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Molecular and Translational Research on Colorectal Cancer 2.0
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Molecular and Translational Research on Colorectal Cancer 2.0

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: closed (31 January 2021) | Viewed by 45376

Special Issue Editors

Prof. Dr. Emanuela Scarpi

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Guest Editor
Unit of Biostatistics and Clinical Trials, IRCCS-Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori"- IRST-Srl, Via P. Maroncelli 40, 47014 Meldola, Italy
Interests: biostatistics; clinical trials; observational study; tumor epidemiology; oncology; palliative care; biomarkers
Special Issues, Collections and Topics in MDPI journals
Dr. Paola Ulivi

E-Mail Website
Guest Editor
Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori “Dino Amadori” (IRST), via P. Maroncelli 40, 47014 Meldola, Italy
Interests: translational research; biomarkers; liquid biopsy; oncology
Special Issues, Collections and Topics in MDPI journals
Dr. Alessandro Passardi

E-Mail Website
Guest Editor
Department of Medical Oncology, IRCCS-Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori"- IRST-Srl, Via P. Maroncelli 40, 47014 Meldola, Italy
Interests: translational research; angiogenesis; colorectal cancer; pancreatic cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in males and the second in females. The genome of colon cancer cells is altered at several sites as a result of point mutations or changes in chromosome integrity. The mutation-associated changes affect oncogenes, tumor suppressor genes, and several metastasis-related genes. Other factors including epigenetic alterations as well as the deregulation of miRNA-mediated control of mRNA functions, contribute to the incidence of cancer and metastasis.

Translational research has led to significant benefits in CRC screening and patient management, and precision medicine is fast becoming the aim of scientific research. Individualized treatment for CRC in both adjuvant and metastatic settings is increasingly emphasized. The introduction of molecular-targeted agents with anti-epidermal growth factor receptor (EGFR) or anti-angiogenic mechanisms of action has significantly improved patient outcome, but predictive markers of efficacy, especially for angiogenesis inhibition, are still lacking. Furthermore immunotherapy has recently been implemented into clinical practice.

A new approach to biomarker detection is the use of liquid biopsy. Free circulating tumor DNA (fctDNA) can be monitored quantitatively and qualitatively for diagnostic, prognostic, or predictive purposes. Liquid biopsy has the potential to replace tumor tissue analysis in clinical practice and could be used to monitor the extent of tumor burden and to detect tumor heterogeneity and molecular resistance to therapy.

Prof. Dr. Emanuela Scarpi
Dr. Paola Ulivi
Dr. Alessandro Passardi
Guest Editors

Manuscript Submission Information

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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

  • Adenoma-carcinoma sequence
  • Predictive biomarkers of response and toxicity in the adjuvant and metastatic settings
  • Genetic and epigenetic marker
  • Immunotherapy
  • Prognostic biomarkers
  • Angiogenesis
  • EGFR pathways
  • Tumor biopsies
  • Circulating tumor cells
  • Tumor heterogeneity
  • Early diagnosis
  • Screening
  • Liquid biopsy
  • Molecular pathology
  • Tumor biology

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Published Papers (7 papers)

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Editorial

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2 pages, 173 KiB  
Editorial
Special Issue on Molecular and Translational Research on Colorectal Cancer 2.0
by Alessandro Passardi, Emanuela Scarpi and Paola Ulivi
Int. J. Mol. Sci. 2021, 22(14), 7479; https://doi.org/10.3390/ijms22147479 - 13 Jul 2021
Cited by 1 | Viewed by 2170
Abstract
The present editorial aims to summarise the six scientific papers that have contributed to this Special Issue, focusing on different aspects of molecular and translational research on colorectal cancer. We believe that the present Special Issue might contribute to the expansion of the [...] Read more.
The present editorial aims to summarise the six scientific papers that have contributed to this Special Issue, focusing on different aspects of molecular and translational research on colorectal cancer. We believe that the present Special Issue might contribute to the expansion of the current knowledge concerning potential molecular predictive and/or prognostic biomarkers in CRC, as well as new targets for anticancer treatment. This may help in identifying new strategies to improve diagnostic and therapeutic approaches. Full article
(This article belongs to the Special Issue Molecular and Translational Research on Colorectal Cancer 2.0)

