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Ramalingam PS, Premkumar T, Sundararajan V, Hussain MS, Arumugam S. Design and development of dual targeting CAR protein for the development of CAR T-cell therapy against KRAS mutated pancreatic ductal adenocarcinoma using computational approaches. Discov Oncol 2024; 15:592. [PMID: 39453574 PMCID: PMC11511808 DOI: 10.1007/s12672-024-01455-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 10/11/2024] [Indexed: 10/26/2024] Open
Abstract
Mutant KRAS promotes the proliferation, metastasis, and aggressiveness of various cancers including pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), and colorectal adenocarcinoma (CRC) respectively. Mutant KRAS therapeutics are limited, while Sotorasib and Adagrasib were the only FDA-approved drugs for the treatment of KRASG12C mutated NSCLC. Chimeric antigen receptor (CAR) T-cell therapy has been emerged as an effective strategy against hematological malignancies and being extended towards solid cancers including PDAC. mesothelin (MSLN) and Carcinoembryonic Antigen (CEA) were reported to be highly overexpressed in KRAS-mutated PDAC. Meanwhile, in clinical trials, several CAR T-cell therapy studies are mainly focused towards these two cancer antigens in PDAC, however, the dual targeting of these two neoantigens is not reported. In the present study, we have designed and developed a novel dual-targeting CAR protein by employing various bioinformatics approaches such as functional analysis (antigenicity, allergenicity, antigen binding sites & signalling cascades), qualitative analysis (physicochemical, prediction, refinement & validation of 2D and 3D structures), molecular docking, and in silico cloning. Our results revealed that the designed CAR protein specifically binds with both MSLN & CEA with significant binding affinities, and was predicted to be stable & non-allergenic. Additionally, the protein-protein interaction network reveals the T-cell mediated antitumor responses of each domain in the designed CAR. Conclusively, we have designed and developed a dual targeting (MSLN & CEA) CAR protein towards KRAS-mutated PDAC using computational approaches. Alongside, we further recommend to engineer this designed CAR in T-cells and evaluating their therapeutic efficiency in in vitro and in vivo studies in the near future.
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Affiliation(s)
- Prasanna Srinivasan Ramalingam
- Protein Engineering Lab, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - T Premkumar
- Integrative Multiomics Lab, School of Bio-Sciences & Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Vino Sundararajan
- Integrative Multiomics Lab, School of Bio-Sciences & Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Md Sadique Hussain
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, Uttarakhand, 248007, India
| | - Sivakumar Arumugam
- Protein Engineering Lab, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India.
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Dash CP, Sonowal D, Dhaka P, Yadav R, Chettri D, Satapathy BP, Sheoran P, Uttam V, Jain M, Jain A. Antitumor activity of genetically engineered NK-cells in non-hematological solid tumor: a comprehensive review. Front Immunol 2024; 15:1390498. [PMID: 38694508 PMCID: PMC11061440 DOI: 10.3389/fimmu.2024.1390498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 03/18/2024] [Indexed: 05/04/2024] Open
Abstract
Recent advancements in genetic engineering have made it possible to modify Natural Killer (NK) cells to enhance their ability to fight against various cancers, including solid tumors. This comprehensive overview discusses the current status of genetically engineered chimeric antigen receptor NK-cell therapies and their potential for treating solid tumors. We explore the inherent characteristics of NK cells and their role in immune regulation and tumor surveillance. Moreover, we examine the strategies used to genetically engineer NK cells in terms of efficacy, safety profile, and potential clinical applications. Our investigation suggests CAR-NK cells can effectively target and regress non-hematological malignancies, demonstrating enhanced antitumor efficacy. This implies excellent promise for treating tumors using genetically modified NK cells. Notably, NK cells exhibit low graft versus host disease (GvHD) potential and rarely induce significant toxicities, making them an ideal platform for CAR engineering. The adoptive transfer of allogeneic NK cells into patients further emphasizes the versatility of NK cells for various applications. We also address challenges and limitations associated with the clinical translation of genetically engineered NK-cell therapies, such as off-target effects, immune escape mechanisms, and manufacturing scalability. We provide strategies to overcome these obstacles through combination therapies and delivery optimization. Overall, we believe this review contributes to advancing NK-cell-based immunotherapy as a promising approach for cancer treatment by elucidating the underlying mechanisms, evaluating preclinical and clinical evidence, and addressing remaining challenges.
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Affiliation(s)
- Chinmayee Priyadarsini Dash
- Non-Coding Ribonucleic Acid (RNA) and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Dhruba Sonowal
- Non-Coding Ribonucleic Acid (RNA) and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Prachi Dhaka
- Non-Coding Ribonucleic Acid (RNA) and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Rohit Yadav
- Non-Coding Ribonucleic Acid (RNA) and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Dewan Chettri
- Non-Coding Ribonucleic Acid (RNA) and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Bibhu Prasad Satapathy
- Non-Coding Ribonucleic Acid (RNA) and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Pooja Sheoran
- Non-Coding Ribonucleic Acid (RNA) and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Vivek Uttam
- Non-Coding Ribonucleic Acid (RNA) and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Manju Jain
- Department of Biochemistry, Central University of Punjab, Bathinda, Punjab, India
| | - Aklank Jain
- Non-Coding Ribonucleic Acid (RNA) and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
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Tong S, Wu R, Zhang L, Lu P, Hu X, Li Y, Peng J. Association of preoperative and recurrent serum carcinoembryonic antigen and outcome of colorectal cancer patients with metastatic relapse. Heliyon 2024; 10:e29347. [PMID: 38617920 PMCID: PMC11015133 DOI: 10.1016/j.heliyon.2024.e29347] [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: 09/12/2023] [Revised: 04/03/2024] [Accepted: 04/05/2024] [Indexed: 04/16/2024] Open
Abstract
Background Seldom have the associations of preoperative CEA (p-CEA) and recurrent CEA (r-CEA) levels as well as changes in p-CEA and r-CEA with survival in patients with stage I-III colorectal cancer (CRC) who have experienced metastatic relapse, been thoroughly examined. Methods 241 consecutive patients with stage I-III CRC who experienced metastatic relapse at Fudan University Shanghai Cancer Center (FUSCC) between January 2008 and January 2016 were investigated. The influence of p-CEA, r-CEA and CEA alteration on the overall survival (OS) and relapse-to-death survival (RDS) was evaluated. The restricted cubic spline regression model was employed to explore the optimal cut-off value of CEA. Results All 241 patients were categorized into four groups built on their CEA alteration patterns as follows: A, patients presenting elevated p-CEA levels but normal r-CEA levels (P-N); B, patients displaying normal levels of both p-CEA and r-CEA (N-N); C, patients exhibiting elevated levels of both p-CEA and r-CEA (P-P); D, patients with normal p-CEA levels but elevated r-CEA levels (N-P). The correlation between p-CEA and OS (P = 0.3266) and RDS (P = 0.2263) was insignificant. However, r-CEA exhibited a significant association with both OS (P = 0.0005) and RDS (P = 0.0002). Group A demonstrated the longest OS and RDS, whereas group D exhibited the poorest OS and RDS outcomes. For both OS and RDS, the CEA alteration groups served as an independent prognostic indicator. The optimal cut-off threshold for CEA was determined to be 5.1 ng/ml via the restricted cubic spline regression model. Conclusion r-CEA has a stronger correlation with OS and RDS in individuals with stage I-III CRC who have experienced metastatic relapse.The change between p-CEA and r-CEA could further indicate post-relapse survival, thereby facilitating the assessment of mortality risk stratification in stage I-III CRC patients experiencing metastatic relapse.
