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1
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Kim JH, Han HW, Song JH, Kim SJ, Kim YK, Kim HJ, Rhee TG, Shim SR. Increased risk of colorectal adenoma and benign colorectal polyp associated with Helicobacter pylori infection: a systematic review and meta-analysis. Transl Cancer Res 2025; 14:2354-2366. [PMID: 40386279 PMCID: PMC12079237 DOI: 10.21037/tcr-24-795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 01/27/2025] [Indexed: 05/20/2025]
Abstract
Background Although the association between Helicobacter pylori (H. pylori) infection and the risk of colorectal adenomas (CRAs) is suggested, specific analysis of the histological subtype of CRA is limited. The aim of the study was to conduct a meta-analysis on the risk of histological classifications of CRA as benign colorectal polyp (BCP), CRA, and advanced CRA to investigate the effects of H. pylori. Methods A comprehensive literature searches of the PubMed, Embase, and Cochrane databases through January 2024. Meta-regression analysis was conducted to identify potential moderators (e.g., histological subtype and ethnic groups). Results Among the 503,365 participants across 40 studies, H. pylori was consistently associated with increased probabilities of BCP, CRA, and advanced CRA. In BCP, H. pylori positive was found to be associated with an increase [odds ratio (OR), 1.430; 95% confidence interval (CI): 1.292-1.583]. In CRA and advanced CRA, H. pylori positive was found to be associated with an increase (OR, 1.711; 95% CI: 1.408-2.080). In subgroup analysis by ethnicity, Western group had lower OR compared to Asian, with a statistically significant difference observed (Western OR, 1.369; 95% CI: 1.222-1.535 vs. Asian OR, 1.990; 95% CI: 1.416-2.796, P=0.04). Conclusions This systematic review and meta-analysis findings revealed a significant association between H. pylori infection and BCP, CRA, and advanced CRA. In particular, meta-regression analysis confirmed that ethnicity acts as a risk factor in both BCP and CRA.
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Affiliation(s)
- Ju Hee Kim
- Department of Biomedical Informatics, CHA University School of Medicine, CHA University, Seongnam, Republic of Korea
- Institute for Biomedical Informatics, School of Medicine, CHA University, Seongnam, Republic of Korea
- Institute of Basic Medical Sciences, School of Medicine, CHA University, Seongnam, Republic of Korea
| | - Hyun Wook Han
- Department of Biomedical Informatics, CHA University School of Medicine, CHA University, Seongnam, Republic of Korea
- Institute for Biomedical Informatics, School of Medicine, CHA University, Seongnam, Republic of Korea
- Institute of Basic Medical Sciences, School of Medicine, CHA University, Seongnam, Republic of Korea
- Healthcare Big-Data Center, Bundang CHA Hospital, Seongnam, Republic of Korea
| | - Joo Hye Song
- Department of Internal Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Republic of Korea
| | - Seong-Jang Kim
- Department of Nuclear Medicine, College of Medicine, Pusan National University, Yangsan, Republic of Korea
- BioMedical Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea
| | - Young Kook Kim
- Department of Ophthalmology, College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea
- EyeLight Data Science Laboratory, Seoul, Republic of Korea
| | - Hye Jun Kim
- Department of Biomedical Informatics, CHA University School of Medicine, CHA University, Seongnam, Republic of Korea
- Institute for Biomedical Informatics, School of Medicine, CHA University, Seongnam, Republic of Korea
- Institute of Basic Medical Sciences, School of Medicine, CHA University, Seongnam, Republic of Korea
| | - Taeho Greg Rhee
- Department of Psychiatry, School of Medicine, Yale University, New Haven, CT, USA
- Mental Illness, Research, Education and Clinical Center (MIRECC) of New England, Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA
- Department of Public Health Sciences, School of Medicine, University of Connecticut, Farmington, CT, USA
| | - Sung Ryul Shim
- Department of Biomedical Informatics, College of Medicine, Konyang University, Daejeon, Republic of Korea
- Konyang Medical data Research group-KYMERA, Konyang University Hospital, Daejeon, Republic of Korea
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2
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Zengin Kurt B, Özmen Ö, Öztürk Civelek D, Şenol H, Sonmez F. Exploring anticancer properties of new triazole-linked benzenesulfonamide derivatives against colorectal carcinoma: Synthesis, cytotoxicity, and in silico insights. Bioorg Med Chem 2025; 119:118060. [PMID: 39793404 DOI: 10.1016/j.bmc.2025.118060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 12/10/2024] [Accepted: 01/01/2025] [Indexed: 01/13/2025]
Abstract
This study reports the design, synthesis, and characterization of a novel series of benzene sulfonamide-triazole hybrid derivatives, to evaluate their anticancer potential against colorectal cancer. The synthesized compounds were characterized using NMR and HRMS spectroscopic techniques. In vitro cytotoxicity assessments revealed that compounds 5g and 5j exhibited significant anticancer effects. 5g showed the highest potency in the DLD-1 cell line (IC50 = 11.84 µM), while 5j demonstrated robust activity in the HT-29 cell line (IC50 = 9.35 µM). Apoptotic analysis indicated that compound 5g effectively induced early and total apoptosis, surpassing the chemotherapeutic agent 5-fluorouracil (5-FU), highlighting its therapeutic potential. Molecular docking studies showed strong binding interactions with key proteins involved in colorectal cancer progression, such as TGFβ2 and VEGFR1. 5j displayed a high binding affinity for TGFβ2 (MM-GBSA ΔG = -92.52 kcal/mol) and 5g showed promising interactions with VEGFR1 (ΔG = -70.63 kcal/mol). Molecular dynamics simulations confirmed the stability of the ligand-protein complexes, indicating potential as targeted therapeutic agents. Compounds 5g and 5j demonstrate significant promise for further development in colorectal cancer treatment.
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Affiliation(s)
- Belma Zengin Kurt
- Bezmialem Vakif University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 34093 Istanbul, Turkiye.
| | - Özge Özmen
- Bezmialem Vakif University, Faculty of Pharmacy, 34093 Istanbul, Turkiye; Kartal Dr. Lutfi Kirdar City Hospital, 34865 Istanbul, Turkiye
| | - Dilek Öztürk Civelek
- Bezmialem Vakif University, Faculty of Pharmacy, Department of Pharmacology, 34093 Istanbul, Turkiye
| | - Halil Şenol
- Bezmialem Vakif University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 34093 Istanbul, Turkiye
| | - Fatih Sonmez
- Sakarya University of Applied Sciences, Pamukova Vocational School, 54055 Sakarya, Turkiye
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Sasaki K, Wang J, Kamphues C, Buettner S, Gagniere J, Ardilles V, Imai K, Wagner D, Pozios I, Papakonstantinou D, Pikoulis E, Antoniou E, Morioka D, Løes IM, Lønning PE, Kornprat P, Aucejo FN, Baba H, de Santibañes E, Kaczirek K, Burkhart R, Endo I, Beyer K, Kreis ME, Pawlik TM, Margonis GA. Evaluating Combinations of Biological and Clinicopathologic Factors Linked to Poor Outcomes in Resected Colorectal Liver Metastasis: An External Validation Study. Ann Surg Oncol 2025; 32:408-417. [PMID: 39377842 DOI: 10.1245/s10434-024-16319-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 09/19/2024] [Indexed: 10/09/2024]
Abstract
BACKGROUND Recent studies have suggested that certain combinations of KRAS or BRAF biomarkers with clinical factors are associated with poor outcomes and may indicate that surgery could be "biologically" futile in otherwise technically resectable colorectal liver metastasis (CRLM). However, these combinations have yet to be validated through external studies. PATIENTS AND METHODS We conducted a systematic search to identify these studies. The overall survival (OS) of patients with these combinations was evaluated in a cohort of patients treated at 11 tertiary centers. Additionally, the study investigated whether using high-risk KRAS point mutations in these combinations could be associated with particularly poor outcomes. RESULTS The recommendations of four studies were validated in 1661 patients. The first three studies utilized KRAS, and their validation showed the following median and 5-year OS: (1) 30 months and 16.9%, (2) 24.3 months and 21.6%, and (3) 46.8 months and 44.4%, respectively. When analyzing only patients with high-risk KRAS mutations, median and 5-year OS decreased to: (1) 26.2 months and 0%, (2) 22.3 months and 15.1%, and (3) not reached and 44.9%, respectively. The fourth study utilized BRAF, and its validation showed a median OS of 10.4 months, with no survivors beyond 21 months. CONCLUSION The combinations of biomarkers and clinical factors proposed to render surgery for CRLM futile, as presented in studies 1 (KRAS high-risk mutations) and 4, appear justified. In these studies, there were no long-term survivors, and survival was similar to that of historic cohorts with similar mutational profiles that received systemic therapies alone for unresectable disease.
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Affiliation(s)
- Kazunari Sasaki
- Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Jane Wang
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Carsten Kamphues
- Department of General and Visceral Surgery, Charité Campus Benjamin Franklin, Berlin, Germany
| | - Stefan Buettner
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Johan Gagniere
- Service de Chirurgie Digestive, CHU Clermont-Ferrand, Inserm, Université Clermont Auvergne, Clermont-Ferrand, France
| | - Victoria Ardilles
- HPB Surgery and Liver Transplant Unit, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Katsunori Imai
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Doris Wagner
- Department of General Surgery, Medical University of Graz, Graz, Austria
| | - Ioannis Pozios
- Department of General and Visceral Surgery, Charité Campus Benjamin Franklin, Berlin, Germany
| | - Dimitris Papakonstantinou
- Third Department of Surgery, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece
| | - Emmanouil Pikoulis
- Third Department of Surgery, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece
| | - Efstathios Antoniou
- Third Department of Surgery, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece
| | - Daisuke Morioka
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Inger Marie Løes
- Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Oncology, Haukeland University, Hospital, Bergen, Norway
| | - Per Eystein Lønning
- Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Oncology, Haukeland University, Hospital, Bergen, Norway
| | - Peter Kornprat
- Department of General Surgery, Medical University of Graz, Graz, Austria
| | - Federico N Aucejo
- Department of General Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Eduardo de Santibañes
- HPB Surgery and Liver Transplant Unit, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Klaus Kaczirek
- Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Richard Burkhart
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Katharina Beyer
- Department of General and Visceral Surgery, Charité Campus Benjamin Franklin, Berlin, Germany
| | - Martin E Kreis
- Department of General and Visceral Surgery, Charité Campus Benjamin Franklin, Berlin, Germany
| | | | - Georgios Antonios Margonis
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Operations Research Center, Massachusetts Institute of Technology, Cambridge, MA, USA.
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Longobardi S. Colorectal cancer: local results and significance in Hungary. J Gastrointest Oncol 2024; 15:2552-2577. [PMID: 39816032 PMCID: PMC11732334 DOI: 10.21037/jgo-24-318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 10/15/2024] [Indexed: 01/18/2025] Open
Abstract
Background Colorectal cancer (CRC) causes substantial morbidity and mortality internationally. In Hungary, the incidence and mortality of CRC are among the world's highest. Fortunately, CRC is a highly preventable disease, since there is a long asymptomatic phase before neoplastic transformation. Numerous countries have instituted programs for CRC screening. However, Hungary did not implement population-based screening programs until December 2018, consisting of a voluntary 2-step screening program based on the fecal immunochemical test (FIT) and if positive, referral to colonoscopy. Asymptomatic individuals aged over 50 years were invited to participate in the 2-step program. This study aims to analyze the results of these colonoscopies and raise public awareness of the CRC disease process and prevention, especially in Hungary. Methods Various literature sources were reviewed, and external information was gathered and consolidated based on CRC etiopathogenesis, management options, screening options, cost, benefits, modalities, and quality control. Semmelweis University Department of Internal Medicine and Hematology's database was accessed for the cross-sectional study results of 168 screening colonoscopies within the 2-step program from 2019 to 2020. I quantified and compared the results obtained during the colonoscopies with that of said literature within Hungary and worldwide. Results Colonoscopy was performed in 168 patients of average age 63.4 years. The incidence of CRCs in the population was 4.76%. Among the CRC cases, 75% were in the rectosigmoid area and 25% were in the remaining colon. The total adenoma detection rate (ADR) in the study was 57.1%, higher than the recommended 25% for adequate screening colonoscopy. The total number of resected polyps was 270; 8.1% were adenomas with high-grade dysplasia and 0.76% contained CRC. Out of the 185 resected adenomas, 141 were tubular, 34 were tubulovillous, and 10 were villous. Adenoma localizations included 14.6% rectum, 38.4% sigmoid, 11.9% descending colon, 8.6% transverse colon, 17.8% ascending colon, and 8.6% cecum. The average age of CRC patients was 63.9 years (range, 56-68 years) with a slight female predominance (5 females, 3 males). The ADR of the different endoscopists did not seem to correlate with experience. Optimal participation rate of the screening program would be >60%. Population outreach through mailed FIT is evidence-based and shown to increase CRC screening rates in underserved populations. Conclusions Hungary would benefit immensely in most aspects from mandatory, population-based CRC screening with this 2-step program. This alternative is proposed in lieu of 1-step screening, because of the limited capacity for colonoscopy in the country and the limited participation rates in the screened population. To reach maximum cost-benefit, the participation rate of the screened population must be >60%, with >80% of FIT positive test results being referred to colonoscopy. Consolidation and distribution of the screening program through population outreach will bring about substantial reductions in mortality from CRC. Further studies are warranted on the feasibility and sustainability of this 2-step program.
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Affiliation(s)
- Stefan Longobardi
- Department of Internal Medicine, HCA Healthcare/USF Morsani College of Medicine GME, HCA Florida Blake Hospital, Bradenton, FL, USA
- Department of Internal Medicine and Hematology, Semmelweis University Alumnus, Budapest, Hungary
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5
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Rastegar-Pouyani N, Zafari J, Nasirpour A, Vazini H, Najjar N, Azarshin SZ, Javani Jouni F. Methylene Blue-Mediated Photodynamic Therapy in Combination With Doxorubicin: A Novel Approach in the Treatment of HT-29 Colon Cancer Cells. J Lasers Med Sci 2024; 15:e64. [PMID: 39949472 PMCID: PMC11822234 DOI: 10.34172/jlms.2024.64] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 12/07/2024] [Indexed: 02/16/2025]
Abstract
Introduction: With an alarmingly growing number of patients diagnosed with colorectal cancer, adopting innovative anti-cancer approaches has recently garnered great attention. One interesting concept is the co-administration of cytotoxic agents and safer modalities such as photodynamic therapy (PDT), which can subsequently improve therapeutic efficacy and potentially reduce the risks of severe adverse effects and drug resistance. In the course of PDT, a locally injected photosensitizer (PS) is irradiated with a light source, which subsequently generates reactive oxygen species (ROS) and induces programmed cell death in tumor cells. Methods: In this study, to evaluate the potential anti-cancer effects of chemotherapy combined with PDT, in comparison to each alone, we employed PDT, comprising methylene blue (MB) and diode lasers at 630 and 810 nm wavelengths, in conjunction with the chemotherapeutic agent doxorubicin (DOX). Results: The MTT assay showed that the viability of colorectal cancer HT-29 cells decreased significantly following DOX+PDT treatment. Similarly, lactate dehydrogenase (LDH) release and lipid peroxidation rates were substantially higher in DOX+PDT treatment groups. Lastly, the catalase (CAT) assay indicated that the combination reduced the ability of CAT in the detoxification of H2 O2. Conclusion: Our study suggests that MB-mediated PDT combined with chemotherapy might provide a promising avenue to improve therapeutic efficacy and potentially reduce the risk of adverse effects and drug resistance. Without a doubt, further investigations need to delve into the pharmacological advantages and disadvantages of PTD-based combination therapy and optimize its administered doses along with other modalities.