Research

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11 pages, 2311 KiB  
Article
Granulin: An Invasive and Survival-Determining Marker in Colorectal Cancer Patients
by Fee Klupp, Christoph Kahlert, Clemens Franz, Niels Halama, Nikolai Schleussner, Naita M. Wirsik, Arne Warth, Thomas Schmidt and Alexis B. Ulrich
Int. J. Mol. Sci. 2021, 22(12), 6436; https://doi.org/10.3390/ijms22126436 - 16 Jun 2021
Cited by 7 | Viewed by 2461
Abstract
Background: Granulin is a secreted, glycosylated peptide—originated by cleavage from a precursor protein—which is involved in cell growth, tumor invasion and angiogenesis. However, the specific prognostic impact of granulin in human colorectal cancer has only been studied to a limited extent. Thus, we [...] Read more.
Background: Granulin is a secreted, glycosylated peptide—originated by cleavage from a precursor protein—which is involved in cell growth, tumor invasion and angiogenesis. However, the specific prognostic impact of granulin in human colorectal cancer has only been studied to a limited extent. Thus, we wanted to assess the expression of granulin in colorectal cancer patients to evaluate its potential as a prognostic biomarker. Methods: Expressional differences of granulin in colorectal carcinoma tissue (n = 94) and corresponding healthy colon mucosa were assessed using qRT-PCR. Immunohistochemistry was performed in colorectal cancer specimens (n = 97), corresponding healthy mucosa (n = 47) and colorectal adenomas (n = 19). Subsequently, the results were correlated with histopathological and clinical patients’ data. HCT-116 cells were transfected with siRNA for invasion and migration assays. Results: Immunohistochemistry and qRT-PCR revealed tumoral over expression of granulin in colorectal cancer specimens compared to corresponding healthy colon mucosa and adenomas. Tumoral overexpression of granulin was associated with a significantly impaired overall survival. Moreover, downregulation of granulin by siRNA significantly diminished the invasive capacities of HCT-116 cells in vitro. Conclusion: Expression of granulin differs in colorectal cancer tissue, adenomas and healthy colon mucosa. Furthermore, granulin features invasive and migrative capabilities and overexpression of granulin correlates with a dismal prognosis. This reveals its potential as a prognostic biomarker and granulin could be a worthwhile molecular target for individualized anticancer therapy. Full article
(This article belongs to the Special Issue Molecular and Translational Research on Colorectal Cancer 2.0)
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14 pages, 2942 KiB  
Article
Dehydroxyhispolon Methyl Ether, A Hispolon Derivative, Inhibits WNT/β-Catenin Signaling to Elicit Human Colorectal Carcinoma Cell Apoptosis
by Hueng-Chuen Fan, Ya-Chu Hsieh, Li-Hsuan Li, Ching-Chin Chang, Karolína Janoušková, Modukuri V. Ramani, Gottumukkala V. Subbaraju, Kur-Ta Cheng and Chia-Che Chang
Int. J. Mol. Sci. 2020, 21(22), 8839; https://doi.org/10.3390/ijms21228839 - 22 Nov 2020
Cited by 25 | Viewed by 2746
Abstract
Colorectal cancer (CRC) is the fourth leading cause of cancer mortality worldwide. Aberrant activation of WNT/β-catenin signaling present in the vast majority of CRC cases is indispensable for CRC initiation and progression, and thus is a promising target for CRC therapeutics. Hispolon is [...] Read more.
