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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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2
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Martín-García D, García-Aranda M, Redondo M. Biomarker Identification through Proteomics in Colorectal Cancer. Int J Mol Sci 2024; 25:2283. [PMID: 38396959 PMCID: PMC10888664 DOI: 10.3390/ijms25042283] [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: 01/26/2024] [Revised: 02/12/2024] [Accepted: 02/13/2024] [Indexed: 02/25/2024] Open
Abstract
Colorectal cancer (CRC) is a devastating disease that ranks third in diagnosis and as the second leading cause of cancer-related deaths. The early detection of CRC has been shown to be the most effective strategy to improve treatment outcomes and patient survival. Therefore, current lines of research focus on the development of reliable diagnostic tools. Targeted therapies, in combination with standard chemotherapy and immune checkpoint inhibitors, have emerged as promising treatment protocols in CRC. However, their effectiveness is linked to the molecular characteristics of each patient. The importance of discovering biomarkers that help predict response to therapies and assess prognosis is evident as they allow for a fundamental step towards personalized care and successful treatments. Among the ongoing efforts to identify them, mass spectrometry-based translational proteomics presents itself as a unique opportunity as it enables the discovery and application of protein biomarkers that may revolutionize the early detection and treatment of CRC. Our objective is to show the most recent studies focused on the identification of CRC-related protein markers, as well as to provide an updated view of advances in the field of proteomics and cancer.
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Affiliation(s)
- Desirée Martín-García
- Surgical Specialties, Biochemistry and Immunology Department, Faculty of Medicine, University of Málaga, 29010 Málaga, Spain;
- Red de Investigación en Cronicidad, Atención Primaria y Promoción de la Salud (RICAPPS), 29590 Málaga, Spain;
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina—IBIMA Plataforma BIONAND, 29590 Málaga, Spain
- Research and Innovation Unit, Hospital Universitario Costa del Sol, 29602 Marbella, Spain
| | - Marilina García-Aranda
- Red de Investigación en Cronicidad, Atención Primaria y Promoción de la Salud (RICAPPS), 29590 Málaga, Spain;
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina—IBIMA Plataforma BIONAND, 29590 Málaga, Spain
- Research and Innovation Unit, Hospital Universitario Costa del Sol, 29602 Marbella, Spain
| | - Maximino Redondo
- Surgical Specialties, Biochemistry and Immunology Department, Faculty of Medicine, University of Málaga, 29010 Málaga, Spain;
- Red de Investigación en Cronicidad, Atención Primaria y Promoción de la Salud (RICAPPS), 29590 Málaga, Spain;
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina—IBIMA Plataforma BIONAND, 29590 Málaga, Spain
- Research and Innovation Unit, Hospital Universitario Costa del Sol, 29602 Marbella, Spain
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3
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Stanojevic A, Samiotaki M, Lygirou V, Marinkovic M, Nikolic V, Stojanovic-Rundic S, Jankovic R, Vlahou A, Panayotou G, Fijneman RJA, Castellví-Bel S, Zoidakis J, Cavic M. Data-Independent Acquisition Mass Spectrometry Analysis of FFPE Rectal Cancer Samples Offers In-Depth Proteomics Characterization of the Response to Neoadjuvant Chemoradiotherapy. Int J Mol Sci 2023; 24:15412. [PMID: 37895091 PMCID: PMC10607861 DOI: 10.3390/ijms242015412] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 09/30/2023] [Accepted: 10/03/2023] [Indexed: 10/29/2023] Open
Abstract
Locally advanced rectal cancer (LARC) presents a challenge in identifying molecular markers linked to the response to neoadjuvant chemoradiotherapy (nCRT). This study aimed to utilize a sensitive proteomic method, data-independent mass spectrometry (DIA-MS), to extensively analyze the LARC proteome, seeking individuals with favorable initial responses suitable for a watch-and-wait approach. This research addresses the unmet need to understand the response to treatment, potentially guiding personalized strategies for LARC patients. Post-treatment assessment included MRI scans and proctoscopy. This research involved 97 LARC patients treated with intense chemoradiotherapy, comprising radiation and chemotherapy. Out of 97 LARC included in this study, we selected 20 samples with the most different responses to nCRT for proteome profiling (responders vs. non-responders). This proteomic approach shows extensive proteome coverage in LARC samples. The analysis identified a significant number of proteins compared to a prior study. A total of 915 proteins exhibited differential expression between the two groups, with certain signaling pathways associated with response mechanisms, while top candidates had good predictive potential. Proteins encoded by genes SMPDL3A, PCTP, LGMN, SYNJ2, NHLRC3, GLB1, and RAB43 showed high predictive potential of unfavorable treatment outcome, while RPA2, SARNP, PCBP2, SF3B2, HNRNPF, RBBP4, MAGOHB, DUT, ERG28, and BUB3 were good predictive biomarkers of favorable treatment outcome. The identified proteins and related biological processes provide promising insights that could enhance the management and care of LARC patients.
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Affiliation(s)
- Aleksandra Stanojevic
- Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia; (A.S.); (R.J.)
| | - Martina Samiotaki
- Institute for Bioinnovation, Biomedical Sciences Research Center “Alexander Fleming”, Fleming 34, 166 72 Vari, Greece; (M.S.); (G.P.)
| | - Vasiliki Lygirou
- Department of Biotechnology, Biomedical Research Foundation, Academy of Athens, 4 Soranou Ephessiou Street, 115 27 Athens, Greece; (V.L.); (A.V.); (J.Z.)
| | - Mladen Marinkovic
- Clinic for Radiation Oncology and Diagnostics, Department of Radiation Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia; (M.M.); (S.S.-R.)
- Faculty of Medicine, University of Belgrade, Dr Subotica 8, 11000 Belgrade, Serbia
| | - Vladimir Nikolic
- Clinic for Medical Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia;
| | - Suzana Stojanovic-Rundic
- Clinic for Radiation Oncology and Diagnostics, Department of Radiation Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia; (M.M.); (S.S.-R.)
- Faculty of Medicine, University of Belgrade, Dr Subotica 8, 11000 Belgrade, Serbia
| | - Radmila Jankovic
- Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia; (A.S.); (R.J.)
| | - Antonia Vlahou
- Department of Biotechnology, Biomedical Research Foundation, Academy of Athens, 4 Soranou Ephessiou Street, 115 27 Athens, Greece; (V.L.); (A.V.); (J.Z.)
| | - George Panayotou
- Institute for Bioinnovation, Biomedical Sciences Research Center “Alexander Fleming”, Fleming 34, 166 72 Vari, Greece; (M.S.); (G.P.)
| | - Remond J. A. Fijneman
- Department of Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands;
| | - Sergi Castellví-Bel
- Gastroenterology Department, Fundació Clínic per la Recerca Biomèdica-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), C/del Rosselló, 149, 08036 Barcelona, Spain;
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) Almagro, 3, 28029 Madrid, Spain
- Hospital Clínic, University of Barcelona, C/del Villarroel, 170, 08036 Barcelona, Spain
| | - Jerome Zoidakis
- Department of Biotechnology, Biomedical Research Foundation, Academy of Athens, 4 Soranou Ephessiou Street, 115 27 Athens, Greece; (V.L.); (A.V.); (J.Z.)