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Affiliation(s)
- Nima Rastegar-Pouyani
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Jaber Zafari
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Alireza Nasirpour
- Department of Electrical and Computer Engineering, Batten College of Engineering, Old Dominion University, Norfolk, VA, United States
| | - Hossein Vazini
- Nursing Department, Basic Sciences Faculty, Islamic Azad University, Hamedan Branch, Hamedan, Iran
| | - Nabaa Najjar
- Basic Medical Science Research Center, Zist Pajooh Afra Company, Tehran, Iran
| | - Seyedeh Zohreh Azarshin
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Javani Jouni
- Department of Biochemistry and Biophysics, Faculty of Advanced Sciences and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
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Zuraik AA, Daboul Y, Awama MA, Yazigi H, Kayasseh MA, Georges M. Effect of Chemotherapy on Fusobacterium nucleatum Abundance in Colorectal Cancer Patients: A Study on Relapsing Patients. Indian J Microbiol 2024; 64:1938-1950. [PMID: 39678992 PMCID: PMC11645352 DOI: 10.1007/s12088-024-01279-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 04/04/2024] [Indexed: 12/17/2024] Open
Abstract
An intricate relationship exists, and interactions occur between the gut microbiota and colorectal cancer (CRC). Recent studies have indicated that inflammatory reactions stimulated by Fusobacterium nucleatum (Fn) lead to the development of CRC. Radical surgery combined with adjuvant chemotherapy is the primary treatment approach for most CRC patients. This study was designed to evaluate the abundance of Fn as part of the gut microbiota in patients with CRC compared to healthy individuals and to assess the effect of the gut microbiota Fn on patients undergoing adjuvant chemotherapy and those experiencing CRC relapse. There were 201 participants, comprising 50 healthy controls and 151 CRC patients. Stool samples were collected from three CRC groups (postoperatively, chemotherapy and relapse), and the fourth was the healthy control group. The amount of Fn in each sample was analyzed using quantitative loop-mediated isothermal amplification-phenol red (QLAMP-PhR), a novel biomolecular method that targets regions encoding the specific Fn FadA gene. Compared with healthy control stool samples, the Fn levels were significantly elevated in all CRC patient groups (P < 0.001), and it was significantly more frequent in the CRC relapse patients (group C) (P < 0.001). In addition, Fn abundance increased significantly in the distal colon compared to the proximal colon (P < 0.001). Both CRC relapse and chemotherapy exert significant reciprocal effects on the gut microbiota Fn of CRC patients. Microbiota-based intervention may be beneficial for patients during postoperative care, especially in CRC relapsing cases. Registration: This study of the clinical trial has been registered in the ISRCTN registry with study registration number ISRCTN53358464. https://www.isrctn.com/ISRCTN53358464. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1007/s12088-024-01279-6.
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Affiliation(s)
- Abdulrahman A. Zuraik
- Department of Biochemistry and Microbiology, Faculty of Pharmacy, Tishreen University, Lattakia, Syria
| | - Yaman Daboul
- School of Biological Sciences, Queens University Belfast, Belfast, UK
| | - M. Ayman Awama
- Department of Biochemistry and Microbiology, Faculty of Pharmacy, Tishreen University, Lattakia, Syria
| | - Haitham Yazigi
- Department of Laboratory Medicine/Faculty of Medicine, Tishreen University & Tishreen University Hospital, Lattakia, Syria
| | - Moh’d Azzam Kayasseh
- Dr. Kayasseh Medical Clinic, Dr. Sulaiman Al Habib Medical Group, DHCC, Dubai, UAE
| | - Michael Georges
- Department of Oncology, Faculty of Medicine, Tishreen University & Tishreen University Hospital, Lattakia, Syria
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Wang K, Yu J, Xu Q, Peng Y, Li H, Lu Y, Ouyang M. Disulfidptosis-related long non-coding RNA signature predicts the prognosis, tumor microenvironment, immunotherapy, and antitumor drug options in colon adenocarcinoma. Apoptosis 2024; 29:2074-2090. [PMID: 39115621 PMCID: PMC11550253 DOI: 10.1007/s10495-024-02011-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/24/2024] [Indexed: 11/10/2024]
Abstract
This study aims to investigate the role and prognostic significance of long non-coding RNAs (lncRNAs) associated with disulfidptosis in colon adenocarcinoma (COAD). The TCGA database's clinical data and transcriptome profiles were employed. Analysis of previous studies identified 10 disulfidptosis-related genes (DRGs). We used these genes to construct a signature that could independently and accurately predict the prognosis of patients with COAD. The Kaplan-Meier (K-M) curve analysis showed that the lower-risk group had a better prognosis. With the help of multivariate Cox regression analysis, the risk score produced from the patient's signature might independently predict the outcomes. Utilizing a nomogram, the receiver operating characteristic (ROC) curve, and principal component analysis (PCA), the signature's predictive ability was also confirmed. It's interesting to note that immunotherapy, especially PD-1 immune checkpoint suppression, was more likely to benefit low-risk patients. The IC50 levels for certain anticancer agents were lower in the high-risk group. Finally, qRT-PCR analyses in colon cancer cell lines revealed elevated levels of lncRNAs CASC9, ZEB1-AS1, ATP2A1-AS1, SNHG7, AL683813.1, and AP003555.1, and reduced levels of FAM160A1-DT and AC112220.2, compared to normal cell lines. This signature offers insights into prognosis, tumor microenvironment, and options for immunotherapy and antitumor drugs in patients with COAD.
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Affiliation(s)
- Kang Wang
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Shunde, Foshan, Guangdong Province, 528300, China
| | - Jing Yu
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Shunde, Foshan, Guangdong Province, 528300, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong Province, 510080, China
| | - Qihuan Xu
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Shunde, Foshan, Guangdong Province, 528300, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong Province, 510080, China
| | - Yuanhong Peng
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Shunde, Foshan, Guangdong Province, 528300, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong Province, 510080, China
| | - Haibin Li
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Shunde, Foshan, Guangdong Province, 528300, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong Province, 510080, China
| | - Yan Lu
- Guangdong Medical University, Zhanjiang, Dongguan, 523808, China.
- GCP Center, Shunde Hospital, Southern Medical University, The First People's Hospital of Shunde Foshan), Foshan, Guangdong, 528300, China.
| | - Manzhao Ouyang
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Shunde, Foshan, Guangdong Province, 528300, China.
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong Province, 510080, China.
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8
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Akash S, Shanto SKHI, Islam MR, Bayil I, Afolabi SO, Guendouzi A, Abdellattif MH, Zaki MEA. Discovery of novel MLK4 inhibitors against colorectal cancer through computational approaches. Comput Biol Med 2024; 182:109136. [PMID: 39298888 DOI: 10.1016/j.compbiomed.2024.109136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 08/20/2024] [Accepted: 09/08/2024] [Indexed: 09/22/2024]
Abstract
Colorectal cancer (CRC) is a significant health issue globally, affecting approximately 10 % of the world's population. The prevalence of CRC highlights the need for effective treatments and prevention strategies. The current therapeutic option, such as chemotherapy, has significant side effects. Thus, this study investigated the anticancer properties of Sanguinarine derivatives, an alkaloid found in traditional herbs via chemoinformatic approaches. Six Sanguinarine derivatives were discovered through virtual screening and molecular docking to determine their binding affinities against the mixed lineage kinase (MLK4) protein which is responsible for CRC. All the compounds were found to be more effective than standard drug used for colorectal cancer treatment, with Sanguinarine derivative 11 showing the highest affinity. The stability of the drug was confirmed through molecular dynamics simulations at 500 ns. This suggests that compound 11 has a higher chance of replacing 5-Fluorouracil, which is currently a widely used chemotherapy drug. Before molecular dynamics simulations, the pharmacokinetic and chemical properties of Sanguinarine derivatives were determined using pkCSM server and DFT method, respectively. The results support that compound 11 is a good drug candidate, as evidenced by Lipinski's Rule of Five. Therefore, compound 11 is recommended for further analysis via in vivo and in vitro studies to confirm its efficacy and safety.
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Affiliation(s)
- Shopnil Akash
- Department of Pharmacy, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka, 1216, Bangladesh.
| | - S K Hasibul Islam Shanto
- Department of Pharmacy, Faculty of Health Science, Northern University Bangladesh, Ashkona, Dhaka, 1230, Bangladesh.
| | - Md Rezaul Islam
- Department of Pharmacy, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka, 1216, Bangladesh
| | - Imren Bayil
- Department of Bioinformatics and Computational Biology, Gaziantep University, Turkey.
| | | | - Abdelkrim Guendouzi
- Laboratory of Chemistry: Synthesis, Properties and Applications (LCSPA), University of Saïda, Algeria.
| | - Magda H Abdellattif
- Chemistry Department, College of Sciences, University College of Taraba, Taif University, Saudi Arabia.
| | - Magdi E A Zaki
- Department of Chemistry, College of Science, Imam Mohammad Ibn Saud Islamic University Riyadh, Saudi Arabia.
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Jakopovic B, Horvatić A, Baranasic J, Car I, Oršolić N, Jakopovich I, Sedić M, Kraljević Pavelić S. Proteomic study of medicinal mushroom extracts reveals antitumor mechanisms in an advanced colon cancer animal model via ribosomal biogenesis, translation, and metabolic pathways. Front Pharmacol 2024; 15:1475102. [PMID: 39494346 PMCID: PMC11528127 DOI: 10.3389/fphar.2024.1475102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 09/23/2024] [Indexed: 11/05/2024] Open
Abstract
Introduction Colorectal cancer ranks as the third most common cancer in both men and women, with approximately 35% of cases being stage IV metastatic at diagnosis. Even with treatment advancements, the survival rates for these patients remain suboptimal. There is a significant focus on developing multi-targeted therapies due to the common issue of drug resistance in standard and targeted cancer treatments. Medicinal mushrooms, both as single compounds and as complex extracts, have undergone extensive research. Numerous types of mushrooms have been shown to be safe, effective inhibitors of cancer pathways and strong enhancers of the immune system. Methods In this study, we performed both qualitative and quantitative proteomic analyses using tandem mass tags (TMT) on CT26 wild type (CT26. WT) colon cancer tissues from Balb/c mice, which were treated with a special blend of medicinal mushroom extracts, either alone or in combination with the chemotherapy drug 5-fluorouracil. Results The results showed a notable increase in survival rates and indicated that medicinal mushroom preparation Agarikon Plus, both alone and combined with 5-fluorouracil or another medicinal mushroom preparation Agarikon.1, impedes multiple key processes in colorectal cancer progression. The analysis of differentially expressed proteins in treated groups was done by use of bioinformatics tools and a decrease in ribosomal biogenesis (e.g., RPS3) and translation processes (e.g., RPL14) as well as an increase in unfolded protein response (e.g., DNAJC3), lipid metabolism (e.g., ACOT7), and the tricarboxylic acid cycle (e.g., FH) were observed. Conclusion The treatment induced various alterations of known biomarkers and protein clusters critical to the progression and prognosis of colorectal cancer, laying a promising foundation for further translational research on this treatment modality.
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Affiliation(s)
| | - Anita Horvatić
- Faculty of Food Technology and Biotechnology, University of Zagreb, Zagreb, Croatia
| | - Jurica Baranasic
- Laboratory for Cell Biology and Signalling, Division of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia
| | - Iris Car
- Centre for Applied Bioanthropology, Institute for Anthropological Research, Zagreb, Croatia
| | - Nada Oršolić
- Division of Animal Physiology, Faculty of Science, University of Zagreb, Zagreb, Croatia
| | | | - Mirela Sedić
- Centre for Applied Bioanthropology, Institute for Anthropological Research, Zagreb, Croatia
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10
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Yaghoubi N, Gholamzad A, Naji T, Gholamzad M. In vitro evaluation of PLGA loaded hesperidin on colorectal cancer cell lines: an insight into nano delivery system. BMC Biotechnol 2024; 24:52. [PMID: 39095760 PMCID: PMC11297711 DOI: 10.1186/s12896-024-00882-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 07/29/2024] [Indexed: 08/04/2024] Open
Abstract
BACKGROUND Colorectal cancer is a common disease worldwide with non-specific symptoms such as blood in the stool, bowel movements, weight loss and fatigue. Chemotherapy drugs can cause side effects such as nausea, vomiting and a weakened immune system. The use of antioxidants such as hesperidin could reduce the side effects, but its low bioavailability is a major problem. In this research, we aimed to explore the drug delivery and efficiency of this antioxidant on the HCT116 colorectal cancer cell line by loading hesperidin into PLGA nanoparticles. MATERIALS AND METHODS Hesperidin loaded PLGA nanoparticles were produced by single emulsion evaporation method. The physicochemical properties of the synthesized hesperidin-loaded nanoparticles were determined using SEM, AFM, FT-IR, DLS and UV-Vis. Subsequently, the effect of the PLGA loaded hesperidin nanoparticles on the HCT116 cell line after 48 h was investigated by MTT assay at three different concentrations of the nanoparticles. RESULT The study showed that 90% of hesperidin were loaded in PLGA nanoparticles by UV-Vis spectrophotometry and FT-IR spectrum. The nanoparticles were found to be spherical and uniform with a hydrodynamic diameter of 76.2 nm in water. The release rate of the drug was about 93% after 144 h. The lowest percentage of cell viability of cancer cells was observed at a concentration of 10 µg/ml of PLGA nanoparticles loaded with hesperidin. CONCLUSION The results indicate that PLGA nanoparticles loaded with hesperidin effectively reduce the survival rate of HCT116 colorectal cancer cells. However, further studies are needed to determine the appropriate therapeutic dosage and to conduct animal and clinical studies.
