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Molecular Mechanisms and Therapies of Colorectal Cancer 3.0
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Molecular Mechanisms and Therapies of Colorectal Cancer 3.0

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 3062

Special Issue Editor

Dr. Donatella Delle Cave

E-Mail Website
Guest Editor
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
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

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

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

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

Related Special Issues

Published Papers (4 papers)

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Research

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10 pages, 1277 KiB  
Communication
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 282
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 [...] Read more.
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  
Article
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 944
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 [...] Read more.
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  
Review
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 608
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 [...] Read more.
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  
Brief 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 676
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 [...] Read more.
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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