- Department of Biology, National and Kapodistrian University of Athens, Panepistimíou 30, 106 79 Athens, Greece
| | - Milena Cavic
- Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia; (A.S.); (R.J.)
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Cheraghi-shavi T, Jalal R, Minuchehr Z. TGM2, HMGA2, FXYD3, and LGALS4 genes as biomarkers in acquired oxaliplatin resistance of human colorectal cancer: A systems biology approach. PLoS One 2023; 18:e0289535. [PMID: 37535601 PMCID: PMC10399784 DOI: 10.1371/journal.pone.0289535] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 07/20/2023] [Indexed: 08/05/2023] Open
Abstract
Acquired resistance to oxaliplatin is considered as the primary reason for failure in colorectal cancer (CRC) therapy. Identifying the underlying resistance mechanisms may improve CRC treatment. The present study aims to identify the key genes involved in acquired oxaliplatin-resistant in CRC by confirming the oxaliplatin resistance index (OX-RI). To this aim, two public microarray datasets regarding oxaliplatin-resistant CRC cells with different OX-RI, GSE42387, and GSE76092 were downloaded from GEO database to identify differentially expressed genes (DEGs). The results indicated that the OX-RI affects the gene expression pattern significantly. Then, 54 common DEGs in both datasets including 18 up- and 36 down-regulated genes were identified. Protein-protein interaction (PPI) analysis revealed 13 up- (MAGEA6, TGM2, MAGEA4, SCHIP1, ECI2, CD33, AKAP12, MAGEA12, CALD1, WFDC2, VSNL1, HMGA2, and MAGEA2B) and 12 down-regulated (PDZK1IP1, FXYD3, ALDH2, CEACAM6, QPRT, GRB10, TM4SF4, LGALS4, ALDH3A1, USH1C, KCNE3, and CA12) hub genes. In the next step, two novel up-regulated hub genes including ECI2 and SCHIP1 were identified to be related to oxaliplatin resistance. Functional enrichment and pathway analysis indicated that metabolic pathways, proliferation, and epithelial-mesenchymal transition may play dominant roles in CRC progression and oxaliplatin resistance. In the next procedure, two in vitro oxaliplatin-resistant sub-lines including HCT116/OX-R4.3 and HCT116/OX-R10 cells with OX-IR 3.93 and 10.06 were established, respectively. The results indicated the up-regulation of TGM2 and HMGA2 in HCT116/OX-R10 cells with high OX-RI and down-regulation of FXYD3, LGALS4, and ECI2 in both cell types. Based on the results, TGM2, HMGA2, FXYD3, and LGALS4 genes are related to oxaliplatin-resistant CRC and may serve as novel therapeutic targets.
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Affiliation(s)
- Tayebeh Cheraghi-shavi
- Faculty of Science, Department of Chemistry, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Razieh Jalal
- Faculty of Science, Department of Chemistry, Ferdowsi University of Mashhad, Mashhad, Iran
- Institute of Biotechnology, Novel Diagnostics and Therapeutics Research Group, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Zarrin Minuchehr
- Systems Biotechnology Department, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
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Xu K, Yin X, Zhou B, Zheng X, Wang H, Chen J, Cai X, Gao H, Xu X, Wang L, Shen L, Guo T, Zheng S, Li B, Shao Y, Wang J. FOSL2 promotes intertumoral infiltration of T cells and increases pathological complete response rates in locally advanced rectal cancer patients. Cancer Lett 2023; 562:216145. [PMID: 36997107 DOI: 10.1016/j.canlet.2023.216145] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 03/21/2023] [Accepted: 03/21/2023] [Indexed: 03/30/2023]
Abstract
The outcome of neoadjuvant chemoradiotherapy (nCRT) remains highly unpredictable for individuals with locally advanced rectal cancer (LARC). We set out to characterize effective biomarkers that promote a pathological complete response (pCR). We quantified the abundances of 6483 high-confidence proteins in pre-nCRT biopsies of 58 LARC patients from two hospitals with pressure cycling technology (PCT)-assisted pulse data-independent acquisition (PulseDIA) mass spectrometry. Compared with non-pCR patients, pCR patients achieved long-term disease-free survival (DFS) and had higher tumor immune infiltration, especially CD8+ T cell infiltration, before nCRT. FOSL2 was selected as the candidate biomarker for predicting pCR and was found to be significantly upregulated in pCR patients, which was verified in another 54 pre-nCRT biopsies of LARC patients by immunohistochemistry. FOSL2 expression was able to predict pCR by multiple reaction monitoring (MRM) with high efficiency (Area under curve (AUC) = 0.939, specificity = 1.000, sensitivity = 0.850), and high FOSL2 expression was associated with long-term DFS (p = 0.044). When treated with simulated nCRT, FOSL2 sufficiency resulted in more significant inhibition of cell proliferation, and more significant promotion of cell cycle arrest and cell apoptosis. Moreover, CXCL10 secretion with abnormal cytosolic dsDNA accumulation was found in FOSL2-wildtype (FOSL2-WT) tumor cells over nCRT, which might elevate CD8+ T-cell infiltration and CD8+ T-cell-mediated cytotoxicity to promote nCRT-induced antitumor immunity. Our study revealed proteomic profiles in LARC patients before nCRT and highlighted immune activation in the tumors of patients who achieved pCR. We identified FOSL2 as a promising biomarker to predict pCR and promote long-term DFS by contributing to CD8+ T-cell infiltration.
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Affiliation(s)
- Kailun Xu
- Department of Breast Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China; Zhejiang Provincial Clinical Research Center for Cancer, China; Cancer Center of Zhejiang University, China.
| | - Xiaoyang Yin
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China.
| | - Biting Zhou
- Zhejiang Provincial Clinical Research Center for Cancer, China; Cancer Center of Zhejiang University, China; Department of Radiation Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
| | - Xi Zheng
- Zhejiang Provincial Clinical Research Center for Cancer, China; Cancer Center of Zhejiang University, China; Department of Radiation Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
| | - Hao Wang
- Zhejiang Provincial Clinical Research Center for Cancer, China; Cancer Center of Zhejiang University, China; Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
| | - Jing Chen
- Zhejiang Provincial Clinical Research Center for Cancer, China; Cancer Center of Zhejiang University, China; Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
| | - Xue Cai
- Westlake Intelligent Biomarker Discovery Lab, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China; Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.
| | - Huanhuan Gao
- Westlake Intelligent Biomarker Discovery Lab, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China; Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.
| | - Xiaoming Xu
- Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
| | - Liuhong Wang
- Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
| | - Li Shen
- Department of Radiation Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
| | - Tiannan Guo
- Westlake Intelligent Biomarker Discovery Lab, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China; Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.
| | - Shu Zheng
- Zhejiang Provincial Clinical Research Center for Cancer, China; Cancer Center of Zhejiang University, China; Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
| | - Baosheng Li
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China.
| | - Yingkuan Shao
- Department of Breast Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China; Zhejiang Provincial Clinical Research Center for Cancer, China; Cancer Center of Zhejiang University, China.