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Affiliation(s)
- Shanyou Tong
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Renping Wu
- Clinical College of Xiangnan University, Chenzhou, 423000, China
| | - Long Zhang
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Cancer Research Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Ping Lu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Xiang Hu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Yaqi Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Junjie Peng
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
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Fox J, Batchelor DVB, Roberts H, Moorcroft SC, Valleley EM, Coletta PL, Evans SD. Gold Nanotapes and Nanopinecones in a Quantitative Lateral Flow Assay for the Cancer Biomarker Carcinoembryonic Antigen. ACS APPLIED NANO MATERIALS 2023; 6:17769-17777. [PMID: 37854850 PMCID: PMC10580237 DOI: 10.1021/acsanm.3c03053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 09/04/2023] [Indexed: 10/20/2023]
Abstract
Colorectal cancer is the third most common malignancy and the second leading cause of cancer death globally. Multiple studies have linked levels of carcinoembryonic antigen in patient serum to poor disease prognosis. Hence, the ability to detect low levels of carcinoembryonic antigen has applications in earlier disease diagnosis, assessment, and recurrence monitoring. Existing carcinoembryonic antigen detection methods often require multiple reagents, trained operators, or complex procedures. A method alleviating these issues is the lateral flow assay, a paper-based platform that allows the detection and quantification of target analytes in complex mixtures. The tests are rapid, are point-of-care, possess a long shelf life, and can be stored at ambient conditions, making them ideal for use in a range of settings. Although lateral flow assays typically use spherical gold nanoparticles to generate the classic red signal, recent literature has shown that alternate morphologies to spheres can improve the limit of detection. In this work, we report the application of alternative gold nanoparticle morphologies, gold nanotapes (∼35 nm in length) and gold nanopinecones (∼90 nm in diameter), in a lateral flow assay for carcinoembryonic antigen. In a comparative assay, gold nanopinecones exhibited a ∼2× improvement in the limit of detection compared to commercially available spherical gold nanoparticles for the same antibody loading and total gold content, whereas the number of gold nanopinecones in each test was ∼3.2× less. In the fully optimized test, a limit of detection of 14.4 pg/mL was obtained using the gold nanopinecones, representing a 24-fold improvement over the previously reported gold-nanoparticle-based carcinoembryonic antigen lateral flow assay.
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Affiliation(s)
- Joseph Fox
- Molecular
and Nanoscale Physics Group, School of Physics and Astronomy, University of Leeds, Leeds LS2 9JT, United Kingdom
| | - Damien V. B. Batchelor
- Molecular
and Nanoscale Physics Group, School of Physics and Astronomy, University of Leeds, Leeds LS2 9JT, United Kingdom
| | - Holly Roberts
- Molecular
and Nanoscale Physics Group, School of Physics and Astronomy, University of Leeds, Leeds LS2 9JT, United Kingdom
| | - Samuel C.T. Moorcroft
- Molecular
and Nanoscale Physics Group, School of Physics and Astronomy, University of Leeds, Leeds LS2 9JT, United Kingdom
| | - Elizabeth M.A. Valleley
- Leeds
Institute of Medical Research, Wellcome Trust Brenner Building, St James’s University Hospital, Leeds LS9 7TF, United Kingdom
| | - Patricia Louise Coletta
- Leeds
Institute of Medical Research, Wellcome Trust Brenner Building, St James’s University Hospital, Leeds LS9 7TF, United Kingdom
| | - Stephen D. Evans
- Molecular
and Nanoscale Physics Group, School of Physics and Astronomy, University of Leeds, Leeds LS2 9JT, United Kingdom
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Pretreatment Carcinoembryonic Antigen Level Serves as a Potential Biomarker to Guide Adjuvant Radiotherapy in pT4N+ Colon Cancer Patients. JOURNAL OF ONCOLOGY 2023; 2023:4815996. [PMID: 36844877 PMCID: PMC9950319 DOI: 10.1155/2023/4815996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 01/18/2023] [Accepted: 01/31/2023] [Indexed: 02/18/2023]
Abstract
The survival benefit of adjuvant radiotherapy in T4 colon cancer (CC) remains controversial, with conflicting results reported in the literature. This study aimed to explore the relationship between pretreatment carcinoembryonic antigen (CEA) level and overall survival (OS) of pT4N+ CC patients treated with adjuvant radiotherapy. Data of pT4N+ CC patients who received curative surgery between 2004 and 2015 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. The primary outcome was OS, and subgroup analysis was conducted according to pretreatment CEA level. A total of 8763 patients were eligible for our study. In the CEA-normal group, 151 patients received adjuvant radiotherapy, while 3932 patients did not. In the CEA-elevated group, 212 patients received adjuvant radiotherapy, while 4468 patients did not. In general, adjuvant radiotherapy was associated with better OS in pT4N+ CC patients (HR = 0.846, 95% CI = 0.733-0.976, P = 0.022). Intriguingly, only patients with an elevated pretreatment CEA level gained a survival benefit from adjuvant radiotherapy (HR = 0.782; 95% CI = 0.651-0.939; P = 0.008) while those with a normal pretreatment CEA level did not (HR = 0.907; 95% CI = 0.721-1.141; P = 0.403). Multivariable Cox regression analysis demonstrated that adjuvant radiotherapy was an independent protective factor in pT4N+ CC patients with an elevated pretreatment CEA level. Pretreatment CEA levels could serve as a potential biomarker to screen pT4N+ CC patients who would benefit from adjuvant radiotherapy.
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Rajaei M, Rashedi H, Yazdian F, Navaei-Nigjeh M, Rahdar A, Díez-Pascual AM. Chitosan/agarose/graphene oxide nanohydrogel as drug delivery system of 5-fluorouracil in breast cancer therapy. J Drug Deliv Sci Technol 2023. [DOI: 10.1016/j.jddst.2023.104307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/03/2023]
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Roles of anoikis in colorectal cancer therapy and the assessment of anoikis-regulatory molecules as therapeutic targets. Pathol Res Pract 2023; 241:154256. [PMID: 36455367 DOI: 10.1016/j.prp.2022.154256] [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: 04/15/2022] [Revised: 11/21/2022] [Accepted: 11/25/2022] [Indexed: 11/29/2022]
Abstract
Colorectal cancer (CRC) is a deadly malignancy and therapeutic approaches for CRC are evolving every day. Anoikis is a key mechanism for programmed cell death of cancer cells that undergo anchorage-independent growth at a different matrix than the one which is expected. Yet, anoikis is a less studied mechanism of cell death in comparison to other mechanisms such as apoptosis. Relating to this, resistance to anoikis among cancer cells remains critical for improved metastasis and survival in a new environment evading anoikis. Since CRC cells have the ability to metastasize from proximal sites to secondary organs such as liver and promote cancer in those distant sites, a clear knowledge of the mechanisms essential for anchorage-independent growth and subsequent metastasis is necessary to counteract CRC progression and spread. Therefore, the identification of novel drug candidates and studying the roles of anoikis in assisting CRC therapy using such drugs can prevent anchorage-independent cancer cell growth. Additionally, the identification of novel biomarkers or therapeutic targets seems essential for implementing superior therapy, impeding relapse among malignant cells and improving the survival rate of clinical patients. As there are no reviews published on this topic till date, anoikis as a mechanism of cell death and its therapeutic roles in CRC are discussed in this review. In addition, several molecules were identified as therapeutic targets for CRC.
