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Cells
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Novel Biomarkers and Therapeutics in Colorectal Cancer Progression and Metastasis
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Novel Biomarkers and Therapeutics in Colorectal Cancer Progression and Metastasis

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 15663

Special Issue Editors

Dr. Punita Dhawan

E-Mail Website
Guest Editor
Department of Biochemistry and Molecular Biology, Member, Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198, USA
Interests: colorectal cancer; metastasis; Pancreatic cancer; chemoresistance
Dr. Amar B. Singh

E-Mail Website
Guest Editor
Department of Biochemistry and Molecular Biology, Department of Biochemistry and Molecular Biology, Research Scientist, Omaha VA Medical Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
Interests: colorectal cancer; therapeutic targets; inflammatory bowel disease; inflammation; microbiota

Special Issue Information

Dear Colleagues,

Colorectal cancer (CRC) is a major cause of cancer death worldwide. Despite recent advances in CRC screening and anti-CRC therapies, the overall survival of CRC patients with advanced cancer remains very low. Cancer progression, including invasion and metastasis, is a major cause of death among CRC patients, however the underlying mechanisms of action resulting in cancer progression for therapeutic advantages remain ill understood. The reported molecular and biochemical mechanisms that contribute to the phenotypic changes in favor of colorectal carcinogenesis include apoptosis inhibition, enhanced tumor cell proliferation, increased invasiveness, cell adhesion perturbations, angiogenesis promotion, altered cancer stem cell and immune surveillance inhibition. Understanding molecular mechanism/s that regulate the above processes and identifying unique therapeutic targets have improved our understanding of the pathogenesis of CRC and helped in developing more effective therapeutic measures, however, the door to innovation remains open towards improving patient care and survival.

Also, CRC-related poor prognosis among patients has a crucial need for new biomarkers. Recent research has targeted the development of biomarkers that aid in the early diagnosis and prognostic stratification of CRC. However, despite progress in the development of screening programs and in the management of patients with colorectal cancer, gaps remain to be filled, ranging from prevention and early diagnosis to the determination of prognosis factors and treatment of metastatic disease, to establish a personalized approach.

Moreover, recent studies suggest an unexpected increase in the development of highly malignant colorectal cancer in young adults. While recent studies have attempted to map this unexpected increase with socio-economic parameters and altered genomic landscape, this area of research remain quite open for its causal understanding and improve patient management.

This Special Issue aims to summarize the current knowledge on the cellular and molecular mechanisms behind the pathogenesis of colorectal cancer progression, focusing on promising and emerging biomarkers and therapeutic targets in pre-clinical and clinical studies.

We look forward to your contributions.

Dr. Punita Dhawan
Dr. Amar B. Singh
Guest Editors

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. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

  • Colorectal cancer
  • Metastasis
  • Biomarkers
  • Apoptosis
  • Dedifferentiation
  • invasion

Published Papers (5 papers)