| | - Jian Wang
- Zhejiang Provincial Clinical Research Center for Cancer, China; Cancer Center of Zhejiang University, China; Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
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Alnuaimi AR, Bottner J, Nair VA, Ali N, Alnakhli R, Dreyer E, Talaat IM, Busch H, Perner S, Kirfel J, Hamoudi R, Abdel-Rahman WM. Immunohistochemical Expression Analysis of Caldesmon Isoforms in Colorectal Carcinoma Reveals Interesting Correlations with Tumor Characteristics. Int J Mol Sci 2023; 24:2275. [PMID: 36768598 PMCID: PMC9916900 DOI: 10.3390/ijms24032275] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 01/07/2023] [Accepted: 01/10/2023] [Indexed: 01/26/2023] Open
Abstract
Colorectal cancer is a notorious disease, with almost half of the patients succumbing to the disease. The prevalence and incidence rates of colorectal cancer are increasing in many parts of the world, highlighting the need to discover new biomarkers for diagnosis and therapy. Caldesmon (CaD), an actin-binding protein that plays a significant role in controlling cell motility, has emerged as a promising biomarker. The CALD1 gene encodes CaD as multiple transcripts that mainly encode two protein isoforms: High-molecular-weight (h-CaD), expressed in smooth muscle, and low-molecular-weight (l-CaD), expressed in nonsmooth muscle cells. Most studies have suggested an oncogenic role of CaD in colorectal cancer, but the exact subcellular localization of the two CaD isoforms in tumor cells and stroma have not been clarified yet. Here, we analyzed tissue samples from 262 colorectal cancer patients by immunohistochemistry analysis using specific antibodies for l-CaD and h-CaD. The results showed elevated cytoplasmic expression levels of l-Cad in 187/262 (71.4%) cases. l-Cad was expressed at low levels in the normal colon mucosa and was also consistently expressed in the cancer-associated stroma of all cases, suggesting that it could play a role in modulating the tumor microenvironment. l-CaD expression in cancer cells was associated with preinvasive stages of cancer. Survival analysis indicated that patients with high l-CaD expression in tumor cells could respond poorly to selective chemotherapeutic 5FU, but not combination chemotherapy. h-CaD was expressed in colonic and vascular smooth muscle cells as expected and to a lesser extent in the tumor-associated stroma, but it was not expressed in the cancer cells or normal colon mucosal epithelial cells. Collectively, these data clarify how the expression patterns of CaD isoforms in colorectal cancer can have applications in the management of colorectal cancer patients.
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Affiliation(s)
- Alya R. Alnuaimi
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Justus Bottner
- Institute of Pathology, University Hospital Schleswig-Holstein, 23560 Luebeck, Germany
| | - Vidhya A. Nair
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Nival Ali
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Razaz Alnakhli
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Eva Dreyer
- Institute of Pathology, University Hospital Schleswig-Holstein, 23560 Luebeck, Germany
| | - Iman M. Talaat
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Hauke Busch
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- Luebeck Institute for Experimental Dermatology, University of Luebeck, 23562 Luebeck, Germany
| | - Sven Perner
- Institute of Pathology, University Hospital Schleswig-Holstein, 23560 Luebeck, Germany
| | - Jutta Kirfel
- Institute of Pathology, University Hospital Schleswig-Holstein, 23560 Luebeck, Germany
| | - Rifat Hamoudi
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- Division of Surgery and Interventional Science, University College London, London NW3 2PS, UK
| | - Wael M. Abdel-Rahman
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
- Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
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7
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Alnuaimi AR, Nair VA, Malhab LJB, Abu-Gharbieh E, Ranade AV, Pintus G, Hamad M, Busch H, Kirfel J, Hamoudi R, Abdel-Rahman WM. Emerging role of caldesmon in cancer: A potential biomarker for colorectal cancer and other cancers. World J Gastrointest Oncol 2022; 14:1637-1653. [PMID: 36187394 PMCID: PMC9516648 DOI: 10.4251/wjgo.v14.i9.1637] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 05/05/2022] [Accepted: 07/26/2022] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) is a devastating disease, mainly because of metastasis. As a result, there is a need to better understand the molecular basis of invasion and metastasis and to identify new biomarkers and therapeutic targets to aid in managing these tumors. The actin cytoskeleton and actin-binding proteins are known to play an important role in the process of cancer metastasis because they control and execute essential steps in cell motility and contractility as well as cell division. Caldesmon (CaD) is an actin-binding protein encoded by the CALD1 gene as multiple transcripts that mainly encode two protein isoforms: High-molecular-weight CaD, expressed in smooth muscle, and low-molecular weight CaD (l-CaD), expressed in nonsmooth muscle cells. According to our comprehensive review of the literature, CaD, particularly l-CaD, plays a key role in the development, metastasis, and resistance to chemoradiotherapy in colorectal, breast, and urinary bladder cancers and gliomas, among other malignancies. CaD is involved in many aspects of the carcinogenic hallmarks, including epithelial mesenchymal transition via transforming growth factor-beta signaling, angiogenesis, resistance to hormonal therapy, and immune evasion. Recent data show that CaD is expressed in tumor cells as well as in stromal cells, such as cancer-associated fibroblasts, where it modulates the tumor microenvironment to favor the tumor. Interestingly, CaD undergoes selective tumor-specific splicing, and the resulting isoforms are generally not expressed in normal tissues, making these transcripts ideal targets for drug design. In this review, we will analyze these features of CaD with a focus on CRC and show how the currently available data qualify CaD as a potential candidate for targeted therapy in addition to its role in the diagnosis and prognosis of cancer.
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Affiliation(s)
- Alya R Alnuaimi
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Vidhya A Nair
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Lara J Bou Malhab
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Eman Abu-Gharbieh
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
- Department of Clinical Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Anu Vinod Ranade
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
- Department of Basic Medical Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Gianfranco Pintus
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
- Department of Medical Laboratory Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
- Department of Biomedical Sciences, University of Sassari, Sassari 07100, Italy
| | - Mohamad Hamad
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
- Department of Medical Laboratory Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Hauke Busch
- University Cancer Center Schleswig-Holstein and Luebeck Institute for Experimental Dermatology, University of Luebeck, Luebeck 23560, Germany
| | - Jutta Kirfel
- Institute of Pathology, University Hospital Schleswig-Holstein, Luebeck 23560, Germany
| | - Rifat Hamoudi
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
- Department of Clinical Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
- Division of Surgery and Interventional Science, University College London, London WC1E 6BT, United Kingdom
| | - Wael M Abdel-Rahman
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
- Department of Medical Laboratory Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
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8
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Wang H, Ji D, Tian H, Gao Z, Song C, Jia J, Cui X, Zhong L, Shen J, Gu J. Predictive value of proteomic markers for advanced rectal cancer with neoadjuvant chemoradiotherapy. BMC Cancer 2022; 22:868. [PMID: 35945555 PMCID: PMC9361520 DOI: 10.1186/s12885-022-09960-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 07/21/2022] [Indexed: 11/18/2022] Open
Abstract
Background Preoperative neoadjuvant chemoradiation (nCRT) has been the standard treatment for locally advanced rectal cancer. Serum biomarkers to stratify patients with respect to prognosis and response to nCRT are needed due to the diverse response to the therapy. Methods Thirteen paired pre- and post-nCRT sera from rectal cancer patients were analyzed by isobaric tags for relative and absolute quantitation (iTRAQ) method. Twenty-five proteins were selected for validation by parallel reaction monitoring (PRM) in ninety-one patients. Results Totally, 310 proteins were identified and quantified in sera samples. Reactome pathway analysis showed that the immune activation-related pathways were enriched in response to nCRT. Twenty-five proteins were selected for further validation. PRM result showed that the level of PZP was higher in pathological complete response (pCR) patients than non-pCR patients. The Random Forest algorithm identified a prediction model composed of 10 protein markers, which allowed discrimination between pCR patients and non-pCR patients (area under the curve (AUC) = 0.886 on testing set). Higher HEP2 and GELS or lower S10A8 in baseline sera were associated with better prognosis. Higher APOA1 in post nCRT sera was associated with better disease-free survival (DFS). Conclusions We identified and confirmed a 10-protein panel for nCRT response prediction and four potential biomarkers HEP2, GELS, S10A8 and APOA1 for prognosis of rectal cancer based on iTRAQ-based comparative proteomics screening and PRM-based targeted proteomic validation. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09960-z.