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Yusuf A, Odeh OE, Alhassan SO, Atawodi SEO. Evaluation of the preventive potential of graded dietary inclusion of Hyphaene thebaica (Linn) fruit in rat model of colon carcinogenesis. J Food Biochem 2022; 46:e14446. [PMID: 36183199 DOI: 10.1111/jfbc.14446] [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: 07/19/2022] [Revised: 09/05/2022] [Accepted: 09/15/2022] [Indexed: 01/14/2023]
Abstract
The preventive effect of Hyphaene thebaica fruit in colon carcinogenesis was evaluated in Wistar rats at 0, 2.5, 5 and 10% inclusion rates for twelve weeks with concomitant 72-h intra-rectal N-methyl-N-nitrosourea (MNU) instillations. Indices of antioxidant status and carcinogenesis were analyzed using spectrophotometric, ELISA, histological and immunohistochemical techniques. The fruit protected against lipid peroxidation and level of early biomarkers of colon carcinogenesis, accompanied by decrease in some endogenous antioxidant enzymes functionality. It also prevented colon tissues against MNU-induced severe inflammations and damage to the mutL-homolog 1 (MLH1) gene. There was significant negative correlation between endogenous antioxidant enzyme activities and carcinoembryonic antigen (CEA) as well as lipid peroxidation, but relationship between total polyphenols and percentage expression of MLH1 proteins as well as endogenous antioxidant enzyme activities was positive. These results validate the folkloric use of H. thebaica fruit in the management of colorectal disorders. PRACTICAL APPLICATIONS: Hyphaene thebaica fruit which is widely consumed in northern Nigeria and other countries of sub-Saharan Africa is rich in fiber and antioxidant polyphenols. These two classes of compounds have demonstrated capacity to prevent colorectal cancer and cancer of other sites. Therefore, the validated protective Hyphaene thebaica fruit suggests that it can be processed for inclusion in beverages/diets as functional foods for prevention and management of colorectal disorders.
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Affiliation(s)
- Abdulrazaq Yusuf
- Biochemistry Department, Federal University Lokoja, Lokoja, Kogi State, Nigeria
| | - Ochai Emmanuel Odeh
- Biochemistry Department, Federal University Lokoja, Lokoja, Kogi State, Nigeria
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Shen D, Wang X, Wang H, Xu G, Xie Y, Zhuang Z, Huang Z, Li J, Lin J, Wang P, Huang M, Luo Y, Yu H. Current Surveillance After Treatment is Not Sufficient for Patients With Rectal Cancer With Negative Baseline CEA. J Natl Compr Canc Netw 2022; 20:653-662.e3. [PMID: 35231901 DOI: 10.6004/jnccn.2021.7101] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 10/11/2021] [Indexed: 01/21/2023]
Abstract
BACKGROUND Serum CEA has been widely used to screen for potential recurrent disease after resection in rectal cancer. However, the influence of baseline CEA on the performance of CEA in recurrence surveillance needs to be investigated. PATIENTS AND METHODS This longitudinal cohort study included 484 patients with nonmetastatic rectal cancer from 18,013 patients in a prospectively enrolled institutional database program of colorectal disease. Baseline CEA levels were determined before treatment, and CEA-based follow-up tests and examinations were applied in the surveillance after treatment. RESULTS A total of 62.6% (62/99) overall, 53.5% (23/43) local, and 64.9% (50/77) distant recurrences were seen in patients who had similar CEA levels with their baseline statuses. The sensitivity of elevated CEA levels during surveillance for overall recurrence was significantly lower in patients with negative baseline CEA than in those with elevated baseline CEA levels (41.3% vs 69.4%; P =.007). Moreover, similar results were observed in the surveillance for local (50% vs 61.5%; P =.048) and distant (39.6% vs 72.4%; P =.005) recurrences between these 2 patient groups. However, CEA had comparable and excellent specificity during surveillance for recurrent disease in these groups. The addition of CA19-9 to the CEA assay significantly improved the sensitivity in recurrence surveillance for patients with negative baseline CEA (49.2% vs 41.3%; P =.037). Finally, we identified a subgroup of CEA-turn recurrences characterized by negative CEA at baseline, elevated CEA at recurrence, and worse survival outcomes after recurrence (hazard ratio, 1.88; 95% CI, 1.07-3.30; P =.026). CONCLUSIONS In patients with rectal cancer with negative baseline CEA, serum CEA had insufficient sensitivity in recurrence surveillance after treatment, and additional surveillance may improve oncologic outcomes. Baseline CEA should be considered before CEA-based surveillance can be applied in the follow-up trials.
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Affiliation(s)
- Dingcheng Shen
- 1Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, and.,2Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University; and
| | - Xiaolin Wang
- 1Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, and
| | - Heng Wang
- 1Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, and
| | - Gaopo Xu
- 1Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, and
| | - Yumo Xie
- 1Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, and.,2Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University; and
| | - Zhuokai Zhuang
- 1Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, and.,2Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University; and
| | - Ziying Huang
- 3Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Juan Li
- 2Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University; and
| | - Jinxin Lin
- 2Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University; and
| | - Puning Wang
- 2Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University; and
| | - Meijin Huang
- 1Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, and.,2Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University; and
| | - Yanxin Luo
- 1Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, and.,2Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University; and
| | - Huichuan Yu
- 1Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, and.,2Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University; and
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Yang YS, Wen D, Zhao XF. Preventive and therapeutic effect of intraportal oridonin on BALb/c nude mice hemispleen model of colon cancer liver metastasis. Transl Cancer Res 2022; 10:1324-1335. [PMID: 35116458 PMCID: PMC8798652 DOI: 10.21037/tcr-20-3042] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 01/27/2021] [Indexed: 01/15/2023]
Abstract
Background This study is to investigate the preventive and therapeutic effect of intraportal oridonin on colorectal cancer liver metastasis (CRCLM). Methods The inhibitory effect of oridonin on HT29 cells was determined by CCK-8 and MTT assays. The preventive and therapeutic effect of intraportal oridonin on CRCLM were investigated by establishing BALb/c nude mice hemispleen models of colon cancer liver metastasis. The microscopic characteristics of tumor tissues were observed by hematoxylin-eosin staining, immunohistochemistry and TUNEL staining. On the other hand, liver function enzymes, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP), were detected to evaluate the hepatotoxicity of intraportal oridonin. The serum levels of tumor markers, including carcinoembryonic antigen (CEA) and α-fetoprotein (AFP), were used to investigate the intervention effect of intraportal oridonin on CRCLM. Results Oridonin exerted an inhibitory effect on the proliferation of HT29 cells in vitro. Intraportal oridonin was found to effectively prevent the occurrence and formation of CRCLM, whilst intraportal oridonin can also exert a therapeutic effect on CRCLM. Additionally, liver enzymes testing indicated that intraportal oridonin possesses non-hepatotoxicity, instead can effectively alleviate liver injury caused by tumor. Furthermore, intraportal oridonin was also revealed to decrease the serum levels of AFP and CEA. Conclusions Intraportal oridonin can effectively inhibit the formation of liver metastatic tumor and exert a certain degree of preventive and therapeutic effect on CRCLM. These findings indicate intraportal oridonin to be a promising anti-metastasis agent for CRCLM.