Colorectal cancer (CRC) is the fourth leading cause of cancer mortality worldwide. Aberrant activation of WNT/β-catenin signaling present in the vast majority of CRC cases is indispensable for CRC initiation and progression, and thus is a promising target for CRC therapeutics. Hispolon is a fungal-derived polyphenol with a pronounced anticancer effect. Several hispolon derivatives, including dehydroxyhispolon methyl ether (DHME), have been chemically synthesized for developing lead molecules with stronger anticancer activity. Herein, a DHME-elicited anti-CRC effect with the underlying mechanism is reported for the first time. Specifically, DHME was found to be more cytotoxic than hispolon against a panel of human CRC cell lines, while exerting limited toxicity to normal human colon cell line CCD 841 CoN. Additionally, the cytotoxic effect of DHME appeared to rely on inducing apoptosis. This notion was evidenced by DHME-elicited upregulation of poly (ADP-ribose) polymerase (PARP) cleavage and a cell population positively stained by annexin V, alongside the downregulation of antiapoptotic B-cell lymphoma 2 (BCL-2), whereas the blockade of apoptosis by the pan-caspase inhibitor z-VAD-fmk attenuated DHME-induced cytotoxicity. Further mechanistic inquiry revealed the inhibitory action of DHME on β-catenin-mediated, T-cell factor (TCF)-dependent transcription activity, suggesting that DHME thwarted the aberrantly active WNT/β-catenin signaling in CRC cells. Notably, ectopic expression of a dominant–active β-catenin mutant (∆N90-β-catenin) abolished DHME-induced apoptosis while also restoring BCL-2 expression. Collectively, we identified DHME as a selective proapoptotic agent against CRC cells, exerting more potent cytotoxicity than hispolon, and provoking CRC cell apoptosis via suppression of the WNT/β-catenin signaling axis. Full article
(This article belongs to the Special Issue Molecular and Translational Research on Colorectal Cancer 2.0)
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12 pages, 1988 KiB  
Article
Prognostic Relevance of HJURP Expression in Patients with Surgically Resected Colorectal Cancer
by Dong Hyun Kang, Jongsoo Woo, Hyeongjoo Kim, Soo Youn Kim, Sanghee Ji, Gunn Jaygal, Tae Sung Ahn, Han Jo Kim, Hyoung Jong Kwak, Chang-Jin Kim, Moo-Jun Baek and Dongjun Jeong
Int. J. Mol. Sci. 2020, 21(21), 7928; https://doi.org/10.3390/ijms21217928 - 26 Oct 2020
Cited by 24 | Viewed by 2617
Abstract
HJURP is a key factor for CENP-A deposition and maintenance in centromeres. The role of mis-regulation of histone chaperones in cancer initiation and progression has been studied. However, its role in colorectal cancer is still unclear. In this study, we aimed to evaluate [...] Read more.
HJURP is a key factor for CENP-A deposition and maintenance in centromeres. The role of mis-regulation of histone chaperones in cancer initiation and progression has been studied. However, its role in colorectal cancer is still unclear. In this study, we aimed to evaluate the expression of HJURP in 162 colorectal cancer tissue. To investigate the function of HJURP in the colorectal cancer cell, we suppressed HJURP expression by siRNA and confirmed proliferation, migration, invasion, and anchorage independent of colony forming ability. The association between HJURP expression levels and clinicopathological factors was evaluated in 162 CRC tissues using immunohistochemistry. The overall survival rate in patients of HJURP high expression was higher than those in HJURP low expression in CRC. Suppressing HJURP expression decreased cellular proliferation, invasion, and migration in four CRC cell lines: HT29, HCT116, SW480, SW620 in vitro study. Our findings revealed that the knockdown of HJURP suppressed the proliferation, migration, invasion, and tumorigenicity in CRC cells. Due to its strong association with CRC, HJURP could be a potential prognostic biomarker and a novel target for drug discovery. Full article
(This article belongs to the Special Issue Molecular and Translational Research on Colorectal Cancer 2.0)
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Review