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Affiliation(s)
- Hanyang Wang
- Key Laboratory of Carcinogenesis and Translational Research, (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, No. 52 Fucheng Rd, Haidian District, Beijing, 100142, China
| | - Dengbo Ji
- Key Laboratory of Carcinogenesis and Translational Research, (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, No. 52 Fucheng Rd, Haidian District, Beijing, 100142, China
| | - Huifang Tian
- Central Laboratory, Peking University Cancer Hospital & Institute, Beijing, China
| | - Zhaoya Gao
- Peking University S.G. Hospital, Beijing, China
| | - Can Song
- School of Life Sciences, Tsinghua University, Beijing, 100084, China.,Peking-Tsinghua Center for Life Sciences, Beijing, China
| | - Jinying Jia
- Key Laboratory of Carcinogenesis and Translational Research, (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, No. 52 Fucheng Rd, Haidian District, Beijing, 100142, China
| | - Xinxin Cui
- Key Laboratory of Carcinogenesis and Translational Research, (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, No. 52 Fucheng Rd, Haidian District, Beijing, 100142, China
| | - Lijun Zhong
- Medical and Health Analytical Center, Peking University Health Science Center, Beijing, 100191, China
| | - Jing Shen
- Central Laboratory, Peking University Cancer Hospital & Institute, Beijing, China.
| | - Jin Gu
- Key Laboratory of Carcinogenesis and Translational Research, (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, No. 52 Fucheng Rd, Haidian District, Beijing, 100142, China. .,Peking University S.G. Hospital, Beijing, China. .,Peking-Tsinghua Center for Life Sciences, Beijing, China.
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9
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Wanigasooriya K, Barros-Silva JD, Tee L, El-asrag ME, Stodolna A, Pickles OJ, Stockton J, Bryer C, Hoare R, Whalley CM, Tyler R, Sillo T, Yau C, Ismail T, Beggs AD. Patient Derived Organoids Confirm That PI3K/AKT Signalling Is an Escape Pathway for Radioresistance and a Target for Therapy in Rectal Cancer. Front Oncol 2022; 12:920444. [PMID: 35860583 PMCID: PMC9289101 DOI: 10.3389/fonc.2022.920444] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 05/23/2022] [Indexed: 11/17/2022] Open
Abstract
Objectives Partial or total resistance to preoperative chemoradiotherapy occurs in more than half of locally advanced rectal cancer patients. Several novel or repurposed drugs have been trialled to improve cancer cell sensitivity to radiotherapy, with limited success. We aimed to understand the mechanisms of resistance to chemoradiotherapy in rectal cancer using patient derived organoid models. Design To understand the mechanisms underlying this resistance, we compared the pre-treatment transcriptomes of patient-derived organoids (PDO) with measured radiotherapy sensitivity to identify biological pathways involved in radiation resistance coupled with single cell sequencing, genome wide CRISPR-Cas9 and targeted drug screens. Results RNA sequencing enrichment analysis revealed upregulation of PI3K/AKT/mTOR and epithelial mesenchymal transition pathway genes in radioresistant PDOs. Single-cell sequencing of pre & post-irradiation PDOs showed mTORC1 and PI3K/AKT upregulation, which was confirmed by a genome-wide CRSIPR-Cas9 knockout screen using irradiated colorectal cancer (CRC) cell lines. We then tested the efficiency of dual PI3K/mTOR inhibitors in improving cancer cell sensitivity to radiotherapy. After irradiation, significant AKT phosphorylation was detected (p=0.027) which was abrogated with dual PI3K/mTOR inhibitors and lead to significant radiosensitisation of the HCT116 cell line and radiation resistant PDO lines. Conclusions The PI3K/AKT/mTOR pathway upregulation contributes to radioresistance and its targeted pharmacological inhibition leads to significant radiosensitisation in CRC organoids, making it a potential target for clinical trials.
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Affiliation(s)
- Kasun Wanigasooriya
- Institute of Cancer and Genomic Science, College of Medical and Dental Science, University of Birmingham, Birmingham, United Kingdom
- Department of Surgery, University Hospitals Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
| | - Joao D. Barros-Silva
- Institute of Cancer and Genomic Science, College of Medical and Dental Science, University of Birmingham, Birmingham, United Kingdom
| | - Louise Tee
- Institute of Cancer and Genomic Science, College of Medical and Dental Science, University of Birmingham, Birmingham, United Kingdom
| | - Mohammed E. El-asrag
- Institute of Cancer and Genomic Science, College of Medical and Dental Science, University of Birmingham, Birmingham, United Kingdom
| | - Agata Stodolna
- Institute of Cancer and Genomic Science, College of Medical and Dental Science, University of Birmingham, Birmingham, United Kingdom
| | - Oliver J. Pickles
- Institute of Cancer and Genomic Science, College of Medical and Dental Science, University of Birmingham, Birmingham, United Kingdom
- Department of Surgery, University Hospitals Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
| | - Joanne Stockton
- Institute of Cancer and Genomic Science, College of Medical and Dental Science, University of Birmingham, Birmingham, United Kingdom
| | - Claire Bryer
- Institute of Cancer and Genomic Science, College of Medical and Dental Science, University of Birmingham, Birmingham, United Kingdom
| | - Rachel Hoare
- Institute of Cancer and Genomic Science, College of Medical and Dental Science, University of Birmingham, Birmingham, United Kingdom
| | - Celina M. Whalley
- Institute of Cancer and Genomic Science, College of Medical and Dental Science, University of Birmingham, Birmingham, United Kingdom
| | - Robert Tyler
- Institute of Cancer and Genomic Science, College of Medical and Dental Science, University of Birmingham, Birmingham, United Kingdom
- Department of Surgery, University Hospitals Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
| | - Toritseju Sillo
- Institute of Cancer and Genomic Science, College of Medical and Dental Science, University of Birmingham, Birmingham, United Kingdom
- Department of Surgery, University Hospitals Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
| | - Christopher Yau
- Institute of Cancer and Genomic Science, College of Medical and Dental Science, University of Birmingham, Birmingham, United Kingdom
| | - Tariq Ismail
- Department of Surgery, University Hospitals Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
| | - Andrew D. Beggs
- Institute of Cancer and Genomic Science, College of Medical and Dental Science, University of Birmingham, Birmingham, United Kingdom
- Department of Surgery, University Hospitals Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