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Affiliation(s)
- Yu-Shen Yang
- Department of General Surgery, Dalian University Affiliated Xinhua Hospital, Dalian, China
| | - Dan Wen
- Department of General Surgery, Dalian University Affiliated Xinhua Hospital, Dalian, China
| | - Xue-Feng Zhao
- Department of General Surgery, Dalian University Affiliated Xinhua Hospital, Dalian, China
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Cha SE, Kujawski M, J Yazaki P, Brown C, Shively JE. Tumor regression and immunity in combination therapy with anti-CEA chimeric antigen receptor T cells and anti-CEA-IL2 immunocytokine. Oncoimmunology 2021; 10:1899469. [PMID: 33796409 PMCID: PMC7993151 DOI: 10.1080/2162402x.2021.1899469] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Targeted immunotherapy of solid cancers with chimeric antigen receptor (CAR) T cells and immunocytokines are attractive options in that they both rely on the specificity of tumor-targeted antibodies. Since carcinoembryonic antigen (CEA) expression in both colon and breast cancers is correlated with poor prognosis, it was chosen as a model tumor target in immunocompetent CEA transgenic (CEATg) mice. A second-generation anti-CEA CAR derived from CEA-specific antibody T84.66 was used to treat murine MC38 colon or E0771 breast carcinomas transfected with CEA. Anti-CEA CAR vs. mock transduced T cells exhibited a CEA-specific cytotoxic and IFNγ dose response to both CEA transfected cell lines vs. their CEA-negative controls. Anti-CEA CAR vs. mock transduced T cells delayed the median survival of CEA transfected s.c. MC38 or orthotopic E0771 tumor-bearing CEATg mice by 2 days. With the addition of one-day prior cyclophosphamide (CY) lymphodepletion, anti-CEA CAR T cell treatment delayed the median survival of MC38/CEA and E0771/CEA tumor-bearing CEATg mice by ten and 3 days, respectively. Since CAR T cells require IL2 for survival and expansion, anti-CEA-IL2 immunocytokine (ICK) treatment was performed post CAR T cell therapy. Single ICK treatment 1 day after CY plus anti-CEA CAR T cell therapy in the MC38/CEA model, and two ICK treatments every 3 days after CY plus anti-CEA CAR T cell therapy in the E0771/CEA model were ineffective, while four ICK treatments every 3 days after CY plus anti-CEA CAR T cell therapy completely eradicated MC38/CEA tumor growth and induced tumor immunity when the mice were re-challenged with tumor. These studies show the therapeutic potential of anti-CEA CAR T cells combined with ICK to treat CEA-positive tumors. Abbreviations: CAR: Chimeric antigen receptor, CEA: Carcinoembryonic antigen, CEACAM5, ICK: Immunocytokine, CY: Cyclophosphamide, CEATg mouse: transgenic CEA mouse, TDLN: Tumor-draining lymph node
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Affiliation(s)
- Seung E Cha
- Department of Immunology and Theranostics, City of Hope, Duarte, USA.,Irell & Manella Graduate School of Biological Sciences, City of Hope, Duarte, USA
| | - Maciej Kujawski
- Department of Immunology and Theranostics, City of Hope, Duarte, USA
| | - Paul J Yazaki
- Department of Immunology and Theranostics, City of Hope, Duarte, USA
| | - Christine Brown
- Irell & Manella Graduate School of Biological Sciences, City of Hope, Duarte, USA.,Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, USA.,T Cell Therapeutics Research Laboratory, City of Hope, Duarte, USA
| | - John E Shively
- Department of Immunology and Theranostics, City of Hope, Duarte, USA.,Irell & Manella Graduate School of Biological Sciences, City of Hope, Duarte, USA
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12
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Loftis AR, Santos MS, Truex NL, Biancucci M, Satchell KJF, Pentelute BL. Anthrax Protective Antigen Retargeted with Single-Chain Variable Fragments Delivers Enzymes to Pancreatic Cancer Cells. Chembiochem 2020; 21:2772-2776. [PMID: 32369652 PMCID: PMC7541672 DOI: 10.1002/cbic.202000201] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 05/01/2020] [Indexed: 12/15/2022]
Abstract
The nontoxic, anthrax protective antigen/lethal factor N-terminal domain (PA/LFN ) complex is an effective platform for translocating proteins into the cytosol of cells. Mutant PA (mPA) was recently fused to epidermal growth factor (EGF) to retarget delivery of LFN to cells bearing EGF receptors (EGFR), but the requirement for a known cognate ligand limits the applicability of this approach. Here, we render practical protective antigen retargeting to a variety of receptors with mPA single-chain variable fragment (scFv) fusion constructs. Our design enables the targeting of two pancreatic cancer-relevant receptors, EGFR and carcinoembryonic antigen. We demonstrate that fusion to scFvs does not disturb the basic functions of mPA. Moreover, mPA-scFv fusions enable cell-specific delivery of diphtheria toxin catalytic domain and Ras/Rap1-specific endopeptidase to pancreatic cancer cells. Importantly, mPA-scFv fusion-based treatments display potent cell-specific toxicity in vitro, opening fundamentally new routes toward engineered immunotoxins and providing a potential solution to the challenge of targeted protein delivery to the cytosol of cancer cells.
