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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 49395

Special Issue Editors


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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

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

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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

Jump to: Research, Review

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 2286
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

Jump to: Editorial, Review

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 8 | Viewed by 2651
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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Figure 1

Figure 1
<p>Expression level of granulin. Granulin in tumoral tissue of colorectal cancer specimen and corresponding healthy colon mucosa normalized to 18s rRNA (<span class="html-italic">n</span> = 94), (<span class="html-italic">p</span> = 0.059). Bar represents mean + SEM.</p>
Full article ">Figure 2
<p>Immunohistochemistry revealing spatial localization of granulin protein. Granulin was strongly expressed in the tumor cells (<b>A</b>), particularly in the cytoplasm, and showed a descending expression in colorectal adenomas (<b>B</b>), whereas there was almost no expression of granulin in healthy mucosa cells (<b>C</b>).</p>
Full article ">Figure 3
<p>Invasion (<b>A</b>) and migration (<b>B</b>) assays. Granulin siRNA-transfected HCT-116 cells were less migratory (<span class="html-italic">p</span> = 0.074) and significantly less invasive (* <span class="html-italic">p</span> = 0.013). Bars represent mean + SEM.</p>
Full article ">Figure 4
<p>Correlation of granulin expression and overall survival (<span class="html-italic">n</span> = 89). Overall survival was significantly impaired in patients with high tumoral granulin expression (<span class="html-italic">p</span> = 0.047).</p>
Full article ">
14 pages, 2942 KiB  
Article
Dehydroxyhispolon Methyl Ether, A Hispolon Derivative, Inhibits WNT/?-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 2923
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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Figure 1
<p>Anti-colorectal cancer (CRC) effect of dehydroxyhispolon methyl ether (DHME). (<b>A</b>) Selective cytotoxicity of DHME against malignant but not normal human colorectal epithelial cell lines. A panel of human CRC cell lines, such as HCT 116, HCT-15, and LoVo, in addition to one normal human colorectal epithelial cell line, CCD 841 CoN, were treated with DHME for 48 h, followed by cell viability evaluation using MTS assay. (<b>B</b>) DHME suppresses CRC cells to form colonies. A total of 2 × 10<sup>2</sup> of human CRC cells, after 24 h of treatment with DHME, were allowed to grow in drug-free media for 10 days to form colonies, which were visualized by crystal violet staining. (<b>C</b>) Quantitative analysis of DHME-induced suppression of CRC clonogenicity. Colonies displayed in (B) were scored, and the results were subjected to statistical analysis. * <span class="html-italic">p</span> &lt; 0.05; *** <span class="html-italic">p</span> &lt; 0.001.</p>
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<p>DHME is more potent than hispolon in inducing CRC cell death. HCT 116, HCT-15, and LoVo cells were treated with indicated concentration (0.00, 6.25, 12.50, and 50.00 μM) of hispolon or DHME for 48 h, and the viability of drug-treated cells was determined by MTS assay thereafter.</p>
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<p>Apoptosis induction is essential for the anti-CRC action of DHME. (<b>A</b>) DHME induces poly (ADP-ribose) polymerase (PARP) cleavage. HCT 116, HCT-15, and LoVo cells were treated with DHME (0, 10, or 20 μM) for 24 h, followed by immunoblotting for the levels of cleaved PARP (c-PARP). The levels of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) served as the loading control. (<b>B</b>) DHME enhances the levels of annexin V-positive cell population. Human CRC cell lines treated with DHME (0, 10, 20 μM) for 24 h were subjected to annexin V/Propidium iodide (PI) dual staining using flow cytometry analysis. Annexin V-positive cells were regarded as cells undergoing apoptosis. The levels of the cell population in each quadrant were expressed as the percentage of total cell population. The horizontal axis denotes the intensity of annexin V, and the vertical axis indicates PI levels. (<b>C</b>) Quantitative analysis of DHME-induced CRC cell apoptosis. The annexin V-positive (apoptotic) cell population shown in (<b>B</b>) were scored. (<b>D</b>–<b>F</b>) Apoptosis blockade by z-VAD-fmk (50 μM) attenuates DHME-induced apoptosis as well as clonogenicity in CRC cells. The levels of the protein-to-GAPDH ratio relative to DHME-untreated controls were quantitated by ImageJ algorithm and are indicated below each blot. * <span class="html-italic">p</span> &lt; 0.05; ** <span class="html-italic">p</span> &lt; 0.01; *** <span class="html-italic">p</span> &lt; 0.001.</p>