- *Correspondence: Andrew D. Beggs,
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10
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Lawrence YR, Shacham-Shmueli E, Yarom N, Khaikin M, Venturero M, Apter S, Inbar Y, Symon Z, Aderka D, Halpern N, Berger R, Boursi B, Jacobson G, Raskin S, Ackerstein A, Margalit O, Appel S, Schvimer M, Crochiere M, Yang F, Landesman Y, Rashal T, Shacham S, Golan T. Nuclear Export Inhibition for Radiosensitization; a Proof-of-Concept Phase I Clinical Trial of Selinexor (KPT-330) Combined with Neoadjuvant Chemoradiation in Locally Advanced Rectal Cancer. Int J Radiat Oncol Biol Phys 2022; 114:250-255. [PMID: 35667526 DOI: 10.1016/j.ijrobp.2022.05.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 05/05/2022] [Accepted: 05/18/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND Selinexor (KPT-330, XPOVIO®) is a first-in-class, oral selective inhibitor of nuclear export (SINE) compound that blocks XPO1, forcing nuclear retention of tumor suppressor proteins. Selinexor potentiates radiation-induced cell death in preclinical models, but has yet to be combined with radiation in the clinic. We hypothesized that selinexor would increase the activity of neoadjuvant fluoropyrimidine-based chemoradiation (ChRT) for locally advanced rectal cancer (LARC). METHODS A phase I clinical trial of selinexor plus ChRT for LARC was performed, 3+3 design. Eligibility criteria included stage II-III LARC requiring neoadjuvant chemoradiation, and ECOG 0-1 performance status. Patients received 50.4 Gy over 5.5 weeks plus capecitabine 825 mg/m2 twice daily on radiation days. Three selinexor dose-levels were tested: 1) 20 mg/m2 twice weekly concurrent with ChRT, 2) 35 mg/m2 twice weekly concurrent with ChRT, and 3) 35 mg/m2 twice weekly concurrent with ChRT, and for an additional two weeks. Subsequently, patients underwent definitive curative resection. DNA variant analysis and RNAseq were performed to characterize responders. RESULTS Eleven patients were enrolled, median age 60.5 years, six were stage III. Nine completed selinexor plus ChRT; two patients withdrew consent. Side effects attributed to selinexor included fatigue, hyponatremia and mild thrombocytopenia. Dose level 3 was poorly tolerated, (dehydration, anorexia). Of the 9 patients who completed treatment, median volumetric tumor shrinkage was 93% (IQR 59-98). Comparing baseline clinical stage to final pathological stage, 82% of patients were down-staged. Two patients experienced a complete / near-complete pathological response. Expression of PTGS2 and CD177 were identified as potential biomarkers of response. CONCLUSION Selinexor combined with neoadjuvant ChRT in LARC is well tolerated. Potential biomarkers were identified based upon a preliminary analysis.
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Affiliation(s)
- Yaacov R Lawrence
- Sheba Medical Center affiliated with Tel Aviv University, Israel; Department Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University.
| | | | | | - Marat Khaikin
- Sheba Medical Center affiliated with Tel Aviv University, Israel
| | | | - Sara Apter
- Sheba Medical Center affiliated with Tel Aviv University, Israel
| | - Yael Inbar
- Sheba Medical Center affiliated with Tel Aviv University, Israel
| | - Zvi Symon
- Sheba Medical Center affiliated with Tel Aviv University, Israel
| | - Dan Aderka
- Sheba Medical Center affiliated with Tel Aviv University, Israel
| | - Naama Halpern
- Sheba Medical Center affiliated with Tel Aviv University, Israel
| | - Raanan Berger
- Sheba Medical Center affiliated with Tel Aviv University, Israel
| | - Ben Boursi
- Sheba Medical Center affiliated with Tel Aviv University, Israel
| | - Galia Jacobson
- Sheba Medical Center affiliated with Tel Aviv University, Israel; Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Stephen Raskin
- Sheba Medical Center affiliated with Tel Aviv University, Israel
| | - Aliza Ackerstein
- Sheba Medical Center affiliated with Tel Aviv University, Israel
| | - Ofer Margalit
- Sheba Medical Center affiliated with Tel Aviv University, Israel
| | - Sarit Appel
- Sheba Medical Center affiliated with Tel Aviv University, Israel
| | - Michael Schvimer
- Sheba Medical Center affiliated with Tel Aviv University, Israel
| | | | - Fan Yang
- Karyopharm Therapeutics, Newton, MA, USA
| | | | - Tami Rashal
- Sheba Medical Center affiliated with Tel Aviv University, Israel
| | | | - Talia Golan
- Sheba Medical Center affiliated with Tel Aviv University, Israel
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11
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Chauvin A, Bergeron D, Vencic J, Lévesque D, Paquette B, Scott MS, Boisvert FM. Downregulation of KRAB zinc finger proteins in 5-fluorouracil resistant colorectal cancer cells. BMC Cancer 2022; 22:363. [PMID: 35379199 PMCID: PMC8981854 DOI: 10.1186/s12885-022-09417-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 03/15/2022] [Indexed: 12/23/2022] Open
Abstract
Radio-chemotherapy with 5-flu orouracil (5-FU) is the standard of care treatment for patients with colorectal cancer, but it is only effective for a third of them. Despite our understanding of the mechanism of action of 5-FU, drug resistance remains a significant limitation to the clinical use of 5-FU, as both intrinsic and acquired chemoresistance represents the major obstacles for the success of 5-FU-based chemotherapy. In order to identify the mechanism of acquired resistance, 5-FU chemoresistance was induced in CRC cell lines by passaging cells with increasing concentrations of 5-FU. To study global molecular changes, quantitative proteomics and transcriptomics analyses were performed on these cell lines, comparing the resistant cells as well as the effect of chemo and radiotherapy. Interestingly, a very high proportion of downregulated genes were annotated as transcription factors coding for Krüppel-associated box (KRAB) domain-containing zinc-finger proteins (KZFPs), the largest family of transcriptional repressors. Among nearly 350 KRAB-ZFPs, almost a quarter were downregulated after the induction of a 5-FU-resistance including a common one between the three CRC cell lines, ZNF649, whose role is still unknown. To confirm the observations of the proteomic and transcriptomic approaches, the abundance of 20 different KZFPs and control mRNAs was validated by RT-qPCR. In fact, several KZFPs were no longer detectable using qPCR in cell lines resistant to 5-FU, and the KZFPs that were downregulated only in one or two cell lines showed similar pattern of expression as measured by the omics approaches. This proteomic, transcriptomic and genomic analysis of intrinsic and acquired resistance highlights a possible new mechanism involved in the cellular adaptation to 5-FU and therefore identifies potential new therapeutic targets to overcome this resistance.
