry was applied. Collectively, 1656 distinct compounds were identified in the breath samples provided by 152 subjects. Twenty-two statistically significant VOCs (p-xylene; hexanal; 2-methyl-1,3-dioxolane; 2,2,4-trimethyl-1,3-pentanediol diisobutyrate; hexadecane; nonane; ethylbenzene; cyclohexanone; diethyl phthalate; 6-methyl-5-hepten-2-one; tetrahydro-2H-pyran-2-one; 2-butanone; benzaldehyde; dodecanal; benzothiazole; tetradecane; 1-dodecanol; 1-benzene; 3-methylcyclopentyl acetate; 1-nonene; toluene) were observed at higher concentrations in the exhaled breath of the CRC group. The elevated levels of these VOCs in CRC patients’ breath suggest the potential for these compounds to serve as biomarkers for CRC. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer 3.0)

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Review

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13 pages, 434 KiB

Open AccessReview

Assessing Circulating Tumour DNA (ctDNA) as a Biomarker for Anal Cancer Management: A Systematic Review

by Hugo C. Temperley, Timothy Fannon, Niall J. O’Sullivan, Maeve O’Neill, Benjamin M. Mac Curtain, Charles Gilham, Jacintha O’Sullivan, Grainne O’Kane, Brian J. Mehigan, Sharon O’Toole, John O. Larkin, David Gallagher, Paul McCormick and Michael E. Kelly

Int. J. Mol. Sci. 2024, 25(7), 4005; https://doi.org/10.3390/ijms25074005 - 3 Apr 2024

Viewed by 737

Abstract

This systematic review investigates the potential of circulating tumour DNA (ctDNA) as a predictive biomarker in the management and prognosis of squamous cell carcinoma of the anal canal (SCCA). PubMed, EMBASE, and Cochrane Central Registry of Controlled Trials were searched until 7 January 2024. Selection criteria included research articles exploring ctDNA in the context of anal cancer treatment response, recurrence risk assessment, and consideration of salvage surgery. A total of eight studies were therefore included in the final review, examining a total of 628 patients. These studies focused on three main themes: SCCA diagnosis and staging, treatment response, and patient outcomes. Significant heterogeneity was observed in terms of patient cohort, study methodology, and ctDNA biomarkers. Four studies provided information on the sensitivity of ctDNA biomarkers in SCCA, with a range of 82–100%. Seven studies noted a correlation between pre-treatment ctDNA levels and SCCA disease burden, suggesting that ctDNA could play a role as a biomarker for the staging of SCCA. Across all seven studies with paired pre- and post-treatment ctDNA samples, a trend was seen towards decreasing ctDNA levels post-treatment, with specific identification of a ‘fast elimination’ group who achieve undetectable ctDNA levels prior to the end of treatment and may be less likely to experience treatment failure. Residual ctDNA detection post-treatment was associated with poorer patient prognosis. This systematic review identifies the broad potential of ctDNA as a useful and decisive tool in the management of SCCA. Further analysis of ctDNA biomarkers that include larger patient cohorts is required in order to clearly evaluate their potential role in clinical decision-making processes. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer 3.0)

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Other

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14 pages, 1624 KiB

Open AccessBrief Report

Renin–Angiotensin Inhibitor, Captopril, Attenuates Growth of Patient-Derived Colorectal Liver Metastasis Organoids

by Georgina E. Riddiough, Theodora Fifis, Vijayaragavan Muralidharan, Christopher Christophi, Bang M. Tran, Marcos V. Perini and Elizabeth Vincan

Int. J. Mol. Sci. 2024, 25(6), 3282; https://doi.org/10.3390/ijms25063282 - 14 Mar 2024

Viewed by 765

Abstract

The recurrence of colorectal liver metastasis (CRLM) following liver resection is common; approximately 40% of patients will experience tumor recurrence post-surgery. Renin–angiotensin inhibitors (RASis) have been shown to attenuate the growth and progression of CRLM in pre-clinical models following liver resection. This study examined the efficacy of the RASi captopril on patient-derived colorectal liver metastasis organoids. Patient-derived organoids (PDOs) were established using fresh samples of colorectal liver metastasis from appropriately consented patients undergoing liver resection. To mimic the regenerating liver post-CRLM liver resection, PDOs were cultured under hepatocyte regeneration conditions in vitro. CRLM PDOs were established from three patients’ parent tissue. CRLM PDOs and parent tissue expressed markers of colorectal cancer, CDX2 and CK20, consistently. Furthermore, CRLM PDOs treated with captopril showed a dose dependent reduction in their expansion in vitro. In conclusion, CRLM PDOs recapitulate in vivo disease and displayed a dose-dependent response to treatment with captopril. RASis may be an additional viable treatment for patients with CRLM. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer 3.0)

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