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Research

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11 pages, 4656 KiB  
Article
Accumulation of Paneth Cells in Early Colorectal Adenomas Is Associated with Beta-Catenin Signaling and Poor Patient Prognosis
by Erika López-Arribillaga, Bing Yan, Teresa Lobo-Jarne, Yolanda Guillén, Silvia Menéndez, Montserrat Andreu, Anna Bigas, Mar Iglesias and Lluís Espinosa
Cells 2021, 10(11), 2928; https://doi.org/10.3390/cells10112928 - 28 Oct 2021
Cited by 1 | Viewed by 2274
Abstract
Background: Previous studies in mice indicated that Paneth cells and c-Kit-positive goblet cells represent the stem cell niche of the small intestine and colon, respectively, partly by supporting Wnt and Notch activation. Whether these cell populations play a similar role in human intestinal [...] Read more.
Background: Previous studies in mice indicated that Paneth cells and c-Kit-positive goblet cells represent the stem cell niche of the small intestine and colon, respectively, partly by supporting Wnt and Notch activation. Whether these cell populations play a similar role in human intestinal cancer remains unexplored. Methods: We performed histopathological evaluation and immunohistochemical analysis of early colorectal adenomas and carcinoma adenoma from patients at the Hospital del Mar in Barcelona. We then determined the possible correlation between the different parameters analyzed and with patient outcomes. Results: Paneth cells accumulate in a subset of human colorectal adenomas directly associated with Notch and Wnt/β-catenin activation. Adenoma areas containing Paneth cells display increased vessel density in the lamina propria and higher levels of the stem cell marker EphB2. In an in-house cohort of 200 colorectal adenoma samples, we also observed a significant correlation between the presence of Paneth cells and Wnt activation. Kaplan–Meier analysis indicated that early adenoma patients carrying Paneth cell-positive tumors display reduced disease-free survival compared with patients with Paneth cell-free lesions. Conclusions: Our results indicate that Paneth cells contribute to the initial steps of cancer progression by providing the stem cell niche to adenoma cells, which could be therapeutically exploited. Full article
(This article belongs to the Special Issue Novel Biomarkers and Therapeutics in Colorectal Cancer Progression and Metastasis)
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13 pages, 2991 KiB  
Article
Epigenetic DNA Modifications Upregulate SPRY2 in Human Colorectal Cancers
by Alexei J. Stuckel, Shuai Zeng, Zhen Lyu, Wei Zhang, Xu Zhang, Urszula Dougherty, Reba Mustafi, Qiong Zhang, Trupti Joshi, Marc Bissonnette, Samrat Roy Choudhury and Sharad Khare
Cells 2021, 10(10), 2632; https://doi.org/10.3390/cells10102632 - 2 Oct 2021
Cited by 4 | Viewed by 2715
Abstract
Conventional wisdom is that Sprouty2 (SPRY2), a suppressor of Receptor Tyrosine Kinase (RTK) signaling, functions as a tumor suppressor and is downregulated in many solid tumors. We reported, for the first time, that increased expression of SPRY2 augments cancer phenotype and Epithelial-Mesenchymal-Transition (EMT) [...] Read more.
Conventional wisdom is that Sprouty2 (SPRY2), a suppressor of Receptor Tyrosine Kinase (RTK) signaling, functions as a tumor suppressor and is downregulated in many solid tumors. We reported, for the first time, that increased expression of SPRY2 augments cancer phenotype and Epithelial-Mesenchymal-Transition (EMT) in colorectal cancer (CRC). In this report, we assessed epigenetic DNA modifications that regulate SPRY2 expression in CRC. A total of 4 loci within SPRY2 were evaluated for 5mC using Combined Bisulfite Restriction Analysis (COBRA). Previously sequenced 5hmC nano-hmC seal data within SPRY2 promoter and gene body were evaluated in CRC. Combined bioinformatics analyses of SPRY2 CRC transcripts by RNA-seq/microarray and 450K methyl-array data archived in The Cancer Genome Atlas (TCGA) and GEO database were performed. SPRY2 protein in CRC tumors and cells was measured by Western blotting. Increased SPRY2 mRNA was observed across several CRC datasets and increased protein expression was observed among CRC patient samples. For the first time, SPRY2 hypomethylation was identified in adenocarcinomas in the promoter and gene body. We also revealed, for the first time, increases of 5hmC deposition in the promoter region of SPRY2 in CRC. SPRY2 promoter hypomethylation and increased 5hmC may play an influential role in upregulating SPRY2 in CRC. Full article
(This article belongs to the Special Issue Novel Biomarkers and Therapeutics in Colorectal Cancer Progression and Metastasis)
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23 pages, 13886 KiB  
Article
A Claudin-Based Molecular Signature Identifies High-Risk, Chemoresistant Colorectal Cancer Patients
by Saiprasad Gowrikumar, Mark Primeaux, Kristina Pravoverov, Chao Wu, Bryan C. Szeglin, Charles-Etienne Gabriel Sauvé, Ishwor Thapa, Dhundy Bastola, Xi Steven Chen, J. Joshua Smith, Amar B. Singh and Punita Dhawan
Cells 2021, 10(9), 2211; https://doi.org/10.3390/cells10092211 - 26 Aug 2021
Cited by 11 | Viewed by 2910
Abstract
Identifying molecular characteristics that are associated with aggressive cancer phenotypes through gene expression profiling can help predict treatment responses and clinical outcomes. Claudins are deregulated in colorectal cancer (CRC). In CRC, increased claudin-1 expression results in epithelial-to-mesenchymal transition and metastasis, while claudin-7 functions [...] Read more.
Identifying molecular characteristics that are associated with aggressive cancer phenotypes through gene expression profiling can help predict treatment responses and clinical outcomes. Claudins are deregulated in colorectal cancer (CRC). In CRC, increased claudin-1 expression results in epithelial-to-mesenchymal transition and metastasis, while claudin-7 functions as a tumor suppressor. In this study, we have developed a molecular signature based on claudin-1 and claudin-7 associated with poor patient survival and chemoresistance. This signature was validated using an integrated approach including publicly available datasets and CRC samples from patients who either responded or did not respond to standard-of-care treatment, CRC cell lines, and patient-derived rectal and colon tumoroids. Transcriptomic analysis from a patient dataset initially yielded 23 genes that were differentially expressed along with higher claudin-1 and decreased claudin-7. From this analysis, we selected a claudins-associated molecular signature including PIK3CA, SLC6A6, TMEM43, and ASAP-1 based on their importance in CRC. The upregulation of these genes and their protein products was validated using multiple CRC patient datasets, in vitro chemoresistant cell lines, and patient-derived tumoroid models. Additionally, blocking these genes improved 5-FU sensitivity in chemoresistant CRC cells. Our findings propose a new claudin-based molecular signature that associates with poor prognosis as well as characteristics of treatment-resistant CRC including chemoresistance, metastasis, and relapse. Full article
(This article belongs to the Special Issue Novel Biomarkers and Therapeutics in Colorectal Cancer Progression and Metastasis)
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17 pages, 3820 KiB  
Article
Honokiol Affects Stem Cell Viability by Suppressing Oncogenic YAP1 Function to Inhibit Colon Tumorigenesis
by Dharmalingam Subramaniam, Sivapriya Ponnurangam, Satish Ramalingam, Deep Kwatra, Prasad Dandawate, Scott J. Weir, Shahid Umar, Roy A. Jensen and Shrikant Anant
Cells 2021, 10(7), 1607; https://doi.org/10.3390/cells10071607 - 26 Jun 2021
Cited by 11 | Viewed by 3245
Abstract
Honokiol (HNK) is a biphenolic compound that has been used in traditional medicine for treating various ailments, including cancers. In this study, we determined the effect of HNK on colon cancer cells in culture and in a colitis-associated cancer model. HNK treatment inhibited [...] Read more.
Honokiol (HNK) is a biphenolic compound that has been used in traditional medicine for treating various ailments, including cancers. In this study, we determined the effect of HNK on colon cancer cells in culture and in a colitis-associated cancer model. HNK treatment inhibited proliferation and colony formation while inducing apoptosis. In addition, HNK suppressed colonosphere formation. Molecular docking suggests that HNK interacts with reserve stem cell marker protein DCLK1, with a binding energy of −7.0 Kcal/mol. In vitro kinase assays demonstrated that HNK suppressed the DCLK1 kinase activity. HNK also suppressed the expression of additional cancer stem cell marker proteins LGR5 and CD44. The Hippo signaling pathway is active in intestinal stem cells. In the canonical pathway, YAP1 is phosphorylated at Ser127 by upstream Mst1/2 and Lats1/2. This results in the sequestration of YAP1 in the cytoplasm, thereby not allowing YAP1 to translocate to the nucleus and interact with TEAD1-4 transcription factors to induce gene expression. However, HNK suppressed Ser127 phosphorylation in YAP1, but the protein remains sequestered in the cytoplasm. We further determined that this occurs by YAP1 interacting with PUMA. To determine if this also occurs in vivo, we performed studies in an AOM/DSS induced colitis-associated cancer model. HNK administered by oral gavage at a dose of 5mg/kg bw for 24 weeks demonstrated a significant reduction in the expression of YAP1 and TEAD1 and in the stem marker proteins. Together, these data suggest that HNK prevents colon tumorigenesis in part by inducing PUMA-YAP1 interaction and cytoplasmic sequestration, thereby suppressing the oncogenic YAP1 activity. Full article
(This article belongs to the Special Issue Novel Biomarkers and Therapeutics in Colorectal Cancer Progression and Metastasis)
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Review