Full article ">Figure 3 Cont.
<p>Apoptosis induction is essential for the anti-CRC action of DHME. (<b>A</b>) DHME induces poly (ADP-ribose) polymerase (PARP) cleavage. HCT 116, HCT-15, and LoVo cells were treated with DHME (0, 10, or 20 μM) for 24 h, followed by immunoblotting for the levels of cleaved PARP (c-PARP). The levels of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) served as the loading control. (<b>B</b>) DHME enhances the levels of annexin V-positive cell population. Human CRC cell lines treated with DHME (0, 10, 20 μM) for 24 h were subjected to annexin V/Propidium iodide (PI) dual staining using flow cytometry analysis. Annexin V-positive cells were regarded as cells undergoing apoptosis. The levels of the cell population in each quadrant were expressed as the percentage of total cell population. The horizontal axis denotes the intensity of annexin V, and the vertical axis indicates PI levels. (<b>C</b>) Quantitative analysis of DHME-induced CRC cell apoptosis. The annexin V-positive (apoptotic) cell population shown in (<b>B</b>) were scored. (<b>D</b>–<b>F</b>) Apoptosis blockade by z-VAD-fmk (50 μM) attenuates DHME-induced apoptosis as well as clonogenicity in CRC cells. The levels of the protein-to-GAPDH ratio relative to DHME-untreated controls were quantitated by ImageJ algorithm and are indicated below each blot. * <span class="html-italic">p</span> &lt; 0.05; ** <span class="html-italic">p</span> &lt; 0.01; *** <span class="html-italic">p</span> &lt; 0.001.</p>
Full article ">Figure 4
<p>DHME inhibits WNT/β-catenin signaling in CRC cells. (<b>A</b>) Suppression of β-catenin–T-cell factor/lymphoid enhancer factor (TCF/LEF)-dependent transcription by DHME. HCT 116, HCT-15, and LoVo cells were transiently transfected with an M50 Super 8x TOPFlash plasmid (TOPFlash), a β-catenin luciferase reporter vector, followed by DHME treatment and then assessment of luciferase activity. The M51 Super 8x FOPFlash plasmid (FOPFlash) was used as a negative control for TOPFlash. * <span class="html-italic">p</span> &lt; 0.05; ** <span class="html-italic">p</span> &lt; 0.01. (<b>B</b>) DHME lowers the levels of c-MYC, cyclin D1, and survivin. Cell lysates of CRC cells, following 24 h treatment with DHME, were subjected to immunoblot analysis. GAPDH levels were used as the loading control. The levels of protein-to-GAPDH ratio relative to DHME-untreated controls were quantitated using ImageJ algorithm, and are indicated below each blot.</p>
Full article ">Figure 5
<p>Blockade of WNT/β-catenin-mediated, pro-survival signaling is required for the anti-CRC action of DHME. (<b>A</b>) Persistent β-catenin activation abolishes DHME-induced PARP cleavage. HCT-15 and LoVo clones stably expressing HA–∆N90-β-catenin, an N-terminal, hemagglutinin (HA)-tagged, dominant-active β-catenin mutant (with N-terminal 90 amino acids deleted), were treated with DHME (0, 10, or 20 μM) for 24 h, followed by immunoblotting for the levels of HA (confirming ectopic expression of HA–∆N90-β-catenin), cleaved PARP (c-PARP), and BCL-2. GAPDH levels were used as the loading control. (<b>B</b>) Persistent β-catenin activation lowers the levels of the DHME-enhanced, annexin V-positive cell population. Stable vector or HA–∆N90-β-catenin clones of HCT-15 and LoVo cells were treated with DHME (0, 10, or 20 μM) for 24 h, followed by flow cytometry analysis for the levels of annexin V-positive (apoptotic) cell population. (<b>C</b>) Persistent β-catenin activation rescued DHME-mediated inhibition of clonogenicity. A total of 2 × 10<sup>2</sup> of stable vector or HA–∆N90-β-catenin clones of HCT-15 and LoVo cells after 24 h treatment of DHME (0, 10, or 20 μM) were assessed for their ability to form colonies. The levels of protein-to-GAPDH ratio relative to DHME-untreated vector controls were quantitated by ImageJ algorithm and are indicated below each blot. *** <span class="html-italic">p</span> &lt; 0.001.</p>
Full article ">Figure 6
<p>Schematic diagram depicting the anti-CRC mechanism of action of DHME elucidated in this study. In brief, DHME induces CRC cell apoptosis via the targeted inhibition of the pro-survival WNT/β-catenin–BCL-2 signaling axis. The chemical structure of DHME is adapted from Balaji et al. [<a href="#B18-ijms-21-08839" class="html-bibr">18</a>]. The dashed line denotes that our data implicated that the transcription of <span class="html-italic">BCL-2</span> likely depends on the β-catenin–TCF/LEF transcription complex, but it still requires evidence to support the direct binding of TCF/LEF to the human <span class="html-italic">BCL-2</span> promoter for driving <span class="html-italic">BCL-2</span> transcription in the CRC cell lines used in this study.</p>
Full article ">
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 26 | Viewed by 2761
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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Figure 1