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Affiliation(s)
- Narges Yaghoubi
- Faculty of Pharmacy and Pharmaceutical Sciences, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Amir Gholamzad
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Tahere Naji
- Department of Basic Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mehrdad Gholamzad
- Department of Microbiology and Immunology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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11
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Hon KW, Naidu R. Synergistic Mechanisms of Selected Polyphenols in Overcoming Chemoresistance and Enhancing Chemosensitivity in Colorectal Cancer. Antioxidants (Basel) 2024; 13:815. [PMID: 39061884 PMCID: PMC11273411 DOI: 10.3390/antiox13070815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 06/29/2024] [Accepted: 07/03/2024] [Indexed: 07/28/2024] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. Despite significant advances in medical treatment, chemotherapy as monotherapy can lead to substantial side effects and chemoresistance. This underscores the need for therapeutic approaches that are not only pharmacologically safe but also modulate multiple potent signaling pathways and sensitize cancer cells to overcome resistance to standard drugs. In recent years, scientists have been searching for natural compounds that can be used as chemosensitizers in addition to conventional medications for the synergistic treatment of CRC. Polyphenols represent a diverse group of natural compounds that can target multiple signaling pathways in cancer cells to induce anti-cancer effects. Additionally, polyphenols have been shown to work synergistically with chemotherapeutics and other natural compounds in cancer cells. This review aims to provide a comprehensive insight into the synergistic mechanisms of selected polyphenols as chemosensitizers in CRC cells. Further research and clinical trials are warranted to fully harness the synergistic mechanisms of selected polyphenols combined with chemotherapy or natural compounds in improving cancer treatment outcomes.
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Affiliation(s)
| | - Rakesh Naidu
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia;
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12
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Sadeghi M, Mestivier D, Sobhani I. Contribution of pks+ Escherichia coli ( E. coli) to Colon Carcinogenesis. Microorganisms 2024; 12:1111. [PMID: 38930493 PMCID: PMC11205849 DOI: 10.3390/microorganisms12061111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 05/24/2024] [Accepted: 05/29/2024] [Indexed: 06/28/2024] Open
Abstract
Colorectal cancer (CRC) stands as a significant global health concern, ranking second in mortality and third in frequency among cancers worldwide. While only a small fraction of CRC cases can be attributed to inherited genetic mutations, the majority arise sporadically due to somatic mutations. Emerging evidence reveals gut microbiota dysbiosis to be a contributing factor, wherein polyketide synthase-positive Escherichia coli (pks+ E. coli) plays a pivotal role in CRC pathogenesis. pks+ bacteria produce colibactin, a genotoxic protein that causes deleterious effects on DNA within host colonocytes. In this review, we examine the role of the gut microbiota in colon carcinogenesis, elucidating how colibactin-producer bacteria induce DNA damage, promote genomic instability, disrupt the gut epithelial barrier, induce mucosal inflammation, modulate host immune responses, and influence cell cycle dynamics. Collectively, these actions foster a microenvironment conducive to tumor initiation and progression. Understanding the mechanisms underlying pks+ bacteria-mediated CRC development may pave the way for mass screening, early detection of tumors, and therapeutic strategies such as microbiota modulation, bacteria-targeted therapy, checkpoint inhibition of colibactin production and immunomodulatory pathways.
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Affiliation(s)
- Mohammad Sadeghi
- EA7375–EC2M3: Early, Detection of Colonic Cancer by Using Microbial & Molecular Markers, Paris East Créteil University (UPEC), 94010 Créteil, France;
| | - Denis Mestivier
- EA7375–EC2M3: Early, Detection of Colonic Cancer by Using Microbial & Molecular Markers, Paris East Créteil University (UPEC), 94010 Créteil, France;
| | - Iradj Sobhani
- EA7375–EC2M3: Early, Detection of Colonic Cancer by Using Microbial & Molecular Markers, Paris East Créteil University (UPEC), 94010 Créteil, France;
- Department of Gastroenterology, Assistance Publique–Hôpitaux de Paris (APHP), Henri Mondor Hospital, 94010 Créteil, France
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13
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Zhou Y, Zhang XL, Ni HX, Shao TJ, Wang P. Impact of frailty on short-term postoperative outcomes in patients undergoing colorectal cancer surgery: A systematic review and meta-analysis. World J Gastrointest Surg 2024; 16:893-906. [PMID: 38577090 PMCID: PMC10989331 DOI: 10.4240/wjgs.v16.i3.893] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 12/28/2023] [Accepted: 02/05/2024] [Indexed: 03/22/2024] Open
Abstract
BACKGROUND Colorectal cancer is a major global health challenge that predominantly affects older people. Surgical management, despite advancements, requires careful consideration of preoperative patient status for optimal outcomes. AIM To summarize existing evidence on the association of frailty with short-term postoperative outcomes in patients undergoing colorectal cancer surgery. METHODS A literature search was conducted using PubMed, EMBASE and Scopus databases for observational studies in adult patients aged ≥ 18 years undergoing planned or elective colorectal surgery for primary carcinoma and/or secondary metastasis. Only studies that conducted frailty assessment using recognized frailty assessment tools and had a comparator group, comprising nonfrail patients, were included. Pooled effect sizes were reported as weighted mean difference or relative risk (RR) with 95% confidence intervals (CIs). RESULTS A total of 24 studies were included. Compared with nonfrail patients, frailty was associated with an increased risk of mortality at 30 d (RR: 1.99, 95%CI: 1.47-2.69), at 90 d (RR: 4.76, 95%CI: 1.56-14.6) and at 1 year (RR: 5.73, 95%CI: 2.74-12.0) of follow up. Frail patients had an increased risk of any complications (RR: 1.81, 95%CI: 1.57-2.10) as well as major complications (Clavien-Dindo classification grade ≥ III) (RR: 2.87, 95%CI: 1.65-4.99) compared with the control group. The risk of reoperation (RR: 1.18, 95%CI: 1.07-1.31), readmission (RR: 1.70, 95%CI: 1.36-2.12), need for blood transfusion (RR: 1.67, 95%CI: 1.52-1.85), wound complications (RR: 1.49, 95%CI: 1.11-1.99), delirium (RR: 4.60, 95%CI: 2.31-9.16), risk of prolonged hospitalization (RR: 2.09, 95%CI: 1.22-3.60) and discharge to a skilled nursing facility or rehabilitation center (RR: 3.19, 95%CI: 2.0-5.08) was all higher in frail patients. CONCLUSION Frailty in colorectal cancer surgery patients was associated with more complications, longer hospital stays, higher reoperation risk, and increased mortality. Integrating frailty assessment appears crucial for tailored surgical management.
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Affiliation(s)
- Yao Zhou
- Department of Operating Room, Affiliated Tumor Hospital of Nantong University & Nantong Tumor Hospital, Nantong 226361, Jiangsu Province, China
| | - Xiao-Lei Zhang
- Department of Gastrointestinal Surgery, The Affiliated Tumor Hospital of Nantong University & Nantong Tumor Hospital, Nantong 226361, Jiangsu Province, China
| | - Hong-Xia Ni
- Department of Operating Room, Affiliated Tumor Hospital of Nantong University & Nantong Tumor Hospital, Nantong 226361, Jiangsu Province, China
| | - Tian-Jing Shao
- Department of Operating Room, Affiliated Tumor Hospital of Nantong University & Nantong Tumor Hospital, Nantong 226361, Jiangsu Province, China
| | - Ping Wang
- Department of Operating Room, Affiliated Tumor Hospital of Nantong University & Nantong Tumor Hospital, Nantong 226361, Jiangsu Province, China
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14
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Nordengen AL, Kværner AS, Krutto A, Alavi DT, Henriksen HB, Henriksen C, Raastad T, Smeland S, Bøhn SK, Shaposhnikov S, Collins AR, Blomhoff R. DNA base oxidation in relation to TNM stages and chemotherapy treatment in colorectal cancer patients 2-9 months post-surgery. Free Radic Biol Med 2024; 212:174-185. [PMID: 38141887 DOI: 10.1016/j.freeradbiomed.2023.12.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 12/01/2023] [Accepted: 12/13/2023] [Indexed: 12/25/2023]
Abstract
Accumulation of DNA damage is a critical feature of genomic instability, which is a hallmark of various cancers. The enzyme-modified comet assay is a recognized method to detect specific DNA lesions at the level of individual cells. In this cross-sectional investigation, we explore possible links between clinicopathological and treatment related factors, nutritional status, physical activity and function, and DNA damage in a cohort of colorectal cancer (CRC) patients with non-metastatic disease. Levels of DNA damage in peripheral mononuclear blood cells (PBMCs) assessed 2-9 months post-surgery, were compared across tumour stage (localized (stage I-II) vs. regional (stage III) disease), localization (colon vs. rectosigmoid/rectum cancer), and adjuvant chemotherapy usage, with the last dosage administrated 2-191 days prior to sampling. Associations between DNA damage and indicators of nutritional status, physical activity and function were also explored. In PBMCs, DNA base oxidation was higher in patients diagnosed with regional compared with localized tumours (P = 0.03), but no difference was seen for DNA strand breaks (P > 0.05). Number of days since last chemotherapy dosage was negatively associated with DNA base oxidation (P < 0.01), and patients recently receiving chemotherapy (<15 days before blood collection) had higher levels of DNA base oxidation than those not receiving chemotherapy (P = 0.03). In the chemotherapy group, higher fat mass (in kg and %) as well as lower physical activity were associated with greater DNA base oxidation (P < 0.05). In conclusion, DNA base oxidation measured with the enzyme-modified comet assay varies according to tumour and lifestyle related factors in CRC patients treated for non-metastatic disease.
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Affiliation(s)
- Anne Lene Nordengen
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Norway; Norgenotech AS, Oslo Cancer Cluster Incubator, Oslo, Norway; Department of Sport Science and Physical Education, Faculty of Health and Sport Sciences, University of Agder, Kristiansand, Norway.
| | - Ane S Kværner
- Section for Colorectal Cancer Screening, The Cancer Registry of Norway, Oslo, Norway
| | - Annika Krutto
- Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Norway
| | - Dena T Alavi
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Norway
| | - Hege B Henriksen
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Norway
| | - Christine Henriksen
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Norway
| | - Truls Raastad
- Department of Physical Performance, Norwegian School of Sport Science, Norway
| | - Sigbjørn Smeland
- Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Norway, Oslo, Norway
| | - Siv K Bøhn
- Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, Ås, Norway
| | | | | | - Rune Blomhoff
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Norway; Department of Clinical Service, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway
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15
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Sampaio Moura N, Schledwitz A, Alizadeh M, Patil SA, Raufman JP. Matrix metalloproteinases as biomarkers and therapeutic targets in colitis-associated cancer. Front Oncol 2024; 13:1325095. [PMID: 38288108 PMCID: PMC10824561 DOI: 10.3389/fonc.2023.1325095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 12/26/2023] [Indexed: 01/31/2024] Open
Abstract
Colorectal cancer (CRC) remains a major cause of morbidity and mortality. Therapeutic approaches for advanced CRC are limited and rarely provide long-term benefit. Enzymes comprising the 24-member matrix metalloproteinase (MMP) family of zinc- and calcium-dependent endopeptidases are key players in extracellular matrix degradation, a requirement for colon tumor expansion, invasion, and metastasis; hence, MMPs are an important research focus. Compared to sporadic CRC, less is known regarding the molecular mechanisms and the role of MMPs in the development and progression of colitis-associated cancer (CAC) - CRC on a background of chronic inflammatory bowel disease (IBD) - primarily ulcerative colitis and Crohn's disease. Hence, the potential of MMPs as biomarkers and therapeutic targets for CAC is uncertain. Our goal was to review data regarding the role of MMPs in the development and progression of CAC. We sought to identify promising prognostic and therapeutic opportunities and novel lines of investigation. A key observation is that since MMPs may be more active in early phases of CAC, using MMPs as biomarkers of advancing neoplasia and as potential therapeutic targets for adjuvant therapy in those with advanced stage primary CAC rather than overt metastases may yield more favorable outcomes.
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Affiliation(s)
- Natalia Sampaio Moura
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Alyssa Schledwitz
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Madeline Alizadeh
- The Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Seema A. Patil
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Jean-Pierre Raufman
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, United States
- Medical Service, Veterans Affairs Maryland Healthcare System, Baltimore, MD, United States
- Marlene and Stewart Greenebaum Cancer Center, University of Maryland Medical Center, Baltimore, MD, United States
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, United States
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16
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Makran M, Garcia-Llatas G, Alegría A, Cilla A. Ethylcoprostanol modulates colorectal cancer cell proliferation and mitigates cytotoxicity of cholesterol metabolites in non-tumor colon cells. Food Funct 2023; 14:10829-10840. [PMID: 37982821 DOI: 10.1039/d3fo01868g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2023]
Abstract
Sterols can be metabolized by gut microbiota. The cholesterol metabolites have been proposed as promoters of colorectal cancer (CRC), while the effect of plant sterol metabolites is unknown. This study aimed to evaluate the cytotoxicity of metabolites from cholesterol (coprostanol, cholestanol, coprostanone and cholestenone) and β-sitosterol (ethylcoprostanol) on human colon tumor (Caco-2) and non-tumor (CCD-18Co) cells at physiological concentrations (9-300 μM) and exposure time (24 h). Ethylcoprostanol reduced the tumor cell proliferation (MTT), showing in flow cytometry assays induction of apoptosis via production of reactive oxygen species (ROS) and ceramide. Transcriptomic analysis (qPCR) showed activation of the intrinsic apoptosis pathway (BAX/BCL2 ratio and CASP9 increased), accompanied by downregulation of the p21 gene. Cholesterol metabolites, mainly the most hydrophobic, induced apoptosis and G0/G1 phase arrest in non-tumor cells through overproduction of ROS. Both the intrinsic and extrinsic (CASP8 increased) apoptosis pathways occurred. In turn, a reduction in the expression of the cyclin E1 gene confirmed the cell cycle arrest. In addition, ethylcoprostanol protected non-tumor cells from the most cytotoxic cholesterol metabolite (cholestenone). In conclusion, ethylcoprostanol is a promising candidate as a therapeutic adjuvant in CRC, while cholesterol metabolites could act as CRC promoters through their cytotoxicity.
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Affiliation(s)
- Mussa Makran
- Nutrition and Food Science Area, Faculty of Pharmacy and Food Sciences, University of Valencia, Av. Vicent Andrés Estellés s/n, 46100 Burjassot, Valencia, Spain.
| | - Guadalupe Garcia-Llatas
- Nutrition and Food Science Area, Faculty of Pharmacy and Food Sciences, University of Valencia, Av. Vicent Andrés Estellés s/n, 46100 Burjassot, Valencia, Spain.
| | - Amparo Alegría
- Nutrition and Food Science Area, Faculty of Pharmacy and Food Sciences, University of Valencia, Av. Vicent Andrés Estellés s/n, 46100 Burjassot, Valencia, Spain.
| | - Antonio Cilla
- Nutrition and Food Science Area, Faculty of Pharmacy and Food Sciences, University of Valencia, Av. Vicent Andrés Estellés s/n, 46100 Burjassot, Valencia, Spain.