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Affiliation(s)
- Anaïs Chauvin
- Department of Immunology and Cell Biology, Université de Sherbrooke, 3201 Jean-Mignault, Sherbrooke, Québec, J1E 4K8, Canada
| | - Danny Bergeron
- Department of Biochemistry and Functional Genomics, Université de Sherbrooke, 3201 Jean-Mignault, Sherbrooke, Québec, J1E 4K8, Canada
| | - Jean Vencic
- Department of Biochemistry and Functional Genomics, Université de Sherbrooke, 3201 Jean-Mignault, Sherbrooke, Québec, J1E 4K8, Canada
| | - Dominique Lévesque
- Department of Immunology and Cell Biology, Université de Sherbrooke, 3201 Jean-Mignault, Sherbrooke, Québec, J1E 4K8, Canada
| | - Benoit Paquette
- Department of Nuclear Medicine and Radiobiology, Université de Sherbrooke, 3201 Jean-Mignault, Sherbrooke, Québec, J1E 4K8, Canada
| | - Michelle S Scott
- Department of Biochemistry and Functional Genomics, Université de Sherbrooke, 3201 Jean-Mignault, Sherbrooke, Québec, J1E 4K8, Canada
| | - François-Michel Boisvert
- Department of Immunology and Cell Biology, Université de Sherbrooke, 3201 Jean-Mignault, Sherbrooke, Québec, J1E 4K8, Canada.
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12
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Luo H, Ge H. Application of Proteomics in the Discovery of Radiosensitive Cancer Biomarkers. Front Oncol 2022; 12:852791. [PMID: 35280744 PMCID: PMC8904368 DOI: 10.3389/fonc.2022.852791] [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: 01/11/2022] [Accepted: 02/04/2022] [Indexed: 12/21/2022] Open
Abstract
Radiation therapy remains an important component of cancer treatment. Gene-encoded proteins were the actual executors of cellular functions. Proteomic was a novel technology that can systematically analysis protein composition and measure their levels of change, this was a high throughput method, and were the import tools in the post genomic era. In recent years, rapid progress of proteomic have been made in the study of cancer mechanism, diagnosis, and treatment. This article elaborates current advances and future directions of proteomics in the discovery of radiosensitive cancer biomarkers.
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Affiliation(s)
- Hui Luo
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Hong Ge
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
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13
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Li M, Xiao Q, Venkatachalam N, Hofheinz RD, Veldwijk MR, Herskind C, Ebert MP, Zhan T. Predicting response to neoadjuvant chemoradiotherapy in rectal cancer: from biomarkers to tumor models. Ther Adv Med Oncol 2022; 14:17588359221077972. [PMID: 35222695 PMCID: PMC8864271 DOI: 10.1177/17588359221077972] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 01/14/2022] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is a major contributor to cancer-associated morbidity worldwide and over one-third of CRC is located in the rectum. Neoadjuvant chemoradiotherapy (nCRT) followed by surgical resection is commonly applied to treat locally advanced rectal cancer (LARC). In this review, we summarize current and novel concepts of neoadjuvant therapy for LARC such as total neoadjuvant therapy and describe how these developments impact treatment response. Moreover, as response to nCRT is highly divergent in rectal cancers, we discuss the role of potential predictive biomarkers. We review recent advances in biomarker discovery, from a clinical as well as a histopathological and molecular perspective. Furthermore, the role of emerging predictive biomarkers derived from the tumor environment such as immune cell composition and gut microbiome is presented. Finally, we describe how different tumor models such as patient-derived cancer organoids are used to identify novel predictive biomarkers for chemoradiotherapy (CRT) in rectal cancer.
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Affiliation(s)
- Moying Li
- Medical Faculty Mannheim, Heidelberg
University, Mannheim
| | - Qiyun Xiao
- Department of Medicine II, Mannheim University
Hospital, Medical Faculty Mannheim, Heidelberg University, Mannheim,
Germany
| | - Nachiyappan Venkatachalam
- Department of Medicine II, Mannheim University
Hospital, Medical Faculty Mannheim, Heidelberg University, Mannheim,
Germany
| | - Ralf-Dieter Hofheinz
- Department of Medicine III, Mannheim University
Hospital, Medical Faculty Mannheim, Heidelberg University, Mannheim,
GermanyMannheim Cancer Center, Medical Faculty Mannheim, Heidelberg
University, Mannheim, Germany
| | - Marlon R. Veldwijk
- Department of Radiation Oncology, Mannheim
University Hospital, Medical Faculty Mannheim, Heidelberg University,
Mannheim, Germany
| | - Carsten Herskind
- Department of Radiation Oncology, Mannheim
University Hospital, Medical Faculty Mannheim, Heidelberg University,
Mannheim, Germany
| | - Matthias P. Ebert
- Department of Medicine II, Mannheim University
Hospital, Medical Faculty Mannheim, Heidelberg University, Mannheim,
GermanyMannheim Cancer Center, Medical Faculty Mannheim, Heidelberg
University, Mannheim, GermanyDKFZ-Hector Cancer Institute, University
Medical Center Mannheim, Mannheim, Germany
| | - Tianzuo Zhan
- Department of Internal Medicine II, Mannheim
University Hospital, Medical Faculty Mannheim, Heidelberg University,
Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, GermanyMannheim Cancer Center,
Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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14
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Sun Y, Lin Y, Deng Y, Wu X, Zhong J, Huang Y, Jiang W, Chi P. Identification of proteins associated with treatment response of neoadjuvant chemoradiotherapy in rectal mucinous adenocarcinoma by co-expression network analysis based on proteomic analysis. J Proteomics 2022; 254:104472. [PMID: 34990823 DOI: 10.1016/j.jprot.2021.104472] [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: 08/07/2021] [Revised: 12/17/2021] [Accepted: 12/29/2021] [Indexed: 11/19/2022]
Abstract
For rectal mucinous adenocarcinoma (MAC), identifying biomarkers of neoadjuvant chemoradiotherapy (NCRT) response has become imperative. This study applied label-free mass spectrometry and weighted gene co-expression network analysis to identify hub proteins in association with the NCRT response in 20 rectal MAC patients. We identified 131 differentially abundant proteins and 7 candidate proteins associated with the NCRT response. The immunostaining expressions of six proteins (ENOA, ILEU, MDHM, RM11, PTGDS, and RL3) were significantly associated with the NCRT response. Logistic regression analysis revealed that ENOA (OR = 6.275, P = 0.006) was independent risk hub protein for the NCRT response. Tow hub proteins (ENOA and PTGDS) were identified as significant risk factors by Cox regression analysis. A prognostic risk score system was constructed: risk score = (0.910 × EXPENOA) + (-1.519 × EXPPTGDS), and found to be an independent predictor of DFS in rectal MAC patients (HR = 10.308, P < 0.001). Our study suggested that ENOA may be a novel biomarker for the NCRT response and prognosis in rectal MAC patients. A two-hub-protein-based risk score system might be used for predicting tumor recurrence in rectal MAC patients. SIGNIFICANCE: NCRT resistance is a major problem in the treatment of rectal MAC patients. Identifying robust predictive biomarkers for NCRT resistance is beneficial to the stratified treatment of rectal MAC patients. In this study, label-free mass spectrometry and weighted gene co-expression network analysis identified ENOA as a potential novel biomarker for the NCRT response and prognosis. ENOA may be involved in the process of the NCRT resistance and tumor recurrence through the carbon metabolism pathway.