Figure 1
<p>Immunohistochemistry for HJURP expression in colorectal cancer tissues. (<b>A</b>–<b>D</b>). One hundred and sixty-two CRC samples were stained with HJURP antibody and scored based on both staining intensity and staining frequency. Representative images of tissue slides and immunohistochemistry are shown ((<b>A</b>), Normal negative HJURP expression; (<b>B</b>), Tumor negative; (<b>C</b>), Tumor low expression; (<b>D</b>), Tumor high expression). Original magnification × 200.</p>
Full article ">Figure 2
<p>HJURP expression is related to overall survival in colorectal cancer patients. Patients were divided into two groups based on the expression of HJURP and survival rate was determined using Kaplan-Meier analysis (<span class="html-italic">p</span> = 0.016).</p>
Full article ">Figure 3
<p>siRNA-mediated HJURP depletion in colorectal cancer cell lines. Colorectal cancer cell lines including HT29, HCT116, SW480, and SW620 were transduced with either control or HJURP siRNA. (<b>A</b>) RT-PCR was performed to determine HJURP mRNA expression cancer cell lines. (<b>B</b>) Immunoblot with anti-HJURP antibody was conducted to analyzed HJRUP protein level. GAPDH and β-actin was used as the loading control for RT-PCR and immunoblot.</p>
Full article ">Figure 4
<p>HJURP depletion impairs cell proliferation in colorectal cancer cell lines. Control or HJURP-siRNA colorectal cancer cell lines such as HT29, HCT116, SW480, and SW620 were analyzed every 24 h for 3 days to determine the proliferation rate by MTT assay. (<b>A</b>) HT29 cells. 24 h; *** <span class="html-italic">p</span> = 0.001, 48 h; ** <span class="html-italic">p</span> = 0.007, 72 h; ** <span class="html-italic">p</span> = 0.01, (<b>B</b>) HCT116. 48 h; * <span class="html-italic">p</span> = 0.021, 72h; *** <span class="html-italic">p</span> = 0.001, (<b>C</b>) SW480. 24 h; *** <span class="html-italic">p</span> = 0.001, 48 h; * <span class="html-italic">p</span> = 0.011, 72 h; * <span class="html-italic">p</span> = 0.021. (<b>D</b>) SW620. 24 h; *** <span class="html-italic">p</span> = 0.001, 48 h; ** <span class="html-italic">p</span> = 0.003, 72 h; ** <span class="html-italic">p</span> = 0.007.</p>
Full article ">Figure 5
<p>HJURP depletion impairs migration and invasion of colorectal cancer cell lines in vitro. Control or HJURP-siRNA colorectal cancer cell lines were seeded on a matrigel uncoated or coated Transwell, followed by incubation for 48 h for assessing migration and invasion, respectively. (<b>A</b>) Imaging was done using an inverted microscope and representative images are shown (× 40). (<b>B</b>) HJURP-siRNA cells displayed significantly reduced ability of migration (HT29; * <span class="html-italic">p</span> = 0.027, HCT116; * <span class="html-italic">p</span> = 0.023, SW480; ** <span class="html-italic">p</span> = 0.007, SW620; * <span class="html-italic">p</span> = 0.031). (<b>C</b>) siRNA mediated depletion of HJURP expression was suppressed the invasion ability of colorectal cancer cells (HT29; * <span class="html-italic">p</span> = 0.021, HCT116; * <span class="html-italic">p</span> = 0.028, SW480; * <span class="html-italic">p</span> = 0.011, SW620; * <span class="html-italic">p</span> = 0.026).</p>
Full article ">Figure 6
<p>HJURP depletion impairs anchorage-independent colony forming ability of colorectal cancer cell lines in vitro. Control or HJURP-siRNA colorectal cancer cell lines were seeded on soft agarose and incubation was done for 14 days to evaluate colony forming ability. (<b>A</b>) Representative images of colonies were shown (× 40). (<b>B</b>) Number of colonies from each colorectal cancer cell lines were quantified (HT29; * <span class="html-italic">p</span> = 0.038, HCT116; * <span class="html-italic">p</span> = 0.05, SW480; ** <span class="html-italic">p</span> = 0.008, SW620; *** <span class="html-italic">p</span> = 0.001).</p>
Full article ">