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17
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Kim YM, Lee JE. Dyadic Effects of Psychological Health on Quality of Life in Patients with Colorectal Cancer and Caregivers: A Systematic Review and Meta-Analysis. Semin Oncol Nurs 2023; 39:151477. [PMID: 37495448 DOI: 10.1016/j.soncn.2023.151477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 05/29/2023] [Accepted: 07/03/2023] [Indexed: 07/28/2023]
Abstract
OBJECTIVES This study aimed to review dyadic research on psychological health and health-related quality of life (HRQL) in patients with colorectal cancer (CRC) and caregivers and examine the pooled partner effects and actor effects based on the Actor-Partner Interdependence Model. DATA SOURCES A systematic review and meta-analysis were conducted. We registered our review protocol with PROSPERO (CRD42021258482). Six databases were searched until June 2021 using the following keywords: colorectal neoplasms, caregivers, depression, anxiety, stress, and quality of life. Two reviewers independently screened 1,597 studies that included both CRC patients and family caregivers. Meta-analyses were performed of the partner and actor effects of psychological health on HRQL in CRC. CONCLUSION Eighteen observational studies involving 2,757 patients with CRC and 2,601 caregivers were included. Regarding partner effects, the distress of patients with CRC affected their family caregivers' distress and burden. There were three types of actor effects among patients with CRC and family caregivers: 1) the social support of patients with CRC affects their level of distress; (2) the distress of patients with CRC affects their HRQL; and (3) caregivers' social support affects their level of distress. This study provides the first comprehensive overview of the dyadic relationships between psychological health and HRQL in patients with CRC and their caregivers. IMPLICATIONS FOR NURSING PRACTICE The development of dyadic interventions for improving psychological health is warranted to help both patients with CRC and their family caregivers live with improved HRQL and well-being.
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Affiliation(s)
- Young Man Kim
- Assistant Professor, College of Nursing, Jeonbuk National University, and Reseach Institute of Nursing Science, Jeonbuk National University, Jeonju-si, Republic of Korea
| | - Jung Eun Lee
- Assistant Professor, University of Rhode Island College of Nursing, Kingston, Rhode Island, USA.
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18
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Zingeta GT, Worku YT, Getachew A, Feyisa JD, Furgassa H, Belay W, Mengesha T, Jemal A, Assefa M. Clinical presentation, treatment patterns, and outcomes of colorectal cancer patients at Tikur Anbessa Specialized Hospital in Addis Ababa, Ethiopia: A prospective cohort study. Cancer Rep (Hoboken) 2023; 6:e1869. [PMID: 37452615 PMCID: PMC10480423 DOI: 10.1002/cnr2.1869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 06/04/2023] [Accepted: 06/30/2023] [Indexed: 07/18/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the third most common cause of cancer death in both genders worldwide. AIMS This study aimed to evaluate the outcomes and prognostic factors of CRC patients at Tikur Anbessa Specialized Hospital in Ethiopia. METHODS AND RESULTS A prospective cohort study was conducted on 209 patients from January 2020 to September 2022. Kaplan-Meier curves and bivariate and multivariate Cox regression analyses were used to analyze overall and progression-free survival, with a significance value of P < .05. Results showed an overall mortality rate was 67.46% (95% confidence interval [CI]: 61.0-74.0), while the 1-year overall survival (OS) rate was 63.16% (95% CI: 56.23-69.29), with a median follow-up duration of 20 months. The median OS and progression-free survival times were 17 and 11 months, respectively. Age above 40 years (hazard ratio [HR] = 1.53, 1.02-2.29, p < .040), lower educational level (high school and below) (HR = 2.20, 1.24-3.90, p < .007), poor performance status (HR = 1.60, 1.03-2.48, p < .035), Hgb ≤12.5 g/dL (HR = 1.55, 1.03-2.08, p < .035), T-4 disease (HR = 6.05, 2.28-16.02, p < .000), and metastases at diagnosis (HR = 8.53, 3.77-19.25, p < .000) were all associated with poorer survival. CONCLUSION These findings suggest that poor survival of CRC patients in Ethiopia is largely due to advanced stage of the disease and lack of timely treatment, and highlight the urgent need for improved access to cancer treatment in the region.
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Affiliation(s)
| | - Yohannes T. Worku
- Department of Oncology, School of MedicineAddis Ababa UniversityAddis AbabaEthiopia
| | - Assefa Getachew
- Department of Radiology, School of MedicineAddis Ababa UniversityAddis AbabaEthiopia
| | - Jilcha Diribi Feyisa
- Department of Oncology, School of MedicineAddis Ababa UniversityAddis AbabaEthiopia
- Department of OncologySaint Paul Hospital Millennium Medical CollegeAddis AbabaEthiopia
| | - Hawi Furgassa
- Department of Oncology, School of MedicineAddis Ababa UniversityAddis AbabaEthiopia
- Department of OncologySaint Paul Hospital Millennium Medical CollegeAddis AbabaEthiopia
| | - Winini Belay
- Department of Reproductive Health and Health Service Management, School of Public HealthAddis Ababa UniversityAddis AbabaEthiopia
| | - Tariku Mengesha
- Department of EpidemiologySt. Peter Specialized HospitalAddis AbabaEthiopia
| | - Ahmedin Jemal
- Department of Surveillance and Health Services ResearchAmerican Cancer SocietyAtlantaGeorgiaUSA
| | - Mathewos Assefa
- Department of Oncology, School of MedicineAddis Ababa UniversityAddis AbabaEthiopia
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Hjazi A, Nasir F, Noor R, Alsalamy A, Zabibah RS, Romero-Parra RM, Ullah MI, Mustafa YF, Qasim MT, Akram SV. The pathological role of C-X-C chemokine receptor type 4 (CXCR4) in colorectal cancer (CRC) progression; special focus on molecular mechanisms and possible therapeutics. Pathol Res Pract 2023; 248:154616. [PMID: 37379710 DOI: 10.1016/j.prp.2023.154616] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 06/07/2023] [Accepted: 06/10/2023] [Indexed: 06/30/2023]
Abstract
Colorectal cancer (CRC) is comprised of transformed cells and non-malignant cells including cancer-associated fibroblasts (CAF), endothelial vasculature cells, and tumor-infiltrating cells. These nonmalignant cells, as well as soluble factors (e.g., cytokines), and the extracellular matrix (ECM), form the tumor microenvironment (TME). In general, the cancer cells and their surrounding TME can crosstalk by direct cell-to-cell contact and via soluble factors, such as cytokines (e.g., chemokines). TME not only promotes cancer progression through growth-promoting cytokines but also provides resistance to chemotherapy. Understanding the mechanisms of tumor growth and progression and the roles of chemokines in CRC will likely suggest new therapeutic targets. In this line, a plethora of reports has evidenced the critical role of chemokine receptor type 4 (CXCR4)/C-X-C motif chemokine ligand 12 (CXCL12 or SDF-1) axis in CRC pathogenesis. In the current review, we take a glimpse into the role of the CXCR4/CXCL12 axis in CRC growth, metastasis, angiogenesis, drug resistance, and immune escape. Also, a summary of recent reports concerning targeting CXCR4/CXCL12 axis for CRC management and therapy has been delivered.
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Affiliation(s)
- Ahmed Hjazi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | | | - Rabia Noor
- Amna Inayat Medical College, Lahore, Pakistan
| | - Ali Alsalamy
- College of Medical Technique, Imam Ja'afar Al-Sadiq University, Al-Muthanna 66002, Iraq
| | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | | | - Muhammad Ikram Ullah
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 75471, Aljouf, Saudi Arabia
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul 41001, Iraq
| | - Maytham T Qasim
- Department of Anesthesia, College of Health and Medical Technololgy, Al-Ayen University, Thi-Qar, Iraq
| | - Shaik Vaseem Akram
- Uttaranchal Institute of Technology, Division of Research & Innovation, Uttaranchal University, Dehradun 248007, India
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20
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Leerhoff S, Raem A, Kolbe EW, Schulz L, Borchers K, Köhler T, Winde G, Kirchner C. Methylated Septin9 identified patients with colorectal carcinoma and showed higher sensitivity than conventional biomarkers in detecting tumor. Cancer Treat Res Commun 2023; 36:100748. [PMID: 37541105 DOI: 10.1016/j.ctarc.2023.100748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 07/20/2023] [Accepted: 07/22/2023] [Indexed: 08/06/2023]
Abstract
INTRODUCTION It is worth noting the limitations in sensitivity of the existing biomarkers carcinoembryonic antigen (CEA) and carbohydrate antigen (CA 19-9) in detection of colorectal cancer (CRC). In our study, we address the performance of the liquid biopsy biomarker "methylated septin 9" (mSEPT9) in the detection and disease surveillance of CRC. MATERIALS AND METHODS The monocentric prospective survey encompassed 120 patients diagnosed with CRC who underwent planned curative resection between December 2018 and December 2020. Blood samples were collected from the participants preoperatively as well as at 7 days, 6 weeks, and 3 months postoperatively. The presence of mSEPT9, CEA, and CA 19-9 was detected using the pro Epi Colon® 2.0 CE test, Elecsys® CEA, and Elecsys® CA19-9 electrochemiluminescence immunoassay, respectively. RESULTS In the preoperative setting, mSEPT9 demonstrated superior capability in identifying patients with CRC compared to CEA and CA 19-9, with detection rates of 57%, 32%, and 18% respectively. Combining all three biomarkers increased the overall sensitivity to 66% preoperatively. In considering UICC stage and T-status, mSEPT9 exhibited higher sensitivity across all stages in comparison with conventional tumor markers, and 65% of patients with metastases were identified postoperatively through mSEPT9. Tumor recognition after surgery was achieved with the sensitivity of 72% and specificity of 91%. CONCLUSIONS We recommend using mSEPT9 as a non-invasive diagnostic tool for the ongoing monitoring of patients with CRC. The sensitivity and specificity exhibited by mSEPT9 in recognition of tumor after surgery, highlights its particular potential for monitoring of CRC patients.
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Affiliation(s)
- Sabine Leerhoff
- Department of General and Visceral Surgery, Thoracic Surgery and Proctology, Ruhr University Bochum, Klinikum Herford, Schwarzenmoorstr. 70, 32049 Herford, Germany
| | - Arnold Raem
- arrows biomedical Deutschland GmbH, Heisenbergstr. 1, 48149 Muenster, Germany
| | - Ernst-Wolfgang Kolbe
- Department of General and Visceral Surgery, Thoracic Surgery and Proctology, Ruhr University Bochum, Klinikum Herford, Schwarzenmoorstr. 70, 32049 Herford, Germany
| | - Laura Schulz
- Department of General and Visceral Surgery, Thoracic Surgery and Proctology, Ruhr University Bochum, Klinikum Herford, Schwarzenmoorstr. 70, 32049 Herford, Germany
| | - Kirsten Borchers
- Department of General and Visceral Surgery, Thoracic Surgery and Proctology, Ruhr University Bochum, Klinikum Herford, Schwarzenmoorstr. 70, 32049 Herford, Germany
| | - Thomas Köhler
- Department of Anaesthesiology and Intensive Care Medicine, Klinikum Halberstadt, Gleimstr. 5, 38820 Halberstadt, Germany
| | - Günther Winde
- Department of General and Visceral Surgery, Thoracic Surgery and Proctology, Ruhr University Bochum, Klinikum Herford, Schwarzenmoorstr. 70, 32049 Herford, Germany.
| | - Carmen Kirchner
- Department of General and Visceral Surgery, Thoracic Surgery and Proctology, Ruhr University Bochum, Klinikum Herford, Schwarzenmoorstr. 70, 32049 Herford, Germany
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21
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Mohammad Mirzaei N, Hao W, Shahriyari L. Investigating the spatial interaction of immune cells in colon cancer. iScience 2023; 26:106596. [PMID: 37168560 PMCID: PMC10165418 DOI: 10.1016/j.isci.2023.106596] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 02/28/2023] [Accepted: 04/03/2023] [Indexed: 05/13/2023] Open
Abstract
The intricate network of interactions between cells and molecules in the tumor microenvironment creates a heterogeneous ecosystem. The proximity of the cells and molecules to their activators and inhibitors is essential in the progression of tumors. Here, we develop a system of partial differential equations coupled with linear elasticity to investigate the effects of spatial interactions on the tumor microenvironment. We observe interesting cell and cytokine distribution patterns, which are heavily affected by macrophages. We also see that cytotoxic T cells get recruited and suppressed at the site of macrophages. Moreover, we observe that anti-tumor macrophages reorganize the patterns in favor of a more spatially restricted cancer and necrotic core. Furthermore, the adjoint-based sensitivity analysis indicates that the most sensitive model's parameters are directly related to macrophages. The results emphasize the widely acknowledged effect of macrophages in controlling cancer cells population and spatially arranging cells in the tumor microenvironment.
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Affiliation(s)
- Navid Mohammad Mirzaei
- Department of Mathematics and Statistics, University of Massachusetts Amherst, Amherst, 01003 MA, USA
| | - Wenrui Hao
- Department of Mathematics, Pennsylvania State University, University Park, 16802 PA, USA
| | - Leili Shahriyari
- Department of Mathematics and Statistics, University of Massachusetts Amherst, Amherst, 01003 MA, USA
- Corresponding author
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22
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Xiang J, Gong W, Liu J, Zhang H, Li M, Wang R, Lv Y, Sun P. Identification of DLL3-related genes affecting the prognosis of patients with colon adenocarcinoma. Front Genet 2023; 14:1098190. [PMID: 37274780 PMCID: PMC10233108 DOI: 10.3389/fgene.2023.1098190] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 04/24/2023] [Indexed: 06/07/2023] Open
Abstract
Background: Delta-like ligand 3 (DLL3) is one of the NOTCH family of ligands, which plays a pro- or anti-carcinogenic role in some cancers. But the role of DLL3 in colon adenocarcinoma (COAD) has not been studied in depth. Materials and methods: First, we used Kaplan-Meier (K-M) curve to evaluate the effect of DLL3 on the prognosis of COAD in The Cancer Genome Atlas (TCGA), which was further validated in clinical samples for immunohistochemistry. Then we screened for differentially expressed genes (DEGs) of DLL3 by analyzing datasets of COAD samples from Gene Expression Omnibus (GEO) and TCGA. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, and Gene Set Enrichment Analysis (GSEA) were conducted to explore the underlying mechanisms of DLL3-related in the development and prognosis of COAD. On the basis of DLL3-related signature genes, a prognostic model and a nomogram were constructed. Finally, CIBERSORT was applied to assess the proportion of immune cell types in COAD sample. Results: Survival analysis showed a significant difference in overall survival between high- and low-expression group (p = 0.0092), with COAD patients in the high-group having poorer 5-year survival rate. Gene functional enrichment analysis revealed that DLL3-related DEGs were mainly enriched in tumor- and immunity-related signaling pathways, containing AMPK pathway and mitophagy-animal. The comparison of COAD tumor and normal, DLL3 high- and low-expression groups by GSEA found that AMPK signaling pathway and mitophagy-animal were inhibited. Nomogram constructed from DLL3-related signature genes had a good predictive effect on the prognosis of COAD. We found the highest correlation between DLL3 and interstitial dendritic cell (iDC), natural killer (NK) cell and Interstitial dendritic cell (Tem). DLL3 was also revealed to be diagnostic for COAD. In clinical sample, we identified higher DLL3 expression in colon cancer tissue than in adjacent control (p < 0.0001) and in metastasis than in primary lesion (p = 0.0056). DLL3 expression was associated with stage and high DLL3 expression was observed to predict poorer overall survival (p = 0.004). Conclusion: It suggested that DLL3 may offer prognostic value and therapeutic potential for individualized treatment of COAD, and that it may has a diagnostic role in COAD.