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Affiliation(s)
- Yanwu Sun
- Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, PR China; Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, PR China; Minimal Invasive Center, Fujian Medical University Union Hospital, Fuzhou, Fujian, PR China; Fujian Medical University, Fuzhou, Fujian, PR China
| | - Yu Lin
- Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, PR China; Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, PR China; Minimal Invasive Center, Fujian Medical University Union Hospital, Fuzhou, Fujian, PR China; Fujian Medical University, Fuzhou, Fujian, PR China
| | - Yu Deng
- Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, PR China; Fujian Medical University, Fuzhou, Fujian, PR China
| | - Xuejing Wu
- Department of Pathology, Fujian Medical University Union Hospital, Fuzhou, Fujian, PR China
| | | | - Ying Huang
- Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, PR China; Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, PR China; Minimal Invasive Center, Fujian Medical University Union Hospital, Fuzhou, Fujian, PR China; Fujian Medical University, Fuzhou, Fujian, PR China
| | - Weizhong Jiang
- Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, PR China; Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, PR China; Minimal Invasive Center, Fujian Medical University Union Hospital, Fuzhou, Fujian, PR China; Fujian Medical University, Fuzhou, Fujian, PR China.
| | - Pan Chi
- Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, PR China; Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, PR China; Minimal Invasive Center, Fujian Medical University Union Hospital, Fuzhou, Fujian, PR China; Fujian Medical University, Fuzhou, Fujian, PR China.
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15
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Hämäläinen S, Kareinen L, Sukura A, Kareinen I. Carboxypeptidase A3 expression in canine mast cell tumors and tissue-resident mast cells. Vet Pathol 2021; 59:236-243. [PMID: 34894899 PMCID: PMC8928232 DOI: 10.1177/03009858211062636] [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] [Indexed: 11/16/2022]
Abstract
Mast cell tumors (MCTs) are one of the most common cutaneous malignancies in dogs. Previous studies have reported expression of mast cell–specific proteases chymase and tryptase in canine cutaneous MCTs and in connective tissue and mucosal mast cells. In humans and rodents, mast cells express an additional specific protease, carboxypeptidase A3 (CPA3). In this article, we describe CPA3 immunoreactivity in connective tissue, visceral, mucosal, and neoplastic mast cells in dogs. Positive immunolabeling for CPA3 was observed in nonneoplastic mast cells in 20/20 formalin-fixed paraffin-embedded normal tissues (skin, liver, spleen, intestine), and in 63/63 MCTs irrespective of their histological grade. CPA3 protein expression was comparable to that of c-kit in both the nonneoplastic and neoplastic mast cells. Three distinct labeling patterns (membranous, diffuse, and focal cytoplasmic) were observed for CPA3 in MCTs. The focal cytoplasmic labeling pattern was associated with high-grade MCTs staged with the Kiupel 2-tier grading criteria. We propose CPA3 as a novel immunohistochemical marker for canine mast cells in health and disease.
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16
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Proteomic Research on the Antitumor Properties of Medicinal Mushrooms. Molecules 2021; 26:molecules26216708. [PMID: 34771120 PMCID: PMC8588050 DOI: 10.3390/molecules26216708] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/27/2021] [Accepted: 11/02/2021] [Indexed: 12/22/2022] Open
Abstract
Medicinal mushrooms are increasingly being recognized as an important therapeutic modality in complementary oncology. Until now, more than 800 mushroom species have been known to possess significant pharmacological properties, of which antitumor and immunomodulatory properties have been the most researched. Besides a number of medicinal mushroom preparations being used as dietary supplements and nutraceuticals, several isolates from mushrooms have been used as official antitumor drugs in clinical settings for several decades. Various proteomic approaches allow for the identification of a large number of differentially regulated proteins serendipitously, thereby providing an important platform for a discovery of new potential therapeutic targets and approaches as well as biomarkers of malignant disease. This review is focused on the current state of proteomic research into antitumor mechanisms of some of the most researched medicinal mushroom species, including Phellinus linteus, Ganoderma lucidum, Auricularia auricula, Agrocybe aegerita, Grifola frondosa, and Lentinus edodes, as whole body extracts or various isolates, as well as of complex extract mixtures.
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17
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Behari J, Borkar P, Vindu A, Dandewad V, Upadrasta S, Shanmugam D, Seshadri V. Conserved RNA Binding Activity of Phosphatidyl Inositol 5-Phosphate 4-Kinase (PIP4K2A). Front Mol Biosci 2021; 8:631281. [PMID: 34124142 PMCID: PMC8194828 DOI: 10.3389/fmolb.2021.631281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 04/28/2021] [Indexed: 12/04/2022] Open
Abstract
Plasmodium falciparum is a causative agent for malaria and has a complex life cycle in human and mosquito hosts. During its life cycle, the malarial parasite Plasmodium goes through different asexual and sexual stages, in humans and mosquitoes. Expression of stage-specific proteins is important for successful completion of its life cycle and requires tight gene regulation. In the case of Plasmodium, due to relative paucity of the transcription factors, it is postulated that posttranscriptional regulation plays an important role in stage-specific gene expression. Translation repression of specific set of mRNA has been reported in gametocyte stages of the parasite. A conserved element present in the 3′UTR of some of these transcripts was identified. Phosphatidylinositol 5-phosphate 4-kinase (PIP4K2A) was identified as the protein that associates with these RNA. We now show that the RNA binding activity of PIP4K2A is independent of its kinase activity. We also observe that PIP4K2A is imported into the parasite from the host on Plasmodium berghei and Toxoplasma gondii. The RNA binding activity of PIP4K2A seems to be conserved across species from Drosophila and C. elegans to humans, suggesting that the RNA binding activity of PIP4K may be important, and there may be host transcripts that may be regulated by PIP4K2A. These results identify a novel RNA binding role for PIP4K2A that may not only play a role in Plasmodium propagation but may also function in regulating gene expression in multicellular organisms.