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Affiliation(s)
- Alexander R Loftis
- Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
| | - Michael S Santos
- Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
| | - Nicholas L Truex
- Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
| | - Marco Biancucci
- Department of Microbiology-Immunology Feinberg School of Medicine, Northwestern University, 420 E Superior Street, Chicago, IL 60611, USA
| | - Karla J F Satchell
- Department of Microbiology-Immunology Feinberg School of Medicine, Northwestern University, 420 E Superior Street, Chicago, IL 60611, USA
| | - Bradley L Pentelute
- Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
- The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA
- Center for Environmental Health Sciences, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
- Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA
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13
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Sabeti Aghabozorgi A, Moradi Sarabi M, Jafarzadeh-Esfehani R, Koochakkhani S, Hassanzadeh M, Kavousipour S, Eftekhar E. Molecular determinants of response to 5-fluorouracil-based chemotherapy in colorectal cancer: The undisputable role of micro-ribonucleic acids. World J Gastrointest Oncol 2020; 12:942-956. [PMID: 33005290 PMCID: PMC7510001 DOI: 10.4251/wjgo.v12.i9.942] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 05/11/2020] [Accepted: 07/19/2020] [Indexed: 02/05/2023] Open
Abstract
5-flurouracil (5-FU)-based chemotherapy is the main pharmacological therapy for advanced colorectal cancer (CRC). Despite significant progress in the treatment of CRC during the last decades, 5-FU drug resistance remains the most important cause of failure in CRC therapy. Resistance to 5-FU is a complex and multistep process. Different mechanisms including microsatellite instability, increased expression level of key enzyme thymidylate synthase and its polymorphism, increased level of 5-FU-activating enzymes and mutation of TP53 are proposed as the main determinants of resistance to 5-FU in CRC cells. Recently, micro-ribonucleic acids (miRNA) and their alterations were found to have a crucial role in 5-FU resistance. In this regard, the miRNA-mediated mechanisms of 5-FU drug resistance reside among the new fields of pharmacogenetics of CRC drug response that has not been completely discovered. Identification of the biological markers that are related to response to 5-FU-based chemotherapy is an emerging field of precision medicine. This approach will have an important role in defining those patients who are most likely to benefit from 5-FU-based chemotherapy in the future. Thereby, the identification of 5-FU drug resistance mechanisms is an essential step to predict and eventually overcome resistance. In the present comprehensive review, we will summarize the latest knowledge regarding the molecular determinants of response to 5-FU-based chemotherapy in CRC by emphasizing the role of miRNAs.
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Affiliation(s)
| | - Mostafa Moradi Sarabi
- Department of Biochemistry and Genetics, School of Medicine, Lorestan University of Medical Sciences, Khorramabad 381251698, Iran
| | - Reza Jafarzadeh-Esfehani
- Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 1394491388, Iran
| | - Shabnaz Koochakkhani
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas 7919915519, Iran
| | - Marziyeh Hassanzadeh
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas 7919915519, Iran
| | - Soudabeh Kavousipour
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas 7919915519, Iran
| | - Ebrahim Eftekhar
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas 7919915519, Iran
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14
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Moradi Sarabi M, Mohammadrezaei Khorramabadi R, Zare Z, Eftekhar E. Polyunsaturated fatty acids and DNA methylation in colorectal cancer. World J Clin Cases 2019; 7:4172-4185. [PMID: 31911898 PMCID: PMC6940323 DOI: 10.12998/wjcc.v7.i24.4172] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 11/27/2019] [Accepted: 12/13/2019] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) has been designated a major global problem, especially due to its high prevalence in developed countries. CRC mostly occurs sporadically (75%-80%), and only 20%-25% of patients have a family history. Several processes are involved in the development of CRC such as a combination of genetic and epigenetic alterations. Epigenetic changes, including DNA methylation play a vital role in the progression of CRC. Complex interactions between susceptibility genes and environmental factors, such as a diet and sedentary lifestyle, lead to the development of CRC. Clinical and experimental studies have confirmed the beneficial effects of dietary polyunsaturated fatty acids (PUFAs) in preventing CRC. From a mechanistic viewpoint, it has been suggested that PUFAs are pleiotropic agents that alter chromatin remodeling, membrane structure and downstream cell signaling. Moreover, PUFAs can alter the epigenome via modulation of DNA methylation. In this review, we summarize recent investigations linking PUFAs and DNA methylation-associated CRC risk.
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Affiliation(s)
- Mostafa Moradi Sarabi
- Department of Biochemistry and Genetics, School of Medicine, Lorestan University of Medical Sciences, Khorramabad 381251698, Iran
| | - Reza Mohammadrezaei Khorramabadi
- Department of Biochemistry and Genetics, School of Medicine, Lorestan University of Medical Sciences, Khorramabad 381251698, Iran
| | - Zohre Zare
- Department of Pharmaceutics, School of Pharmacy, Lorestan University of Medical Sciences, Khorramabad 381251698, Iran
| | - Ebrahim Eftekhar
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas 7919915519, Iran
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15
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Enhancement of chemosensitivity in 5-fluorouracil-resistant colon cancer cells with carcinoembryonic antigen-specific RNA aptamer. Mol Biol Rep 2019; 46:3835-3842. [PMID: 31028570 DOI: 10.1007/s11033-019-04826-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2018] [Accepted: 04/15/2019] [Indexed: 12/24/2022]
Abstract
Colorectal cancer (CRC) is one of the most common cancers, and rates of incidence and diagnosis of CRC have gradually increased. Carcinoembryonic antigen (CEA) is overexpressed in patients with CRC and is associated with cell adhesion, anoikis resistance, and promotion of metastasis to the liver. 5-Fluorouracil (5-FU) is a chemotherapeutic drug used to treat cancer, including CRC. However, a major issue of 5-FU therapy is the occurrence of chemoresistance, and the fact that 5-FU induces CEA overexpression, which may induce the 5-FU resistance. We previously isolated a CEA-specific RNA aptamer that was able to inhibit hepatic metastasis of colon cancer cells in a mouse model. In the present study, we tested whether protecting CEA using the CEA aptamer could enhance 5-FU sensitivity in chemoresistant LS174T colon cancer cells. We observed that the CEA aptamer sensitized the 5-FU-resistant colon cancer cell line to 5-FU more than five-fold (IC50 ~ 5.995 μM), compared with cells treated with 5-FU alone (IC50 ~ 31.46 μM). Moreover, treatment with CEA aptamer combined with 5-FU synergistically regressed growth of chemoresistant tumors in mouse xenografted models. Combinatorial treatment of 5-FU and CEA aptamer augmented caspase-8 activity in the 5-FU-resistant colon cancer cell line via aptamer-mediated disruption of CEA interaction with death receptor 5 and in mouse xenograft tumors. In conclusion, CEA-specific aptamer improved 5-FU sensitivity in chemoresistant colon cancer cells in vitro and in vivo, and thus represents a novel 5-FU adjuvant to overcome the chemoresistance in CRC patients.
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16
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Colloca GA, Venturino A, Guarneri D. Carcinoembryonic antigen reduction after medical treatment in patients with metastatic colorectal cancer: a systematic review and meta-analysis. Int J Colorectal Dis 2019; 34:657-666. [PMID: 30671635 DOI: 10.1007/s00384-018-03230-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/27/2018] [Indexed: 02/07/2023]
Abstract
PURPOSE The introduction of new drugs and multimodal treatments for the management of patients with metastatic colorectal cancer (mCRC) has reduced the importance of time-to-event endpoints and reported the attention on the response-related endpoints. Furthermore, the prognostic role of the surgical scores before the resection of metastases has not been confirmed for multimodal treatments. The purpose of this research is to perform a meta-analysis of the studies that evaluated the relationship between carcinoembryonic antigen (CEA) response and outcome in patients with mCRC receiving systemic chemotherapy. METHODS A systematic review of the literature on two databases and a selection of studies that evaluated the relationship between CEA response and outcome were performed according to predefined criteria. After, three meta-analyses were carried out on the selected studies, each for each outcome variable. RESULTS Nineteen studies have been selected. Fourteen studies (1475 patients) have documented a close association between radiological response and CEA response (odds ratio (OR), 9.03; confidence intervals (CIs), 5.14-15.87; I2 statistic (I2), 72%). Four studies have reported a longer progression-free survival for patients with a CEA response (hazard ratio (HR), 0.73; CIs, 0.64-0.83; I2, 23%). Finally, 10 studies (13 study cohorts) have shown a strong relationship between CEA response and overall survival (OS) (HR, 0. 62; CIs, 0.55-0.70; I2, 35%). CONCLUSIONS CEA response merits further investigation as a surrogate endpoint of clinical trials of first-line medical therapy of patients with mCRC, and should be studied as a prognostic factor for those patients who are candidates for multimodal treatment strategies.