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Affiliation(s)
- Jinyu Xiang
- Departments of Oncology, Yantai Yuhuangding Hospital, Shandong University, Yantai, Shandong, China
| | - Wenjing Gong
- Departments of Oncology, Yantai Yuhuangding Hospital, Shandong University, Yantai, Shandong, China
| | - Jiannan Liu
- Departments of Oncology, Yantai Yuhuangding Hospital, Shandong University, Yantai, Shandong, China
| | - Huijuan Zhang
- Departments of Oncology, Yantai Yuhuangding Hospital, Shandong University, Yantai, Shandong, China
| | - Ming Li
- Departments of Oncology, Yantai Yuhuangding Hospital, Shandong University, Yantai, Shandong, China
| | - Rujian Wang
- Departments of Oncology, Yantai Yuhuangding Hospital, Shandong University, Yantai, Shandong, China
| | - Yaodong Lv
- Departments of Neurology, Yantai Yuhuangding Hospital, Shandong University, Yantai, Shandong, China
| | - Ping Sun
- Departments of Oncology, Yantai Yuhuangding Hospital, Shandong University, Yantai, Shandong, China
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23
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Kim J, Kim H, Lee MS, Lee H, Kim YJ, Lee WY, Yun SH, Kim HC, Hong HK, Hannenhalli S, Cho YB, Park D, Choi SS. Transcriptomes of the tumor-adjacent normal tissues are more informative than tumors in predicting recurrence in colorectal cancer patients. J Transl Med 2023; 21:209. [PMID: 36941605 PMCID: PMC10029176 DOI: 10.1186/s12967-023-04053-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Accepted: 03/10/2023] [Indexed: 03/23/2023] Open
Abstract
BACKGROUND Previous investigations of transcriptomic signatures of cancer patient survival and post-therapy relapse have focused on tumor tissue. In contrast, here we show that in colorectal cancer (CRC) transcriptomes derived from normal tissues adjacent to tumors (NATs) are better predictors of relapse. RESULTS Using the transcriptomes of paired tumor and NAT specimens from 80 Korean CRC patients retrospectively determined to be in recurrence or nonrecurrence states, we found that, when comparing recurrent with nonrecurrent samples, NATs exhibit a greater number of differentially expressed genes (DEGs) than tumors. Training two prognostic elastic net-based machine learning models-NAT-based and tumor-based in our Samsung Medical Center (SMC) cohort, we found that NAT-based model performed better in predicting the survival when the model was applied to the tumor-derived transcriptomes of an independent cohort of 450 COAD patients in TCGA. Furthermore, compositions of tumor-infiltrating immune cells in NATs were found to have better prognostic capability than in tumors. We also confirmed through Cox regression analysis that in both SMC-CRC as well as in TCGA-COAD cohorts, a greater proportion of genes exhibited significant hazard ratio when NAT-derived transcriptome was used compared to when tumor-derived transcriptome was used. CONCLUSIONS Taken together, our results strongly suggest that NAT-derived transcriptomes and immune cell composition of CRC are better predictors of patient survival and tumor recurrence than the primary tumor.
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Affiliation(s)
- Jinho Kim
- Division of Biomedical Convergence, College of Biomedical Science, Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon, 24341, Korea
| | - Hyunjung Kim
- Precision Medicine Center, Future Innovation Research Division, Seoul National University Bundang Hospital, Seongnam, 13620, Korea
| | - Min-Seok Lee
- Division of Biomedical Convergence, College of Biomedical Science, Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon, 24341, Korea
| | - Heetak Lee
- Precision Medicine Center, Future Innovation Research Division, Seoul National University Bundang Hospital, Seongnam, 13620, Korea
- Center for Genome Engineering, Institute for Basic Science, 55, Expo-ro, Yuseng-gu, Daejeon, 34126, Korea
| | - Yeon Jeong Kim
- Samsung Genome Institute, Samsung Medical Center, Seoul, 06351, Korea
| | - Woo Yong Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea
| | - Seong Hyeon Yun
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea
| | - Hee Cheol Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea
| | - Hye Kyung Hong
- Institute for Future Medicine, Samsung Medical Center, Seoul, 06351, Korea
| | - Sridhar Hannenhalli
- Cancer Data Science Lab, Center for Cancer Research, National Cancer Institute, Bethesda, 20814, MD, USA
| | - Yong Beom Cho
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea.
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06351, Korea.
| | | | - Sun Shim Choi
- Division of Biomedical Convergence, College of Biomedical Science, Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon, 24341, Korea.
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24
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Ali F, Hussain S, Memon SA, Iqbal SS. Recently Top Trending Cancers in a Tertiary Cancer Hospital in Pakistan. DR. SULAIMAN AL HABIB MEDICAL JOURNAL 2023. [PMCID: PMC10019439 DOI: 10.1007/s44229-023-00028-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/18/2023] Open
Abstract
Cancer is a leading cause of death, and its incidence is increasing, as reported in recent studies by GLOBOCAN. Cancer registry programs provide insights into currently trending tumors worldwide and aid in determining possible risk factors. This study was based on 7 years of cancer registry data recorded at NIMRA cancer hospital, Sindh, from 2015 to 2021. A total of 16,191 cancer patients were registered. In men, head and neck, lung, liver, colorectal and urinary tract cancers were most common. In women, breast cancer, head and neck cancer, gynecological tumors, esophageal cancer and colorectal cancer predominated. The overall data analysis indicated trending cancers in both sexes, including head and neck cancer (37.76%), breast cancer (13.83%), gynecological tumors (10.22%), esophageal cancer (5.18%), lung cancer (4.79%), colorectal cancer (4.27%), liver cancer (3.87%), lymphoma (3.16%), urinary tract cancer (3.11) and prostate cancer (1.53%). The mean age was 50.41 ± 11.78 years in men and 48.47 ± 11.88 years in women. Cancer prevalence has markedly increased worldwide, and is particularly alarming in developing countries. Various risk factors are involved in this increase, including the use of tobacco, areca nut, chewable tobacco, snuff or niswar. Current disease trends are substantially different from those in older studies at the institute.
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Affiliation(s)
- Faisal Ali
- Nuclear Institute of Medicine and Radiotherapy, Jamshoro, Pakistan
| | - Sadiq Hussain
- Nuclear Medicine Oncology and Radiotherapy Institute, Nawabshah, Pakistan
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25
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Aziz A, Rehman U, Sheikh A, Abourehab MAS, Kesharwani P. Lipid-based nanocarrier mediated CRISPR/Cas9 delivery for cancer therapy. JOURNAL OF BIOMATERIALS SCIENCE. POLYMER EDITION 2023; 34:398-418. [PMID: 36083788 DOI: 10.1080/09205063.2022.2121592] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
CRISPR/Cas mediated gene-editing has opened new avenues for therapies that show great potential for treating or curing cancers, genetic disorders, and microbial infections such as HIV. CRISPR/Cas9 tool is highly efficacious in revolutionizing the advent of genome editing; however, its efficient and safe delivery is a major hurdle due to its cellular impermeability and instability. Nano vectors could be explored to scale up the safe and effective delivery of CRISPR/Cas9. This review highlights the importance of CRISPR/Cas9 genome editing system in cancer treatment along with the effect of lipid-based nanoparticles in its safe delivery to cancer cells. The solid-lipid nanoparticles, nanostructured lipid carrier, lipid nanoparticles and niosomes have shown great effect in the delivery of CRISPR compounds to the cancer cells. The design and genome editing application in cancer therapy has been discussed along with the future concern and prospects of lipid nanoparticle based CRISPR/Cas9 has been focused toward the end.
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Affiliation(s)
- Aisha Aziz
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Urushi Rehman
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Afsana Sheikh
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Mohammed A S Abourehab
- Department of Pharmaceutics, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia.,Department of Pharmaceutics and Industrial Pharmacy, College of Pharmacy, Minia University, Minia, Egypt
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India.,University Institute of Pharma Sciences, Chandigarh University, Mohali, Punjab, India
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26
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Abstract
The etiology of colorectal cancer (CRC) is influenced by bacterial communities that colonize the gastrointestinal tract. These microorganisms derive essential nutrients from indigestible dietary or host-derived compounds and activate molecular signaling pathways necessary for normal tissue and immune function. Associative and mechanistic studies have identified bacterial species whose presence may increase CRC risk, including notable examples such as Fusobacterium nucleatum, Enterotoxigenic Bacteroides fragilis, and pks+ E. coli. In recent years this work has expanded in scope to include aspects of host mutational status, intra-tumoral microbial heterogeneity, transient infection, and the cumulative influence of multiple carcinogenic bacteria after sequential or co-colonization. In this review, we will provide an updated overview of how host-bacteria interactions influence CRC development, how this knowledge may be utilized to diagnose or prevent CRC, and how the gut microbiome influences CRC treatment efficacy.
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Affiliation(s)
- Michael W. Dougherty
- Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA
| | - Christian Jobin
- Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA
- Department of Infectious Diseases and Immunology, University of Florida College of Medicine, Gainesville, FL, USA
- Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL, USA
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27
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Ganduri V, Rajasekaran K, Duraiyarasan S, Adefuye MA, Manjunatha N. Colorectal Carcinoma, Cyclooxygenases, and COX Inhibitors. Cureus 2022; 14:e28579. [PMID: 36185863 PMCID: PMC9521169 DOI: 10.7759/cureus.28579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/29/2022] [Indexed: 12/24/2022] Open
Abstract
Colorectal carcinoma (CRC) is the most common of gastrointestinal cancers, the majority presenting with sporadic occurrence compared to the less frequently inherited syndromes. The increasing incidence, decreasing gender and age disparities, and the prevalent risk factors are concerning. The malignancy arising from benign precursor polyps transforms slowly over time. The adenoma variant polyps reported a marked upregulation of cyclooxygenases (COX), significantly COX-2 isoform, influenced by various determinants such as genetics, pathology, histology, and site of the carcinoma. These COX enzymes are responsible for prostaglandin synthesis and the consequent cascade of cell inflammation and proliferation. Therefore, COX inhibition by non-steroidal anti-inflammatory drugs (NSAIDs) targeted against both the isoforms COX-1 and COX-2 have been studied for decades in anticipation of preventing the occurrence of colorectal carcinoma in high-risk populations. This article has collated and highlighted the overexpression of COX enzymes by the adenomatous polyps and provides corroborating evidence from multiple studies in favor of COX inhibition by NSAIDs. Aspirin and Sulindac were two drugs to be initially proven to halt the progression and cause regression of the polyps. Celecoxib, a selective COX-2 inhibitor besides NSAIDs, was also used in experimental studies.
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28
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Clinicopathological Characteristics and Overall 5-Year Survival of Colorectal Cancer: A Retrospective Study. Med Sci (Basel) 2022; 10:medsci10030042. [PMID: 35997334 PMCID: PMC9396983 DOI: 10.3390/medsci10030042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 08/03/2022] [Accepted: 08/05/2022] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer-related death. We aimed to investigate the clinicopathological characteristics and 5-year survival in CRC. This retrospective study reviewed King Abdulaziz University Hospital records from 2009 to 2019. Tumor staging was performed using Dukes’ pathological classification. Additionally, we measured the frequency of qualitative data and performed the chi-square and Mann−Whitney U-tests. Kaplan−Meier analysis was performed to calculate overall survival. Of the 574 included patients (age (mean ± standard deviation), 55.51 ± 14.28 years), 43.2% were Saudis, and most were male (58.7%). The rectum was the most common location of CRC (30.8%); 33.1% of patients presented with abdominal pain. The dominant histological variant was mucinous adenocarcinoma (95.5%). Age at diagnosis was significantly associated with Dukes’ staging; 36.3% of individuals aged <50 years had Dukes’ D stage. The 5-year survival rate was 47.9%. Better survival was noted for those of Saudi nationality, those with Dukes’ A stage, and those who were overweight (51.6%, 56.3%, and 46.8%, respectively). Significantly better survival was seen in Saudi patients due to accessible healthcare and in overweight patients due to better treatment tolerance. The outcome of CRC was not related to sex or metformin use in patients with diabetes mellitus.
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29
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Polarimetric biomarkers of peri-tumoral stroma can correlate with 5-year survival in patients with left-sided colorectal cancer. Sci Rep 2022; 12:12652. [PMID: 35879367 PMCID: PMC9314438 DOI: 10.1038/s41598-022-16178-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 07/06/2022] [Indexed: 12/24/2022] Open
Abstract
Using a novel variant of polarized light microscopy for high-contrast imaging and quantification of unstained histology slides, the current study assesses the prognostic potential of peri-tumoral collagenous stroma architecture in 32 human stage III colorectal cancer (CRC) patient samples. We analyze three distinct polarimetrically-derived images and their associated texture features, explore different unsupervised clustering algorithm models to group the data, and compare the resultant groupings with patient survival. The results demonstrate an appreciable total accuracy of ~ 78% with significant separation (p < 0.05) across all approaches for the binary classification of 5-year patient survival outcomes. Surviving patients preferentially belonged to Cluster 1 irrespective of model approach, suggesting similar stromal microstructural characteristics in this sub-population. The results suggest that polarimetrically-derived stromal biomarkers may possess prognostic value that could improve clinical management/treatment stratification in CRC patients.