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17 pages, 795 KiB  
Review
Current and Prospective Methods for Assessing Anti-Tumor Immunity in Colorectal Cancer
by Yulia I. Nussbaum, Yariswamy Manjunath, Kanve N. Suvilesh, Wesley C. Warren, Chi-Ren Shyu, Jussuf T. Kaifi, Matthew A. Ciorba and Jonathan B. Mitchem
Int. J. Mol. Sci. 2021, 22(9), 4802; https://doi.org/10.3390/ijms22094802 - 30 Apr 2021
Cited by 8 | Viewed by 3932
Abstract
Colorectal cancer (CRC) remains one of the deadliest malignancies worldwide despite recent progress in treatment strategies. Though immune checkpoint inhibition has proven effective for a number of other tumors, it offers benefits in only a small group of CRC patients with high microsatellite [...] Read more.
Colorectal cancer (CRC) remains one of the deadliest malignancies worldwide despite recent progress in treatment strategies. Though immune checkpoint inhibition has proven effective for a number of other tumors, it offers benefits in only a small group of CRC patients with high microsatellite instability. In general, heterogenous cell groups in the tumor microenvironment are considered as the major barrier for unveiling the causes of low immune response. Therefore, deconvolution of cellular components in highly heterogeneous microenvironments is crucial for understanding the immune contexture of cancer. In this review, we assimilate current knowledge and recent studies examining anti-tumor immunity in CRC. We also discuss the utilization of novel immune contexture assessment methods that have not been used in CRC research to date. Full article
(This article belongs to the Special Issue Molecular and Translational Research on Colorectal Cancer 2.0)
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23 pages, 1711 KiB  
Review
Molecular Mechanisms of Colon Cancer Progression and Metastasis: Recent Insights and Advancements
by Ahmed Malki, Rasha Abu ElRuz, Ishita Gupta, Asma Allouch, Semir Vranic and Ala-Eddin Al Moustafa
Int. J. Mol. Sci. 2021, 22(1), 130; https://doi.org/10.3390/ijms22010130 - 24 Dec 2020
Cited by 209 | Viewed by 21291
Abstract
Colorectal cancer (CRC), the third most common type of cancer, is the second leading cause of cancer-related mortality rates worldwide. Although modern research was able to shed light on the pathogenesis of CRC and provide enhanced screening strategies, the prevalence of CRC is [...] Read more.
Colorectal cancer (CRC), the third most common type of cancer, is the second leading cause of cancer-related mortality rates worldwide. Although modern research was able to shed light on the pathogenesis of CRC and provide enhanced screening strategies, the prevalence of CRC is still on the rise. Studies showed several cellular signaling pathways dysregulated in CRC, leading to the onset of malignant phenotypes. Therefore, analyzing signaling pathways involved in CRC metastasis is necessary to elucidate the underlying mechanism of CRC progression and pharmacotherapy. This review focused on target genes as well as various cellular signaling pathways including Wnt/β-catenin, p53, TGF-β/SMAD, NF-κB, Notch, VEGF, and JAKs/STAT3, which are associated with CRC progression and metastasis. Additionally, alternations in methylation patterns in relation with signaling pathways involved in regulating various cellular mechanisms such as cell cycle, transcription, apoptosis, and angiogenesis as well as invasion and metastasis were also reviewed. To date, understanding the genomic and epigenomic instability has identified candidate biomarkers that are validated for routine clinical use in CRC management. Nevertheless, better understanding of the onset and progression of CRC can aid in the development of early detection molecular markers and risk stratification methods to improve the clinical care of CRC patients. Full article
(This article belongs to the Special Issue Molecular and Translational Research on Colorectal Cancer 2.0)
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23 pages, 665 KiB  
Review
Colorectal Adenomas—Genetics and Searching for New Molecular Screening Biomarkers
by Anna Siskova, Klara Cervena, Jan Kral, Tomas Hucl, Pavel Vodicka and Veronika Vymetalkova
Int. J. Mol. Sci. 2020, 21(9), 3260; https://doi.org/10.3390/ijms21093260 - 5 May 2020
Cited by 34 | Viewed by 9216
Abstract
Colorectal cancer (CRC) is a malignant disease with an incidence of over 1.8 million new cases per year worldwide. CRC outcome is closely related to the respective stage of CRC and is more favorable at less advanced stages. Detection of early colorectal adenomas [...] Read more.
Colorectal cancer (CRC) is a malignant disease with an incidence of over 1.8 million new cases per year worldwide. CRC outcome is closely related to the respective stage of CRC and is more favorable at less advanced stages. Detection of early colorectal adenomas is the key to survival. In spite of implemented screening programs showing efficiency in the detection of early precancerous lesions and CRC in asymptomatic patients, a significant number of patients are still diagnosed in advanced stages. Research on CRC accomplished during the last decade has improved our understanding of the etiology and development of colorectal adenomas and revealed weaknesses in the general approach to their detection and elimination. Recent studies seek to find a reliable non-invasive biomarker detectable even in the blood. New candidate biomarkers could be selected on the basis of so-called liquid biopsy, such as long non-coding RNA, microRNA, circulating cell-free DNA, circulating tumor cells, and inflammatory factors released from the adenoma into circulation. In this work, we focused on both genetic and epigenetic changes associated with the development of colorectal adenomas into colorectal carcinoma and we also discuss new possible biomarkers that are detectable even in adenomas prior to cancer development. Full article
(This article belongs to the Special Issue Molecular and Translational Research on Colorectal Cancer 2.0)
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