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Affiliation(s)
- Giuseppe Antonio Colloca
- Department of Oncology, Ospedale Civile di Sanremo, Via G. Borea n. 56, I-18038, Sanremo (Imperia), Italy.
| | - Antonella Venturino
- Department of Oncology, Ospedale Civile di Sanremo, Via G. Borea n. 56, I-18038, Sanremo (Imperia), Italy
| | - Domenico Guarneri
- Department of Oncology, Ospedale Civile di Sanremo, Via G. Borea n. 56, I-18038, Sanremo (Imperia), Italy
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17
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18
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Tatar M, Bagheri Z, Varedi M, Naghibalhossaini F. Blackberry Extract Inhibits Telomerase Activity in Human Colorectal Cancer Cells. Nutr Cancer 2018; 71:461-471. [DOI: 10.1080/01635581.2018.1506491] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Affiliation(s)
- Mohsen Tatar
- Department of Biochemistry, Shiraz University of Medical Sciences, School of Medicine, Shiraz, Iran
| | - Zohreh Bagheri
- Department of Physiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Masoumeh Varedi
- Department of Physiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fakhraddin Naghibalhossaini
- Department of Biochemistry, Shiraz University of Medical Sciences, School of Medicine, Shiraz, Iran
- School of Medicine, Autoimmune Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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19
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Shiozawa M, Chang CH, Huang YC, Chen YC, Chi MS, Hao HC, Chang YC, Takeda S, Chi KH, Wang YS. Pharmacologically upregulated carcinoembryonic antigen-expression enhances the cytolytic activity of genetically-modified chimeric antigen receptor NK-92MI against colorectal cancer cells. BMC Immunol 2018; 19:27. [PMID: 30075754 PMCID: PMC6091054 DOI: 10.1186/s12865-018-0262-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 07/11/2018] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The natural killer cell line, NK-92MI, is cytotoxic against various types of cancer. The aim of this study was to develop chimeric antigen receptor-modified (CAR) NK-92MI cells targeting carcinoembryonic antigen-expressing (CEA) tumours and increase killing efficacy by pharmacologically modifying CEA-expression. RESULT We generated anti-CEA-CAR NK-92MI cells by retroviral vector transduction. This genetically-modified cell line recognised and lysed high CEA-expressing tumour cell lines (LS174T) at 47.54 ± 12.60% and moderate CEA-expressing tumour cell lines (WiDr) at 31.14 ± 16.92% at a 5:1 effector: target (E/T) ratio. The cell line did not lyse low CEA-expressing tumour cells (HCT116) as they did their parental cells (NK-92MI cells). The histone deacetylase-inhibitor (HDAC) sodium butyrate (NaB) and the methylation-inhibitor 5-azacytidine (5-AZA), as epigenetic modifiers, induced CEA-expression in HCT116 and WiDr cells. Although the IC50 of 5 fluorouracil (5-FU) increased, both cell lines showed collateral sensitivity to anti-CEA-CAR NK-92MI cells. The cytolytic function of anti-CEA-CAR NK-92MI cells was increased from 22.99 ± 2.04% of lysis background to 69.20 ± 11.92% after NaB treatment, and 69.70 ± 9.93% after 5-AZA treatment, at a 10:1 E/T ratio in HCT116 cells. The WiDr cells showed similar trend, from 22.99 ± 4.01% of lysis background to 70.69 ± 10.19% after NaB treatment, and 59.44 ± 10.92% after 5-AZA treatment, at a 10:1 E/T ratio. CONCLUSIONS This data indicates that the effector-ability of anti-CEA-CAR NK-92MI increased in a CEA-dependent manner. The combination of epigenetic-modifiers like HDAC-inhibitors, methylation-inhibitors, and adoptive-transfer of ex vivo-expanded allogeneic-NK cells may be clinically applicable to patients with in 5-FU resistant condition.
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Affiliation(s)
- Masayuki Shiozawa
- Department of Obstetrics and Gynecology, Juntendo University Hospital, 3-1-3 Hongo, Bunkyo-ku, Tokyo, Japan
| | - Chuan-Hsin Chang
- Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, No.95, Wenchang Road, Shilin District, Taipei, Taiwan.,Department of Research and Development, Johnpro Biotech Inc., 2F., No.118, Hougang St., Shilin Dist., Taipei City, Taiwan
| | - Yi-Chun Huang
- Department of Research and Development, Johnpro Biotech Inc., 2F., No.118, Hougang St., Shilin Dist., Taipei City, Taiwan
| | - Yi-Ching Chen
- Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, No.95, Wenchang Road, Shilin District, Taipei, Taiwan.,Department of Research and Development, Johnpro Biotech Inc., 2F., No.118, Hougang St., Shilin Dist., Taipei City, Taiwan
| | - Mau-Shin Chi
- Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, No.95, Wenchang Road, Shilin District, Taipei, Taiwan.,Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Room 117 Lab Building 1, 75 Bo-Ai Street, Hsinchu, Taiwan
| | - Hsu-Chao Hao
- Department of Biotechnology, Hungkuang University, No. 1018, Sec. 6, Taiwan Boulevard, Shalu District, Taichung City, Taiwan
| | - Yue-Cune Chang
- Department of Mathematics, Tamkang University, No.151, Yingzhuan Rd., Tamsui Dist., New Taipei City, Taiwan
| | - Satoru Takeda
- Department of Obstetrics and Gynecology, Juntendo University Hospital, 3-1-3 Hongo, Bunkyo-ku, Tokyo, Japan
| | - Kwan-Hwa Chi
- Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, No.95, Wenchang Road, Shilin District, Taipei, Taiwan. .,Institute of Veterinary Clinical Science, School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan. .,Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan.
| | - Yu-Shan Wang
- Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, No.95, Wenchang Road, Shilin District, Taipei, Taiwan. .,Department of Research and Development, Johnpro Biotech Inc., 2F., No.118, Hougang St., Shilin Dist., Taipei City, Taiwan. .,Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Room 117 Lab Building 1, 75 Bo-Ai Street, Hsinchu, Taiwan.