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30
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Khan AA, Mannan V, Pervaiz MA, Akram A, Momin ES, Sanusi M, Kashyap T, Elshaikh AO. The Role of Glucosamine and Chondroitin Sulfate in the Prevention of Colorectal Cancer: A Systematic Review. Cureus 2022; 14:e25401. [PMID: 35774674 PMCID: PMC9236665 DOI: 10.7759/cureus.25401] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 05/25/2022] [Indexed: 12/24/2022] Open
Abstract
Currently, colorectal cancer is the third most common cancer in the world. Recently, glucosamine and chondroitin have gained popularity for their beneficial effects on cancer. They have already been recognized for their therapeutic role in osteoarthritis. This systematic review aims to analyze the relationship between the combined consumption of glucosamine and chondroitin and the prevention of colorectal cancer. Three databases: PubMed, Google Scholar, and Science Direct, were searched to collect relevant articles. After screening full-text articles, seven studies were included in the systematic review. The review found a supportive association between glucosamine and chondroitin and the decreased incidence of colorectal cancer. Through an anti-inflammatory effect on the cell signaling pathway, the supplementation caused a reduction in colorectal cancer occurrence. The dose, frequency of usage of the supplement, and weight of individuals, along with the use of non-steroidal anti-inflammatory drugs, also affected the efficacy. To further assess this relationship, it is necessary to conduct double-blind, randomized controls trials for the supplements in cancer prevention and further explore their safety and efficacy with different ethnicities, drugs, doses, and weight individuals.
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Affiliation(s)
- Asma A Khan
- College of Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Vij Mannan
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Muhammad Ahad Pervaiz
- Urology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Aqsa Akram
- Internal Medicine, Dallah Hospital, Riyadh, SAU.,Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Elina S Momin
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.,Internal Medicine, Smt. Nathiba Hargovandas Lakhmichand Municipal Medical College, Ahmedabad, IND
| | - Muhammad Sanusi
- Internal Medicine, Cardiology, Shenyang Medical College, Shenyang, CHN.,Internal Medicine, Cardiology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Tejasvi Kashyap
- General Practice, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Abeer O Elshaikh
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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31
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Wang J, Zhuo LG, Zhao P, Liao W, Wei H, Yang Y, Peng S, Yang X. Screening for a 177Lu-labeled CA19-9 monoclonal antibody via PET imaging for colorectal cancer therapy. CHINESE CHEM LETT 2022. [DOI: 10.1016/j.cclet.2022.03.056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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32
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Theyra-Enias H, Tumba N, Popoola OB. Management and outcome of colorectal cancer in a resource-limited setting: Ahmadu Bello university teaching hospital, Zaria, Nigeria. Niger J Clin Pract 2022; 25:923-930. [DOI: 10.4103/njcp.njcp_1948_21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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33
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Mohammed M, Mboya IB, Mwambi H, Elbashir MK, Omolo B. Predictors of colorectal cancer survival using cox regression and random survival forests models based on gene expression data. PLoS One 2021; 16:e0261625. [PMID: 34965262 PMCID: PMC8716055 DOI: 10.1371/journal.pone.0261625] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 12/06/2021] [Indexed: 12/30/2022] Open
Abstract
Understanding and identifying the markers and clinical information that are associated with colorectal cancer (CRC) patient survival is needed for early detection and diagnosis. In this work, we aimed to build a simple model using Cox proportional hazards (PH) and random survival forest (RSF) and find a robust signature for predicting CRC overall survival. We used stepwise regression to develop Cox PH model to analyse 54 common differentially expressed genes from three mutations. RSF is applied using log-rank and log-rank-score based on 5000 survival trees, and therefore, variables important obtained to find the genes that are most influential for CRC survival. We compared the predictive performance of the Cox PH model and RSF for early CRC detection and diagnosis. The results indicate that SLC9A8, IER5, ARSJ, ANKRD27, and PIPOX genes were significantly associated with the CRC overall survival. In addition, age, sex, and stages are also affecting the CRC overall survival. The RSF model using log-rank is better than log-rank-score, while log-rank-score needed more trees to stabilize. Overall, the imputation of missing values enhanced the model’s predictive performance. In addition, Cox PH predictive performance was better than RSF.
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Affiliation(s)
- Mohanad Mohammed
- School of Mathematics, Statistics and Computer Science, University of KwaZulu-Natal, Pietermaritzburg, Scottsville, South Africa
- Faculty of Mathematical and Computer Sciences, University of Gezira, Wad Madani, Sudan
- * E-mail:
| | - Innocent B. Mboya
- School of Mathematics, Statistics and Computer Science, University of KwaZulu-Natal, Pietermaritzburg, Scottsville, South Africa
- Department of Epidemiology and Biostatistics, Kilimanjaro Christian Medical University College (KCMUCo), Moshi, Tanzania
| | - Henry Mwambi
- School of Mathematics, Statistics and Computer Science, University of KwaZulu-Natal, Pietermaritzburg, Scottsville, South Africa
| | - Murtada K. Elbashir
- College of Computer and Information Sciences, Jouf University, Sakaka, Saudi Arabia
| | - Bernard Omolo
- School of Mathematics, Statistics and Computer Science, University of KwaZulu-Natal, Pietermaritzburg, Scottsville, South Africa
- Division of Mathematics & Computer Science, University of South Carolina-Upstate, Spartanburg, United States of America
- School of Public Health, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa
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Li R, He C, Shen L, Wang S, Shen Y, Feng F, Zhang J, Zheng J. NDRG4 sensitizes CRC cells to 5-FU by upregulating DDIT3 expression. Oncol Lett 2021; 22:782. [PMID: 34594423 PMCID: PMC8456512 DOI: 10.3892/ol.2021.13043] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Accepted: 08/13/2021] [Indexed: 11/05/2022] Open
Abstract
The incidence of colorectal cancer (CRC) has remained high in recent years, and 5-fluorouracil (5-FU) is a vital chemotherapeutic agent for its treatment. Our previous study reported that N-myc downstream-regulated gene 4 (NDRG4) plays a tumor-suppressive role in CRC, but the mechanisms associated with NDRG4 and 5-FU chemosensitivity remain unclear. The results of the present study demonstrate that NDRG4 sensitized CRC cells to 5-FU by upregulating DNA damage inducible transcript 3 (DDIT3). NDRG4 inhibited the proliferation of CRC cells and the activation of PI3K/AKT and ERK signaling. Furthermore, NDRG4 promoted CRC cell apoptosis induced by 5-FU. Mechanistic analyses revealed that NDRG4 upregulated DDIT3 expression, and that the proapoptotic effect of NDRG4 under 5-FU treatment conditions was dependent on DDIT3. These findings support the biological value of the association between NDRG4, DDIT3 and 5-FU chemosensitivity in CRC, and may advance the clinical treatment of CRC in the future.
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Affiliation(s)
- Ruikai Li
- Department of Gastrointestinal Surgery, Xijing Hospital, Xi'an, Shaanxi 710032, P.R. China.,State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Chenxiang He
- Department of General Surgery, Shanghai Fourth People's Hospital Affiliated to Tongji University of Medicine, Shanghai 200080, P.R. China
| | - Liangliang Shen
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.,Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Shuai Wang
- Department of Gastrointestinal Surgery, Xijing Hospital, Xi'an, Shaanxi 710032, P.R. China.,State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Yao Shen
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.,Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Fan Feng
- Department of Gastrointestinal Surgery, Xijing Hospital, Xi'an, Shaanxi 710032, P.R. China.,State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Jian Zhang
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.,Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Jianyong Zheng
- Department of Gastrointestinal Surgery, Xijing Hospital, Xi'an, Shaanxi 710032, P.R. China.,State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
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35
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Lawal B, Wang YC, Wu ATH, Huang HS. Pro-Oncogenic c-Met/EGFR, Biomarker Signatures of the Tumor Microenvironment are Clinical and Therapy Response Prognosticators in Colorectal Cancer, and Therapeutic Targets of 3-Phenyl-2H-benzo[e][1,3]-Oxazine-2,4(3H)-Dione Derivatives. Front Pharmacol 2021; 12:691234. [PMID: 34512327 PMCID: PMC8429938 DOI: 10.3389/fphar.2021.691234] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 08/16/2021] [Indexed: 12/11/2022] Open
Abstract
Genetic and environmental factors play important roles in cancer progression, metastasis, and drug resistance. Herein, we used a multiomics data analysis to evaluate the predictive and prognostic roles of genetic and epigenetic modulation of c-MET (hepatocyte growth factor receptor)/epidermal growth factor receptor (EGFR) in colorectal cancer (CRC). First, we found that overexpressions of c-MET/EGFR were associated with the infiltration of tumor immune cells and cancer-associated fibroblasts, and were of prognostic relevance in CRC cohorts. We also observed that genetic alterations of c-MET/EGFR in CRC co-occurred with other gene alterations and were associated with overexpression of messenger (m)RNA of some cancer hallmark proteins. More specifically, DNA-methylation and somatic copy number alterations of c-MET/EGFR were associated with immune infiltration, dysfunctional T-cell phenotypes, and poor prognoses of the cohorts. Moreover, we describe two novel gefitinib-inspired small molecules derivatives of 3-phenyl-2H-benzo[e] [1,3]-oxazine-2,4(3H)-dione, NSC777205 and NSC777207, which exhibited wide-spectrum antiproliferative activities and selective cytotoxic preference for drug-sensitive and multidrug-resistant melanoma, renal, central nervous system, colon, and non-small cell lung cancer cell lines. We further provided in silico mechanistic evidence implicating c-MET/EGFR/phosphatidylinositol 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) inhibition in anticancer activities of those compounds. Our overall structure-activity relationship study revealed that the addition of an –OCH3 group to salicylic core of NSC777207 was not favorable, as the added moiety led to overall less-favorable drug properties as well as weaker anticancer activities compared to the properties and activities demonstrated by NSC777205 that has no –OCH3 substituent group. Further in vitro and in vivo analyses in tumor-bearing mice are ongoing in our lab to support this claim and to unravel the full therapeutic efficacies of NSC777205 and NSC777207 in CRC.
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Affiliation(s)
- Bashir Lawal
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan.,Graduate Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Yu-Chi Wang
- Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Alexander T H Wu
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan.,The PhD Program of Translational Medicine, College of Science and Technology, Taipei Medical University, Taipei, Taiwan.,Clinical Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.,Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Hsu-Shan Huang
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan.,Graduate Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.,Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.,School of Pharmacy, National Defense Medical Center, Taipei, Taiwan.,PhD Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
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Wang Y, Cui X, Ma S, Zhang H. Decreased expression of miR-3135b reduces sensitivity to 5-fluorouracil in colorectal cancer by direct repression of PIM1. Exp Ther Med 2021; 22:1151. [PMID: 34504596 PMCID: PMC8392875 DOI: 10.3892/etm.2021.10585] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 05/21/2021] [Indexed: 12/14/2022] Open
Abstract
5-Fluorouracil (5-FU)-based chemotherapy is the conventional treatment approach for patients with colorectal cancer (CRC). However, de novo and acquired resistance to 5-FU are frequently observed during treatment, which eventually lead to patients succumbing to the disease. Accumulating data have revealed an association of CRC resistance to 5-FU with aberrant expression of microRNAs (miRs). In the present study, Cell Counting Kit-8 was performed to measure cell viability, flow cytometry was performed to detect cell apoptosis, reverse transcription-quantitative PCR was conducted to measure proviral integration site for Moloney murine leukemia virus 1 (PIM1) and miR-3135b expression, western blotting was conducted to measure PIM1 expression. Microarray data analysis indicated that the level of miR-3135b expression was decreased in patients with recurrent CRC that were treated with 5-FU when compared with non-recurrent cases. Overexpression of miR-3135b increased the sensitivity of CRC cells to 5-FU treatment. Moreover, PIM1 was identified as a target gene of miR-3135b using bioinformatics analysis, reverse transcription-quantitative PCR and western blotting. The direct interaction between these two targets was confirmed by luciferase reporter assays. Notably, PIM1 overexpression compensated the effect of miR-3135b in CRC cells. Furthermore, an inverse correlation between PIM1 mRNA expression levels and miR-3135b expression was observed in clinical samples. Therefore, the present study identified miR-3135b as a novel regulator of 5-FU sensitivity in CRC.
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Affiliation(s)
- Yan Wang
- Science Research Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Xiaofeng Cui
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Shurong Ma
- Endoscopic Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Haishan Zhang
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
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Nanocarriers as a Tool for the Treatment of Colorectal Cancer. Pharmaceutics 2021; 13:pharmaceutics13081321. [PMID: 34452282 PMCID: PMC8399070 DOI: 10.3390/pharmaceutics13081321] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 07/13/2021] [Accepted: 07/20/2021] [Indexed: 12/13/2022] Open
Abstract
Nanotechnology is a promising tool for the treatment of cancer. In the past decades, major steps have been made to bring nanotechnology into the clinic in the form of nanoparticle-based drug delivery systems. The great hope of drug delivery systems is to reduce the side effects of chemotherapeutics while simultaneously increasing the efficiency of the therapy. An increased treatment efficiency would greatly benefit the quality of life as well as the life expectancy of cancer patients. However, besides its many advantages, nanomedicines have to face several challenges and hurdles before they can be used for the effective treatment of tumors. Here, we give an overview of the hallmarks of cancer, especially colorectal cancer, and discuss biological barriers as well as how drug delivery systems can be utilized for the effective treatment of tumors and metastases.
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38
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Blockade of fructose transporter protein GLUT5 inhibits proliferation of colon cancer cells: proof of concept for a new class of anti-tumor therapeutics. Pharmacol Rep 2021; 73:939-945. [PMID: 34052986 PMCID: PMC8180478 DOI: 10.1007/s43440-021-00281-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 04/30/2021] [Accepted: 05/18/2021] [Indexed: 12/14/2022]
Abstract
Background Despite the fact that colorectal cancer (CRC) is one of the most commonly diagnosed cancers in men and women, its current treatment remains unsatisfactory and therefore novel studies proposing new approaches are necessary. A high sugar diet is believed to promote carcinogenesis. Fructose is absorbed from the gastrointestinal tract by members of the glucose transporter family—GLUT. The aim of the study was to characterize the expression of GLUT5 at mRNA level in CRC patients. Moreover, our goal was to elucidate the molecular role of GLUT5 in CRC and assess whether GLUT5 inhibitor may affect the viability of colon cancer cells. Methods The expression of GLUT5 at mRNA level was characterized based on 30 samples from resected colorectal cancers and 30 healthy colonic mucosa specimens from surgical margins. The inhibitory effect of N-[4-(methylsulfonyl)-2-nitrophenyl]-1,3-benzodioxol-5-amine (MSBNA) was assessed on a colon cancer cell line, HT-29, and normal colon epithelium cells—CCD 841 CoN Cells. Results GLUT5 expression was found in 96.7% of cancer specimens and only in 53.3% of healthy mucosa fragments. In cancer tissue, real-time PCR analysis showed almost 2, fivefold (p< 0.001) increase of GLUT5 mRNA expression level compared with the healthy intestinal mucosa. GLUT5 inhibitor, MSNBA (10 µM) significantly decreased the viability of colon cancer cells, while barely affected the viability of normal colon epithelium cells. Conclusions Our study suggests that a strong focus should be put on GLUT5 and its inhibitors for both diagnostic and therapeutic purposes in CRC.