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22 pages, 1958 KiB  
Review
Fluorescence Molecular Targeting of Colon Cancer to Visualize the Invisible
by Thinzar M. Lwin, Michael A. Turner, Siamak Amirfakhri, Hiroto Nishino, Robert M. Hoffman and Michael Bouvet
Cells 2022, 11(2), 249; https://doi.org/10.3390/cells11020249 - 12 Jan 2022
Cited by 14 | Viewed by 3456
Abstract
Colorectal cancer (CRC) is a common cause of cancer and cancer-related death. Surgery is the only curative modality. Fluorescence-enhanced visualization of CRC with targeted fluorescent probes that can delineate boundaries and target tumor-specific biomarkers can increase rates of curative resection. Approaches to enhancing [...] Read more.
Colorectal cancer (CRC) is a common cause of cancer and cancer-related death. Surgery is the only curative modality. Fluorescence-enhanced visualization of CRC with targeted fluorescent probes that can delineate boundaries and target tumor-specific biomarkers can increase rates of curative resection. Approaches to enhancing visualization of the tumor-to-normal tissue interface are active areas of investigation. Nonspecific dyes are the most-used approach, but tumor-specific targeting agents are progressing in clinical trials. The present narrative review describes the principles of fluorescence targeting of CRC for diagnosis and fluorescence-guided surgery with molecular biomarkers for preclinical or clinical evaluation. Full article
(This article belongs to the Special Issue Novel Biomarkers and Therapeutics in Colorectal Cancer Progression and Metastasis)
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