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20
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van der Velden DL, Opdam FL, Opdam FL. TAS-102 and the quest for predictive biomarkers. ESMO Open 2017; 2:e000263. [PMID: 29018579 PMCID: PMC5623337 DOI: 10.1136/esmoopen-2017-000263] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/21/2017] [Indexed: 11/03/2022] Open
Affiliation(s)
- Daphne L van der Velden
- Department of Molecular Oncology, Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis, Amsterdam, Netherlands
| | - Frans L Opdam
- Department of Clinical Pharmacology, Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis, Amsterdam, Noord-Holland, Netherlands
| | - Frans L Opdam
- Department of Clinical Pharmacology, Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis, Amsterdam, Noord-Holland, Netherlands
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21
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Martins CD, Kramer-Marek G, Oyen WJG. Radioimmunotherapy for delivery of cytotoxic radioisotopes: current status and challenges. Expert Opin Drug Deliv 2017; 15:185-196. [PMID: 28893110 DOI: 10.1080/17425247.2018.1378180] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Radioimmunotherapy (RIT) with monoclonal antibodies and their fragments labelled with radionuclides emitting α -particles, β-particles or Auger electrons have been used for many years in the development of anticancer strategies. While RIT has resulted in approved radiopharmaceuticals for the treatment of hematological malignancies, its use in solid tumors still remains challenging. AREAS COVERED In this review, we discuss the exciting progress towards elucidating the potential of current and novel radioimmunoconjugates and address the challenges for translation into clinical practice. EXPERT OPINION There are still technical and logistical challenges associated with the use of RIT in routine clinical practice, including development of novel and more specific targeting moieties, broader access α to α-emitters and better tailoring of pre-targeting approaches. Moreover, improved understanding of the heterogeneous nature of solid tumors and the critical role of tumor microenvironments will help to optimize clinical response to RIT by delivering sufficient radiation doses to even more radioresistant tumor cells.
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Affiliation(s)
- Carlos Daniel Martins
- a Division of Radiotherapy and Imaging , The Institute of Cancer Research , London , UK
| | - Gabriela Kramer-Marek
- a Division of Radiotherapy and Imaging , The Institute of Cancer Research , London , UK
| | - Wim J G Oyen
- a Division of Radiotherapy and Imaging , The Institute of Cancer Research , London , UK.,b The Royal Marsden NHS Foundation Trust , Department of Nuclear Medicine , London , UK
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22
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Cai Z, Xiao J, He X, Ke J, Zou Y, Chen Y, Wu X, Li X, Wang L, Wang J, Lan P, Wu X. Accessing new prognostic significance of preoperative carcinoembryonic antigen in colorectal cancer receiving tumor resection: More than positive and negative. Cancer Biomark 2017; 19:161-168. [PMID: 28128739 DOI: 10.3233/cbm-160287] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Affiliation(s)
- Zerong Cai
- Department of Colorectal Surgery, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Department of Colorectal Surgery, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jian Xiao
- Department of Medical Oncology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Department of Colorectal Surgery, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xiaosheng He
- Department of Colorectal Surgery, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jia Ke
- Department of Colorectal Surgery, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yifeng Zou
- Department of Colorectal Surgery, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yufeng Chen
- Department of Colorectal Surgery, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xianrui Wu
- Department of Colorectal Surgery, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xiaoling Li
- Faculty of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Lei Wang
- Department of Colorectal Surgery, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jianping Wang
- Department of Colorectal Surgery, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Ping Lan
- Department of Colorectal Surgery, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xiaojian Wu
- Department of Colorectal Surgery, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
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23
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Wang H, Meng AM, Li SH, Zhou XL. A nanobody targeting carcinoembryonic antigen as a promising molecular probe for non-small cell lung cancer. Mol Med Rep 2017; 16:625-630. [PMID: 28586008 PMCID: PMC5482067 DOI: 10.3892/mmr.2017.6677] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Accepted: 03/23/2017] [Indexed: 12/18/2022] Open
Abstract
Carcinoembryonic antigen (CEA) is a biomarker and therapy target for non-small cell lung cancer (NSCLC), which is the most common type of lung cancer. Nanobodies with high target specificity are promising candidates to function as anti-CEA probes. In the present study, the targeting effects of an anti-CEA nanobody obtained from phage display were investigated using technetium-99 m (99mTc) and fluorescence labeling. In vitro binding and immunofluorescent staining assays, as well as in vivo blood clearance and biodistribution assays were performed. High specificity and affinity of the nanobody for CEA-positive H460 cells was observed in vitro. The pharmacokinetics assay of the 99mTc-nanobody in Wistar rats demonstrated that the nanobody had appropriate T1/2α and T1/2β, which were 20.2 and 143.5 min, respectively. The biodistribution assay using H460 xenograft-bearing nude mice demonstrated a high ratio of signal in tumor compared with background, which confirmed that the nanobody may be useful as a molecular probe for CEA-positive cancer, particularly in NSCLC.
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Affiliation(s)
- Hao Wang
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, P.R. China
| | - Ai-Min Meng
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, P.R. China
| | - Sheng-Hua Li
- Tianjin Shengfa NabioTech Co., Ltd., Tianjin 300457, P.R. China
| | - Xiao-Liang Zhou
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, P.R. China
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24
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The Roles of Carcinoembryonic Antigen in Liver Metastasis and Therapeutic Approaches. Gastroenterol Res Pract 2017; 2017:7521987. [PMID: 28588612 PMCID: PMC5447280 DOI: 10.1155/2017/7521987] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Accepted: 04/16/2017] [Indexed: 12/22/2022] Open
Abstract
Metastasis is a highly complicated and sequential process in which primary cancer spreads to secondary organic sites. Liver is a well-known metastatic organ from colorectal cancer. Carcinoembryonic antigen (CEA) is expressed in most gastrointestinal, breast, and lung cancer cells. Overexpression of CEA is closely associated with liver metastasis, which is the main cause of death from colorectal cancer. CEA is widely used as a diagnostic and prognostic tumor marker in cancer patients. It affects many steps of liver metastasis from colorectal cancer cells. CEA inhibits circulating cancer cell death. CEA also binds to heterogeneous nuclear RNA binding protein M4 (hnRNP M4), a Kupffer cell receptor protein, and activates Kupffer cells to secrete various cytokines that change the microenvironments for the survival of colorectal cancer cells in the liver. CEA also activates cell adhesion-related molecules. The close correlation between CEA and cancer has spurred the exploration of many CEA-targeted approaches as anticancer therapeutics. Understanding the detailed functions and mechanisms of CEA in liver metastasis will provide great opportunities for the improvement of anticancer approaches against colorectal cancers. In this report, the roles of CEA in liver metastasis and CEA-targeting anticancer modalities are reviewed.
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Guo H, Zhou X, Lu Y, Xie L, Chen Q, Keller ET, Liu Q, Zhou Q, Zhang J. Translational progress on tumor biomarkers. Thorac Cancer 2015; 6:665-71. [PMID: 26557902 PMCID: PMC4632916 DOI: 10.1111/1759-7714.12294] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Accepted: 06/15/2015] [Indexed: 12/30/2022] Open
Abstract
There is an urgent need to apply basic research achievements to the clinic. In particular, mechanistic studies should be developed by bench researchers, depending upon clinical demands, in order to improve the survival and quality of life of cancer patients. To date, translational medicine has been addressed in cancer biology, particularly in the identification and characterization of novel tumor biomarkers. This review focuses on the recent achievements and clinical application prospects in tumor biomarkers based on translational medicine.