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39
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Kumar M, Tata MD, Sahid Nik Lah NA. A case of rectal cancers in teenager: A conundrum of genetics and clinical medicine. Ann Med Surg (Lond) 2021; 65:102353. [PMID: 34007446 PMCID: PMC8111589 DOI: 10.1016/j.amsu.2021.102353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Revised: 04/17/2021] [Accepted: 04/25/2021] [Indexed: 11/30/2022] Open
Abstract
Introduction Signet cell carcinoma (SRCC)of the rectum is a rare subtype of the rectum cancer which accounts for only 0.8% of colorectal cancer in adolescents and young adults (AYAs) which spread aggressively to other organs and peritoneum. Case presentation We present a case of 15-year-old boy from rural area, presented with chronic diarrhea and per rectal bleeding for 3 months. The diagnosis was determined by colonoscope which revealed a fungating mass identified at 10cm from anal verge. Histological examination confirmed diagnosis of signet ring cell adenocarcinoma. CT scan of the abdomen showed thickening involving the recto-sigmoid colon and rectal mass, without evidence of distant metastatic disease. The patient's carcinoembryonic antigen level was within the normal range. He underwent a colostomy and was subjected to neoadjuvant CCRT and surgery. Discussion This CASE highlights the importance and challenges in achieving early diagnosis and surgical intervention of signet-ring cell carcinoma in adolescents, as most cases are detected at an advanced stage coupled with the scarcity of information on these rarer subtypes which leads to a poor prognosis. Conclusion In managing Signet cell carcinoma of the colorectal, physician have to know that it has a poor prognosis in patients of any age. However, in young teenagers delayed diagnosis and treatment option are narrowed to palliative management. Genetic profiling of family members and similar environment population may be a key to early detection.
We present a case of 15-year-old boy from rural area, presented with chronic diarrhea and per rectal bleeding for 3 months. Histological examination confirmed diagnosis of signet ring cell adenocarcinoma. This case highlights the importance and challenges in achieving early diagnosis and surgical intervention of signet-ring cell carcinoma in adolescents. Most cases are detected at an advanced stage due to rarity of this subtypes which leads to a poor prognosis. Young teenagers delayed diagnosis and treatment option are narrowed to palliative management. Genetic profiling of family members and similar environment population may be a key to early detection.
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Affiliation(s)
- Moveendra Kumar
- Department of Surgery, Hospital Keningau, Peti Surat 11, 89007, Sabah, Malaysia
| | | | - Nik Amin Sahid Nik Lah
- Department of Surgery, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Sabah, Malaysia
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40
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Gao L, Wu X, Zhang L, Dai Y, Zhu Z, Zhi Y, Wang K. REG4 is a Potential Biomarker for Radiochemotherapy Sensitivity in Colorectal Cancer. Onco Targets Ther 2021; 14:1605-1611. [PMID: 33688207 PMCID: PMC7936684 DOI: 10.2147/ott.s296031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 02/03/2021] [Indexed: 12/24/2022] Open
Abstract
Purpose Colorectal cancer (CRC) is one of the most common types of malignancies, and radiochemotherapy (RCT) followed by surgery is the recommended approach for CRC treatment. However, some cases do not respond to first-line conventional chemotherapy or even progress further after treatment. Moreover, there is a risk of severe side effects, such as radiodermatitis. Therefore, identifying predictors for RCT sensitivity is an essential step toward predicting and eventually overcoming resistance. Materials and Methods We used integrative bioinformatics analysis and experimental validation to show that regenerating family member 4 (REG4) may be a potential biomarker for RCT sensitivity in CRC. Results REG4, whose expression is upregulated in some CRC tissues and downregulated in RCT-sensitive CRC cells, was identified as a potential genetic marker for RCT sensitivity in CRC. Immunohistochemistry-based tissue microarray of human CRC was used to experimentally validate REG4 data obtained from the bioinformatics analysis. Conclusion Collectively, these results indicate that REG4 may be a potential biomarker for RCT sensitivity in CRC.
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Affiliation(s)
- Lei Gao
- Department of Thoracic Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China (USTC), Hefei, Anhui, 230001, People's Republic of China
| | - Xingjun Wu
- Department of Oncology, Jiangsu Taizhou NO. 2 People Hospital, Jiangsu, People's Republic of China
| | - Libo Zhang
- Department of Hepatological Surgery, General Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China
| | - Yang Dai
- Department of Transplantation, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Zhe Zhu
- Department of Hepatological Surgery, General Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China
| | - Yunqing Zhi
- Department of Transplantation, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.,Department of Gynecology, Shanghai Changning Maternity and Infant Health Hospital, Shanghai, People's Republic of China
| | - Kaijing Wang
- Department of Hepatological Surgery, General Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China
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41
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Pitchumoni CS. Colorectal Cancer. GERIATRIC GASTROENTEROLOGY 2021:1963-1989. [DOI: 10.1007/978-3-030-30192-7_80] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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42
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Oyenuga M, Vierkant RA, Lynch CF, Pengo T, Tillmans LS, Cerhan JR, Church TR, Lazovich D, Anderson KE, Limburg PJ, Prizment AE. Associations between tissue-based CD3+ T-lymphocyte count and colorectal cancer survival in a prospective cohort of older women. Mol Carcinog 2020; 60:15-24. [PMID: 33200476 DOI: 10.1002/mc.23267] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 10/18/2020] [Accepted: 10/28/2020] [Indexed: 12/11/2022]
Abstract
Tumor-infiltrating lymphocytes in colorectal cancer (CRC) predict better survival. However, associations between T-lymphocyte count in histologically normal tissues from patients with CRC and survival remain uncertain. We examined associations of CD3+ T-cells in colorectal tumor and histologically normal tissues with CRC-specific and all-cause mortality in the prospective Iowa Women's Health Study. Tissue microarrays were constructed using paraffin-embedded colorectal tissue samples from 464 women with tumor tissues and 314 women with histologically normal tissues (55-69 years at baseline) diagnosed with incident CRC from 1986 to 2002 and followed through 2014 (median follow-up 20.5 years). Three tumor and two histologically normal tissue cores for each patient were immunostained using CD3+ antibody and quantified, and the counts were averaged across the cores in each tissue. Cox proportional hazards regression estimated hazard ratios (HR) and 95% confidence interval (CI) for CRC-specific and all-cause mortality. After adjustment for age at diagnosis, body mass index, smoking status, tumor grade, and stage, HRs (95% CI) for the highest versus lowest tertile of tumor CD3+ score were 0.59 (0.38-0.89) for CRC-specific mortality and 0.82 (0.63-1.05) for all-cause mortality; for histologically normal CD3+ score, the corresponding HRs (95% CI) were 0.47 (0.19-1.17) and 0.50 (0.27-0.90), respectively. The CD3+ score combining the tumor and histologically normal scores was inversely associated with CRC-specific and all-cause mortality. Although the association between tumor CD3+ score and all-cause mortality was not significant, both higher CD3+ T-lymphocyte counts in tumor and histologically normal scores tended to be associated with lower CRC-specific and all-cause mortality.
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Affiliation(s)
- Mosunmoluwa Oyenuga
- Department of Internal Medicine, SSM St Mary's Hospital, St. Louis, Missouri, USA.,Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA
| | - Robert A Vierkant
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA
| | - Charles F Lynch
- Department of Epidemiology, University of Iowa, Iowa City, Iowa, USA
| | - Thomas Pengo
- University of Minnesota Informatics Institute, University of Minnesota, Minneapolis, Minnesota, USA
| | - Lori S Tillmans
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - James R Cerhan
- Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA
| | - Timothy R Church
- Division of Environmental Health Sciences, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA
| | - DeAnn Lazovich
- Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.,Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Kristin E Anderson
- Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.,Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Paul J Limburg
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Anna E Prizment
- Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.,Division of Hematology, Oncology, and Transplantation, University of Minnesota Medical School, Minneapolis, Minnesota, USA.,Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
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Makhafola TJ, Mbele M, Yacqub-Usman K, Hendren A, Haigh DB, Blackley Z, Meyer M, Mongan NP, Bates DO, Dlamini Z. Apoptosis in Cancer Cells Is Induced by Alternative Splicing of hnRNPA2/B1 Through Splicing of Bcl-x, a Mechanism that Can Be Stimulated by an Extract of the South African Medicinal Plant, Cotyledon orbiculata. Front Oncol 2020; 10:547392. [PMID: 33163396 PMCID: PMC7580256 DOI: 10.3389/fonc.2020.547392] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 08/21/2020] [Indexed: 01/09/2023] Open
Abstract
Alternative splicing is deregulated in cancer and alternatively spliced products can be linked to cancer hallmarks. Targeting alternative splicing could offer novel effective cancer treatments. We investigated the effects of the crude extract of a South African medicinal plant, Cotyledon orbiculata, on cell survival of colon (HCT116) and esophageal (OE33 and KYSE70) cancer cell lines. Using RNASeq, we discovered that the extract interfered with mRNA regulatory pathways. The extract caused hnRNPA2B1 to splice from the hnRNPB1 to the hnRNPA2 isoform, resulting in a switch in the BCL2L1 gene from Bcl-xL to Bcl-xS causing activation of caspase-3-cleavage and apoptosis. Similar splicing effects were induced by the known anti-cancer splicing modulator pladienolide B. Knockdown of hnRNPB1 using siRNA resulted in decreased cell viability and increased caspase-3-cleavage, and over-expression of hnRNPB1 prevented the effect of C. orbiculata extract on apoptosis and cell survival. The effect of the hnRNPA2/B1 splicing switch by the C. orbiculata extract increased hnRNPA2B1 binding to Bcl-xl/s, BCL2, MDM2, cMYC, CD44, CDK6, and cJUN mRNA. These findings suggest that apoptosis in HCT116, OE33, and KYSE cancer cells is controlled by switched splicing of hnRNPA2B1 and BCL2L1, providing evidence that hnRNPB1 regulates apoptosis. Inhibiting this splicing could have therapeutic potential for colon and esophageal cancers. Targeting hnRNPA2B1 splicing in colon cancer regulates splicing of BCL2L1 to induce apoptosis. This approach could be a useful therapeutic strategy to induce apoptosis and restrain cancer cell proliferation and tumor progression. Here, we found that the extract of Cotyledon orbiculata, a South African medicinal plant, had an anti-proliferative effect in cancer cells, mediated by apoptosis induced by alternative splicing of hnRNPA2B1 and BCL2L1.
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Affiliation(s)
- Tshepiso Jan Makhafola
- SA-Medical Research Council (MRC)/UP Precision Prevention & Novel Drug Targets for HIV-Associated Cancers Extramural Unit, Faculty of Health Sciences, Pan African Cancer Research Institute (PACRI), University of Pretoria, Pretoria, South Africa.,Division of Cancer and Stem Cells, Centre for Cancer Sciences, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Mzwandile Mbele
- SA-Medical Research Council (MRC)/UP Precision Prevention & Novel Drug Targets for HIV-Associated Cancers Extramural Unit, Faculty of Health Sciences, Pan African Cancer Research Institute (PACRI), University of Pretoria, Pretoria, South Africa.,Division of Cancer and Stem Cells, Centre for Cancer Sciences, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Kiren Yacqub-Usman
- Division of Cancer and Stem Cells, Centre for Cancer Sciences, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Amy Hendren
- Division of Cancer and Stem Cells, Centre for Cancer Sciences, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Daisy Belle Haigh
- School of Veterinary Medicine and Science, University of Nottingham, Nottingham, United Kingdom
| | - Zoe Blackley
- Division of Cancer and Stem Cells, Centre for Cancer Sciences, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Mervin Meyer
- Biolabels Unit, Department of Biotechnology, Department of Science and Technology (DST)/Mintek Nanotechnology Innovation Centre (NIC), University of the Western Cape, Bellville, South Africa
| | - Nigel Patrick Mongan
- School of Veterinary Medicine and Science, University of Nottingham, Nottingham, United Kingdom
| | - David Owen Bates
- Division of Cancer and Stem Cells, Centre for Cancer Sciences, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Zodwa Dlamini
- SA-Medical Research Council (MRC)/UP Precision Prevention & Novel Drug Targets for HIV-Associated Cancers Extramural Unit, Faculty of Health Sciences, Pan African Cancer Research Institute (PACRI), University of Pretoria, Pretoria, South Africa
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Vacante M, Ciuni R, Basile F, Biondi A. The Liquid Biopsy in the Management of Colorectal Cancer: An Overview. Biomedicines 2020; 8:E308. [PMID: 32858879 PMCID: PMC7555636 DOI: 10.3390/biomedicines8090308] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 08/19/2020] [Accepted: 08/24/2020] [Indexed: 02/07/2023] Open
Abstract
Currently, there is a crucial need for novel diagnostic and prognostic biomarkers with high specificity and sensitivity in patients with colorectal cancer. A "liquid biopsy" is characterized by the isolation of cancer-derived components, such as circulating tumor cells, circulating tumor DNA, microRNAs, long non-coding RNAs, and proteins, from peripheral blood or other body fluids and their genomic or proteomic assessment. The liquid biopsy is a minimally invasive and repeatable technique that could play a significant role in screening and diagnosis, and predict relapse and metastasis, as well as monitoring minimal residual disease and chemotherapy resistance in colorectal cancer patients. However, there are still some practical issues that need to be addressed before liquid biopsy can be widely used in clinical practice. Potential challenges may include low amounts of circulating tumor cells and circulating tumor DNA in samples, lack of pre-analytical and analytical consensus, clinical validation, and regulatory endorsement. The aim of this review was to summarize the current knowledge of the role of liquid biopsy in the management of colorectal cancer.
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Affiliation(s)
- Marco Vacante
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, Via S. Sofia 78, 95123 Catania, Italy; (R.C.); (F.B.); (A.B.)