Review

Jump to: Editorial, Research

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 4234
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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Figure 1
<p>Schematic representation of the tumor microenvironment and its cellular composition. (<b>a</b>) Tumor microenvironment. Graphic representing various cellular components of vasculature and tumor microenvironment [<a href="#B20-ijms-22-04802" class="html-bibr">20</a>]. (<b>b</b>,<b>c</b>) Immune cell composition in the tumor microenvironment: cellular and molecular components involved in pro-inflammatory, tumor-killing activity (<b>b</b>) and anti-inflammatory, immunosuppressive, tumor-promoting activity (<b>c</b>) [<a href="#B21-ijms-22-04802" class="html-bibr">21</a>].</p>
Full article ">Figure 2
<p>Examples of using immunofluorescence. (<b>a</b>) Live–dead cell staining for MC38 cell lines cultured in AIM 3D Chip. (<b>b</b>) Immunostaining of MC38-tumor-derived spheroids. Spheroids were stained with conjugated antibodies targeting panCK, CD4, and CD8 (overnight at 4 °C). Hoechst 33,342 was used to label nuclei. Images were taken using a fluorescence microscope.</p>
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<p>Schematic representation of scRNA sequencing and data analysis pipeline.</p>
Full article ">
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 234 | Viewed by 23654
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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Figure 1
<p>Multistep genetic model for colorectal adenocarcinoma sequence. There are three pathways regulating the adenocarcinoma sequence: chromosomal instability (CIN), microsatellite instability (MSI), and CpG island methylator phenotype (CIMP) hypermethylation.</p>
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<p>Schematic representation of the molecular pathways involved in CRC pathogenesis.</p>
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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 37 | Viewed by 9897
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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Figure 1

Figure 1
<p>Arise of tumor-initiating cells from aberrant colon crypt and subsequent transition of early adenoma to metastatic cancer.</p>
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