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Affiliation(s)
- Hongwei Guo
- Key Laboratory of Longevity and Aging-Related Diseases, Ministry of Education Nanning, China ; Center for Translational Medicine, Guangxi Medical University Nanning, China
| | - Xiaolin Zhou
- Key Laboratory of Longevity and Aging-Related Diseases, Ministry of Education Nanning, China ; Center for Translational Medicine, Guangxi Medical University Nanning, China
| | - Yi Lu
- Key Laboratory of Longevity and Aging-Related Diseases, Ministry of Education Nanning, China ; Center for Translational Medicine, Guangxi Medical University Nanning, China
| | - Liye Xie
- Key Laboratory of Longevity and Aging-Related Diseases, Ministry of Education Nanning, China ; Center for Translational Medicine, Guangxi Medical University Nanning, China
| | - Qian Chen
- Key Laboratory of Longevity and Aging-Related Diseases, Ministry of Education Nanning, China ; Center for Translational Medicine, Guangxi Medical University Nanning, China
| | - Evan T Keller
- Department of Urology and Pathology, School of Medicine, University of Michigan Ann Arbor, Michigan, USA
| | - Qian Liu
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital Tianjin, China
| | - Qinghua Zhou
- Lung Cancer Center, Huaxi Hospital, Sichuan University Chengdu, China
| | - Jian Zhang
- Key Laboratory of Longevity and Aging-Related Diseases, Ministry of Education Nanning, China ; Center for Translational Medicine, Guangxi Medical University Nanning, China ; Department of Urology and Pathology, School of Medicine, University of Michigan Ann Arbor, Michigan, USA
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Dolatkhah R, Somi MH, Bonyadi MJ, Asvadi Kermani I, Farassati F, Dastgiri S. Colorectal cancer in iran: molecular epidemiology and screening strategies. J Cancer Epidemiol 2015; 2015:643020. [PMID: 25685149 PMCID: PMC4312646 DOI: 10.1155/2015/643020] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2014] [Revised: 12/05/2014] [Accepted: 12/15/2014] [Indexed: 12/22/2022] Open
Abstract
Purpose. The increasing incidence of colorectal cancer (CRC) in the past three decades in Iran has made it a major public health burden. This study aimed to report its epidemiologic features, molecular genetic aspects, survival, heredity, and screening pattern in Iran. Methods. A comprehensive literature review was conducted to identify the relevant published articles. We used medical subject headings, including colorectal cancer, molecular genetics, KRAS and BRAF mutations, screening, survival, epidemiologic study, and Iran. Results. Age standardized incidence rate of Iranian CRCs was 11.6 and 10.5 for men and women, respectively. Overall five-year survival rate was 41%, and the proportion of CRC among the younger age group was higher than that of western countries. Depending on ethnicity, geographical region, dietary, and genetic predisposition, mutation genes were considerably diverse and distinct among CRCs across Iran. The high occurrence of CRC in records of relatives of CRC patients showed that family history of CRC was more common among young CRCs. Conclusion. Appropriate screening strategies for CRC which is amenable to early detection through screening, especially in relatives of CRCs, should be considered as the first step in CRC screening programs.
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Affiliation(s)
- Roya Dolatkhah
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Hossein Somi
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Iraj Asvadi Kermani
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Faris Farassati
- Department of Medicine, The University of Kansas Medical School, Molecular Medicine Laboratory, KUMC, Kansas City, KS, USA
| | - Saeed Dastgiri
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Mokarram P, Estiar MA, Ashktorab H. Methylation in Colorectal Cancer. EPIGENETICS TERRITORY AND CANCER 2015:373-455. [DOI: 10.1007/978-94-017-9639-2_13] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Gurzu S, Bara T, Bara T, Kadar Z, Molnar C, Kovecsi A, Jung I. Clinical significance of carcinoembryonic antigen expression of acellular mucin pools after preoperative chemoradiotherapy of rectal carcinoma. Cancer Biother Radiopharm 2014; 29:295-297. [PMID: 25203146 DOI: 10.1089/cbr.2014.1640] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
INTRODUCTION Although several studies have shown that the presence of acellular mucin pools in surgical specimens with rectal carcinomas examined after preoperative chemoradiotherapy indicated complete response to therapy, the proper meaning of these pools has yet to be elucidated. The aims of this study were to analyze the immunoprofile of acellular mucin pools and to review the relevant literature. METHODS In 30 consecutive rectal cancers that were preoperatively treated with chemoradiotherapy, the clinicopathologic features were correlated with the immunoexpression of AE1/AE3 keratin and carcinoembryonic antigen (CEA). RESULTS Acellular mucin pools were present in all the cases, independently by their preoperative histological aspect. In remnant tumors (n=20), they were present at the invasion front and were marked by CEA. In cases without remnant tumor cells (n=10), they also displayed CEA positivity. In 2 of the 10 cases, isolated tumor cells were identified after multilevel sectioning of paraffin-embedded blocks. CONCLUSIONS The presence of acellular mucin pools in surgical specimens of rectal cancers cannot be interpreted as an indicator of complete response to radiotherapy if at least 10 multilevel sections are performed in at least three tumor blocks per case, and CEA negativity is not proved.
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Affiliation(s)
- Simona Gurzu
- 1 Department of Pathology, University of Medicine and Pharmacy of Tirgu-Mures , Tirgu-Mures, Romania
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Yu M, Zhang Z, Yu H, Xue C, Yuan K, Miao M, Shi H. KIN enhances stem cell-like properties to promote chemoresistance in colorectal carcinoma. Biochem Biophys Res Commun 2014; 448:63-9. [PMID: 24755081 DOI: 10.1016/j.bbrc.2014.04.057] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Accepted: 04/11/2014] [Indexed: 11/20/2022]
Abstract
Chemotherapy is widely used in colorectal cancer (CRC) treatment, especially in advanced stage patients. However, it is inevitable to develop chemoresistance. Recently, cancer cells acquired stem cell-like properties or cancer stem cells (CSC) were proved to attribute to chemoresistance. Here, we found that KIN protein was elevated in CRC cell lines and tissue specimens as compared to normal controls. Upregulation of KIN positively correlates with the metastatic status of CRC patients. Patients with high KIN expression showed poor prognosis and were with a short survival time. Overexpression of KIN enhanced, while silencing KIN impaired, chemoresistance to oxaliplatin (Ox) or 5-fluorouracil (5-FU) in CRC cell lines. Further investigation demonstrated that overexpression of KIN rendered CRC cells enriching CSC markers and CSC phenotype, and silencing KIN reduced CSC markers and CSC phenotype. Our findings suggest that the KIN level may be a suitable marker for predicting chemotherapy response in CRC, and silencing KIN plus chemotherapy may be a novel therapy for CRC treatment.
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Affiliation(s)
- Miao Yu
- Department of Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, Guangdong 510080, China
| | - Zhenwei Zhang
- Department of Biochemistry and Molecular Biology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China
| | - Honglan Yu
- Department of Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, Guangdong 510080, China
| | - Conglong Xue
- Department of Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, Guangdong 510080, China
| | - Kaitao Yuan
- Department of Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, Guangdong 510080, China
| | - Mingyong Miao
- Department of Biochemistry and Molecular Biology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China.
| | - Hanping Shi
- Department of Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, Guangdong 510080, China.
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