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Liu LH, Shi RJ, Chen ZC. Paeonol exerts anti‑tumor activity against colorectal cancer cells by inducing G0/G1 phase arrest and cell apoptosis via inhibiting the Wnt/β‑catenin signaling pathway. Int J Mol Med 2020; 46:675-684. [PMID: 32626954 PMCID: PMC7307818 DOI: 10.3892/ijmm.2020.4629] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 05/19/2020] [Indexed: 12/15/2022] Open
Abstract
Paeonol is a simple phenolic compound isolated from herbal root bark, which has been reported to possess numerous biological and pharmacological characteristics, including a desirable anti‑tumor effect. To date, the effect of paeonol against colorectal cancer (CRC) cells is yet to be fully elucidated. Therefore, the present study aimed to identify the underlying mechanism via which paeonol exerts its anti‑tumor activity on HCT116 cells. After incubation with various concentrations of paeonol (7.8125, 15.625, 31.25, 62.5, 125, 250 and 500 µg/ml), the inhibitory effect of paeonol on cell viability was assessed using a Cell Counting Kit‑8 assay. Cell apoptosis and cell cycle distribution were measured using flow cytometry. Moreover, caspase activity was measured using a colorimetric caspase assay. Luciferase assay was also used to determine the β‑catenin‑mediated transcriptional activity of T‑cell specific transcription factor/lymphoid‑enhancer binding factor (TCF/LEF), and western blotting analysis was performed to measure the related expression of proteins. The results indicated that paeonol exhibited a notable effect against HCT116 cells by inducing G0/G1‑phase arrest, as demonstrated by downregulation of the cell cycle regulators cyclin‑dependent kinase 4 and cyclin D1 and upregulation of p21Cip1 in a dose‑dependent manner. Furthermore, paeonol dose‑dependently induced cell apoptosis, accompanied by an increase in the Bax/Bcl‑2 ratio, release of cytochrome c and further activation of caspases. Paeonol also dose‑dependently blocked the activation of the Wnt/β‑catenin signaling pathway by suppressing the expression of β‑catenin, resulting in a decrease in β‑catenin‑mediated activity of TCF/LEF and downregulation of downstream target genes, including cyclin D1, survivin and c‑Myc. Therefore, the present results suggested that paeonol exerted its anti‑tumor effects on CRC cells, including the inhibition of cell proliferation, induction of cell cycle arrest and initiation of apoptosis, at least partly by suppressing the Wnt/β‑catenin pathway, which may offer a promising therapeutic strategy for CRC.
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Affiliation(s)
- Li-Hua Liu
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029
| | - Ren-Jie Shi
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029
- Department of Anorectal Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023
| | - Zhi-Cheng Chen
- Department of Anorectal Surgery, Zhongda Hospital Affiliated to Southeast University, Nanjing, Jiangsu 210009, P.R. China
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46
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Kasahun GG, Gebretekle GB, Hailemichael Y, Woldemariam AA, Fenta TG. Catastrophic healthcare expenditure and coping strategies among patients attending cancer treatment services in Addis Ababa, Ethiopia. BMC Public Health 2020; 20:984. [PMID: 32571275 PMCID: PMC7310089 DOI: 10.1186/s12889-020-09137-y] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 06/17/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND With the rapid increase in magnitude and mortality of cancer, which is costly disease to manage, several patients particularly in developing countries are facing a huge financial burden. The study aimed to examine the incidence of catastrophic health expenditure (CHE), identify associated factors and coping strategies among patients attending cancer treatment services in Addis Ababa, Ethiopia. METHODS A hospital-based cross-sectional survey of patients with cancer was conducted in public and private hospitals between January and March 2018. Data was collected using a structured questionnaire. All direct medical and nonmedical expenditures were measured and reported as expenditure (US$) per patient (1US$ equivalent to 23.41 Ethiopian Birr). The CHE was estimated using a threshold of 10% of annual household income. RESULTS A total of 352 (response rate of 87.1%) participants were interviewed. Majority (73.3%) of the respondents were females; most (94%) from public hospitals and their mean (±SD) age was 48 ± 13.2 years. Vast majority (74.4%) of patients experienced CHE with mean overall expenditure of $2366 per patient (median: $1708). Medical expenditure shared the highest overall expenditure (83.6%) with mean medical and nonmedical costs of $1978 (median: $1394) and $388 (median: $222), respectively. Patients who took greater than six cycles of chemotherapy (AOR: 3.64; 95% CI: 1.11-11.92), and age (AOR: 1.03; 95% CI: 1.01-1.06) were significantly associated with CHE. Household saving (85.5%) followed by financial support received (43.0%) was the main coping strategy. CONCLUSION A substantial number of patients with cancer were exposed to CHE with a considerable medical expenditure. Hence, in addition to the popularization of the already introduced health insurance scheme, other better prepayment or insurance mechanisms should also be considered to ensure financial risk protection and realize universal health coverage for patients with cancer.
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Affiliation(s)
| | - Gebremedhin Beedemariam Gebretekle
- Department of Pharmaceutics and Social Pharmacy, School of Pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
| | - Yohannes Hailemichael
- School of Public Health, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
| | | | - Teferi Gedif Fenta
- Department of Pharmaceutics and Social Pharmacy, School of Pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
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Drug-Drug Interactions of Irinotecan, 5-Fluorouracil, Folinic Acid and Oxaliplatin and Its Activity in Colorectal Carcinoma Treatment. Molecules 2020; 25:molecules25112614. [PMID: 32512790 PMCID: PMC7321123 DOI: 10.3390/molecules25112614] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Revised: 05/30/2020] [Accepted: 06/01/2020] [Indexed: 12/24/2022] Open
Abstract
The combination of folinic acid, 5-fluorouracil, oxaliplatin and/or irinotecan (FOLFOXIRI) is the standard of care for metastatic colorectal cancer (CRC). This strategy inhibits tumor growth but provokes drug resistance and serious side effects. We aimed to improve FOLFOXIRI by optimization of the dosing and the sequence of drug administration. We employed an orthogonal array composite design and linear regression analysis to obtain cell line-specific drug combinations for four CRC cell lines (DLD1, SW620, HCT116, LS174T). Our results confirmed the synergy between folinic acid and 5-fluorouracil and additivity, or even antagonism, between the other drugs of the combination. The drug combination administered at clinical doses resulted in significantly higher antagonistic interactions compared to the low-dose optimized drug combination (ODC). We found that the concomitant administration of the optimized drug combination (ODC) was comparatively active to sequential administration. However, the administration of oxaliplatin or the active metabolite of irinotecan seemed to sensitize the cells to the combination of folinic acid and 5-fluorouracil. ODCs were similarly active in non-cancerous cells as compared to the clinically used doses, indicating a lack of reduction of side effects. Interestingly, ODCs were inactive in CRC cells chronically pretreated with FOLFOXIRI, suggesting the occurrence of resistance. We were unable to improve FOLFOXIRI in terms of efficacy or specificity. Improvement of CRC treatment should come from the optimization of targeted drugs and immunotherapy strategies.
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Zhong W, Xue X, Dai L, Li R, Nie K, Zhou S. Neoadjuvant treatments for resectable rectal cancer: A network meta-analysis. Exp Ther Med 2020; 19:2604-2614. [PMID: 32256740 PMCID: PMC7086160 DOI: 10.3892/etm.2020.8494] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 11/06/2019] [Indexed: 12/18/2022] Open
Abstract
Different neoadjuvant therapy regimens are available for rectal cancer, but the relative effects are controversial. The aim of the present network meta-analysis (NMA) was to estimate the relative efficacy and safety of neoadjuvant therapies for resectable rectal cancer. MEDLINE, EMBASE and Cochrane Central Registry of Controlled Trials were searched for publications dated from 1946 up to June 2018. The present study included randomized clinical trials that compared treatments for resected rectal cancer: Surgery alone, surgery preceded by neoadjuvant radiotherapy (RT), neoadjuvant chemotherapy (CT) or neoadjuvant chemoradiotherapy (CRT). Direct pairwise comparisons and NMA were conducted. A total of 23 randomized controlled trials were included in the present study. RT had an overall survival (OS) benefit when compared with surgery alone [HR (hazard ratio), 0.89; 95% confidence interval (CI), 0.82-0.97; quality of evidence, high]. All three neoadjuvant regimens were associated with lower local recurrence (LR) when compared with surgery alone [RT: odds ratio (OR), 0.44; 95% CI, 0.35-0.65; quality of evidence, high; CRT: OR, 0.34; 95% CI, 0.23-0.56; quality of evidence, low and CT: OR, 0.32; 95% CI, 0.11-1.00; quality of evidence, low]. There were no significant differences in OS and LR between CRT and RT (OS: OR, 1.10); 95% CI, 0.93-1.20; LR: OR, 0.81; 95% CI, 0.61-1.10). Ranking probabilities indicated that CRT was the best strategy for local control, with a surface under the cumulative ranking curve (SUCRA) of 78.78%. Patients treated with RT had improved disease-free survival compared with those treated with surgery alone (HR, 0.82; 95% CI, 0.64-1.00; quality of evidence, low). Neoadjuvant RT or CRT did not significantly improve distant metastases compared with surgery alone (RT: OR, 0.87; 95% CI, 0.69-1.10 and CRT: OR, 0.75; 95% CI, 0.47-1.10). CRT had an improved pathological complete response rate compared with RT (OR, 4.90; 95% CI, 21.80-17.00; quality of evidence, low). No significant difference for the risk of anastomotic leak between each treatment was observed in the NMA. In conclusion, RT decreased the LR and improved OS compared with surgery alone for resected rectal cancer. CRT was the best neoadjuvant therapy analyzed and CT was likely the second best for all outcomes based on SUCRA. However, these findings were limited by overall low quality of evidence.
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Affiliation(s)
- Wei Zhong
- Department of General Surgery, The Affiliated Southeast Hospital of Xiamen University, Zhangzhou, Fujian 363000, P.R. China
| | - Xiaojun Xue
- Department of General Surgery, The Affiliated Southeast Hospital of Xiamen University, Zhangzhou, Fujian 363000, P.R. China
| | - Lianzhi Dai
- Medical Affairs Department, The Affiliated Southeast Hospital of Xiamen University, Zhangzhou, Fujian 363000, P.R. China
| | - Ranran Li
- Department of General Surgery, The Affiliated Southeast Hospital of Xiamen University, Zhangzhou, Fujian 363000, P.R. China
| | - Kai Nie
- Department of General Surgery, The Affiliated Southeast Hospital of Xiamen University, Zhangzhou, Fujian 363000, P.R. China
| | - Song Zhou
- Department of General Surgery, The Affiliated Southeast Hospital of Xiamen University, Zhangzhou, Fujian 363000, P.R. China
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Zhang Z, Zhang Y, Qin X, Wang Y, Fu J. FGF9 promotes cisplatin resistance in colorectal cancer via regulation of Wnt/β-catenin signaling pathway. Exp Ther Med 2019; 19:1711-1718. [PMID: 32104224 PMCID: PMC7026987 DOI: 10.3892/etm.2019.8399] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Accepted: 10/09/2019] [Indexed: 12/12/2022] Open
Abstract
Development of cisplatin resistance in colorectal cancer is largely caused by dysregulation of signaling pathways, including the Wnt/β-catenin signaling pathway, in cancer cells. Further investigation into the molecular mechanism of chemoresistance could improve outcomes for patients with colorectal cancer. The present study determined that fibroblast growth factor 9 (FGF9) was overexpressed in tumor tissues compared with normal tissues from patients with colorectal cancer. Using the colorectal cancer cell line LoVo, transfection of recombinant FGF9 decreased cisplatin-induced cell apoptosis whilst FGF9 silencing increased cisplatin-induced apoptosis. Western blot analysis and reverse transcription-quantitative polymerase chain reaction demonstrated that FGF9 decreased adenomatous polyposis coli (APC) mRNA and protein expression and contributed to activation of the Wnt/β-catenin signaling pathway. Notably, an increase in FGF9 and β-catenin protein expression and a decrease in APC protein expression was observed in the established LoVo cisplatin resistant cell line (LoVo/cisplatin). Silencing of FGF9 reversed cisplatin resistance of LoVo/cisplatin cells. In conclusion, the present findings suggested that FGF9 activated the Wnt signaling pathway and was a mediator of cisplatin resistance in colorectal cancer.
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Affiliation(s)
- Zhijin Zhang
- Department of Gastroenterological Surgery, Shanghai Eighth People's Hospital, Shanghai 200235, P.R. China
| | - Yuhao Zhang
- Department of Gastroenterological Surgery, Shanghai Eighth People's Hospital, Shanghai 200235, P.R. China
| | - Xinju Qin
- Department of Gastroenterological Surgery, Shanghai Eighth People's Hospital, Shanghai 200235, P.R. China
| | - Yuexia Wang
- Department of Gastroenterological Surgery, Shanghai Eighth People's Hospital, Shanghai 200235, P.R. China
| | - Jun Fu
- Department of Gastroenterological Surgery, Shanghai Eighth People's Hospital, Shanghai 200235, P.R. China
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Vodenkova S, Buchler T, Cervena K, Veskrnova V, Vodicka P, Vymetalkova V. 5-fluorouracil and other fluoropyrimidines in colorectal cancer: Past, present and future. Pharmacol Ther 2019; 206:107447. [PMID: 31756363 DOI: 10.1016/j.pharmthera.2019.107447] [Citation(s) in RCA: 580] [Impact Index Per Article: 96.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 11/13/2019] [Indexed: 02/07/2023]
Abstract
5-Fluorouracil (5-FU) is an essential component of systemic chemotherapy for colorectal cancer (CRC) in the palliative and adjuvant settings. Over the past four decades, several modulation strategies including the implementation of 5-FU-based combination regimens and 5-FU pro-drugs have been developed and tested to increase the anti-tumor activity of 5-FU and to overcome the clinical resistance. Despite the encouraging progress in CRC therapy to date, the patients' response rates to therapy continue to remain low and the patients' benefit from 5-FU-based therapy is frequently compromised by the development of chemoresistance. Inter-individual differences in the treatment response in CRC patients may originate in the unique genetic and epigenetic make-up of each individual. The critical element in the current trend of personalized medicine is the proper comprehension of causes and mechanisms contributing to the low or lack of sensitivity of tumor tissue to 5-FU-based therapy. The identification and validation of predictive biomarkers for existing 5-FU-based and new targeted therapies for CRC treatment will likely improve patients' outcomes in the future. Herein we present a comprehensive review summarizing options of CRC treatment and the mechanisms of 5-FU action at the molecular level, including both anabolic and catabolic ways. The main part of this review comprises the currently known molecular mechanisms underlying the chemoresistance in CRC patients. We also focus on various 5-FU pro-drugs developed to increase the amount of circulating 5-FU and to limit toxicity. Finally, we propose future directions of personalized CRC therapy according to the latest published evidence.
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Affiliation(s)
- Sona Vodenkova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic; Department of Medical Genetics, Third Faculty of Medicine, Charles University, Ruska 2411/87, 100 00 Prague, Czech Republic
| | - Tomas Buchler
- Department of Oncology, First Faculty of Medicine, Charles University and Thomayer Hospital, Videnska 800, 140 59 Prague, Czech Republic
| | - Klara Cervena
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic
| | - Veronika Veskrnova
- Department of Oncology, First Faculty of Medicine, Charles University and Thomayer Hospital, Videnska 800, 140 59 Prague, Czech Republic
| | - Pavel Vodicka
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic; Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 76, 323 00 Pilsen, Czech Republic
| | - Veronika Vymetalkova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic; Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 76, 323 00 Pilsen, Czech Republic.
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