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Affiliation(s)
- Jatin Behari
- National Centre for Cell Science, Pune, India.,Department of Biotechnology, SPPU, Pune, India
| | - Pranita Borkar
- National Centre for Cell Science, Pune, India.,Department of Biotechnology, SPPU, Pune, India
| | - Arya Vindu
- National Centre for Cell Science, Pune, India.,Department of Biotechnology, SPPU, Pune, India
| | - Vishal Dandewad
- National Centre for Cell Science, Pune, India.,Department of Biotechnology, SPPU, Pune, India
| | - Sindhuri Upadrasta
- CSIR-National Chemical Laboratory, Pune, India.,Academy of Scientific and Innovative Research, Ghaziabad, India
| | - Dhanasekaran Shanmugam
- CSIR-National Chemical Laboratory, Pune, India.,Academy of Scientific and Innovative Research, Ghaziabad, India
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18
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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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19
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Wilkins A, Fontana E, Nyamundanda G, Ragulan C, Patil Y, Mansfield D, Kingston J, Errington-Mais F, Bottomley D, von Loga K, Bye H, Carter P, Tinkler-Hundal E, Noshirwani A, Downs J, Dillon M, Demaria S, Sebag-Montefiore D, Harrington K, West N, Melcher A, Sadanandam A. Differential and longitudinal immune gene patterns associated with reprogrammed microenvironment and viral mimicry in response to neoadjuvant radiotherapy in rectal cancer. J Immunother Cancer 2021; 9:e001717. [PMID: 33678606 PMCID: PMC7939016 DOI: 10.1136/jitc-2020-001717] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/14/2021] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Rectal cancers show a highly varied response to neoadjuvant radiotherapy/chemoradiation (RT/CRT) and the impact of the tumor immune microenvironment on this response is poorly understood. Current clinical tumor regression grading systems attempt to measure radiotherapy response but are subject to interobserver variation. An unbiased and unique histopathological quantification method (change in tumor cell density (ΔTCD)) may improve classification of RT/CRT response. Furthermore, immune gene expression profiling (GEP) may identify differences in expression levels of genes relevant to different radiotherapy responses: (1) at baseline between poor and good responders, and (2) longitudinally from preradiotherapy to postradiotherapy samples. Overall, this may inform novel therapeutic RT/CRT combination strategies in rectal cancer. METHODS We generated GEPs for 53 patients from biopsies taken prior to preoperative radiotherapy. TCD was used to assess rectal tumor response to neoadjuvant RT/CRT and ΔTCD was subjected to k-means clustering to classify patients into different response categories. Differential gene expression analysis was performed using statistical analysis of microarrays, pathway enrichment analysis and immune cell type analysis using single sample gene set enrichment analysis. Immunohistochemistry was performed to validate specific results. The results were validated using 220 pretreatment samples from publicly available datasets at metalevel of pathway and survival analyses. RESULTS ΔTCD scores ranged from 12.4% to -47.7% and stratified patients into three response categories. At baseline, 40 genes were significantly upregulated in poor (n=12) versus good responders (n=21), including myeloid and stromal cell genes. Of several pathways showing significant enrichment at baseline in poor responders, epithelial to mesenchymal transition, coagulation, complement activation and apical junction pathways were validated in external cohorts. Unlike poor responders, good responders showed longitudinal (preradiotherapy vs postradiotherapy samples) upregulation of 198 immune genes, reflecting an increased T-cell-inflamed GEP, type-I interferon and macrophage populations. Longitudinal pathway analysis suggested viral-like pathogen responses occurred in post-treatment resected samples compared with pretreatment biopsies in good responders. CONCLUSION This study suggests potentially druggable immune targets in poor responders at baseline and indicates that tumors with a good RT/CRT response reprogrammed from immune "cold" towards an immunologically "hot" phenotype on treatment with radiotherapy.
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Affiliation(s)
- Anna Wilkins
- Division of Radiotherapy and Imaging, Institute of Cancer Research, London, UK
- The Francis Crick Institute, London, UK
| | - Elisa Fontana
- Division of Molecular Pathology, Institute of Cancer Research, London, UK
- Current Affiliation: Sarah Cannon Research Institute, London, UK
| | - Gift Nyamundanda
- Division of Molecular Pathology, Institute of Cancer Research, London, UK
| | | | - Yatish Patil
- Division of Molecular Pathology, Institute of Cancer Research, London, UK
| | - David Mansfield
- Division of Radiotherapy and Imaging, Institute of Cancer Research, London, UK
| | - Jennifer Kingston
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK
| | - Fiona Errington-Mais
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK
| | - Daniel Bottomley
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK
| | - Katharina von Loga
- Division of Molecular Pathology, Institute of Cancer Research, London, UK
- The Royal Marsden Hospital, London, UK
| | - Hannah Bye
- Division of Molecular Pathology, Institute of Cancer Research, London, UK
- The Royal Marsden Hospital, London, UK
| | - Paul Carter
- Division of Molecular Pathology, Institute of Cancer Research, London, UK
- The Royal Marsden Hospital, London, UK
| | - Emma Tinkler-Hundal
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK
| | - Amir Noshirwani
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK
| | - Jessica Downs
- Division of Cancer Biology, Institute of Cancer Research, London, UK
| | - Magnus Dillon
- Division of Radiotherapy and Imaging, Institute of Cancer Research, London, UK
| | | | | | - Kevin Harrington
- Division of Radiotherapy and Imaging, Institute of Cancer Research, London, UK
| | - Nick West
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK
| | - Alan Melcher
- Division of Radiotherapy and Imaging, Institute of Cancer Research, London, UK
| | - Anguraj Sadanandam
- Division of Molecular Pathology, Institute of Cancer Research, London, UK
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20
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Jakopovic B, Horvatić A, Klobučar M, Gelemanović A, Grbčić P, Oršolić N, Jakopovich I, Kraljević Pavelić S. Treatment With Medicinal Mushroom Extract Mixture Inhibits Translation and Reprograms Metabolism in Advanced Colorectal Cancer Animal Model as Evidenced by Tandem Mass Tags Proteomics Analysis. Front Pharmacol 2020; 11:1202. [PMID: 32973493 PMCID: PMC7472604 DOI: 10.3389/fphar.2020.01202] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 07/23/2020] [Indexed: 01/01/2023] Open
Abstract
Colorectal cancer (CRC) is the third most frequent cancer type in both males and females, with about 35% of patients being diagnosed in stage IV metastatic disease. Despite advancements in treatment, life expectancy in patients with metastatic disease is still not satisfying. Due to frequent drug resistance during conventional and targeted cancer treatments, the development and testing of multi-target therapies is an important research field. Medicinal mushrooms specific isolated compounds as well as complex extract mixtures have been studied in depth, and many mushroom species have been proven to be non-toxic multi-target inhibitors of specific oncogenic pathways, as well as potent immunomodulators. In this study, we have performed a tandem mass tags qualitative and quantitative proteomic analyses of CT26.WT colon cancer tumor tissues from Balb/c mice treated with the studied medicinal mushroom extract mixture, with or without 5-fluorouracil. Besides significantly improved survival, obtained results reveal that Agarikon.1 alone, and in combination with 5-fluorouracil exert their anticancer effects by affecting several fundamental processes important in CRC progression. Bioinformatic analysis of up- and downregulated proteins revealed that ribosomal biogenesis and translation is downregulated in treatment groups, while the unfolded protein response (UPR), lipid metabolism and tricarboxylic acid cycle (TCA) are upregulated. Moreover, we found that many known clinical biomarkers and protein clusters important in CRC progression and prognosis are affected, which are a good basis for an expanded translational study of the herein presented treatment.
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Affiliation(s)
| | - Anita Horvatić
- Proteomics Laboratory, Faculty of Veterinary Medicine, University of Zagreb, Zagreb, Croatia
| | - Marko Klobučar
- Department of Biotechnology, University of Rijeka, Rijeka, Croatia
| | | | - Petra Grbčić
- Department of Biotechnology, University of Rijeka, Rijeka, Croatia
| | - Nada Oršolić
- Division of Animal Physiology, Faculty of Science, University of Zagreb, Zagreb, Croatia
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21
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Izzotti A, Ceccaroli C, Geretto M, Ruggieri FG, Schenone S, Di Maria E. Predicting Response to Neoadjuvant Therapy in Colorectal Cancer Patients the Role of Messenger-and Micro-RNA Profiling. Cancers (Basel) 2020; 12:cancers12061652. [PMID: 32580435 PMCID: PMC7352797 DOI: 10.3390/cancers12061652] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 06/12/2020] [Accepted: 06/17/2020] [Indexed: 12/19/2022] Open
Abstract
Colorectal cancer patients' responses to neoadjuvant therapy undergo broad inter-individual variations. The aim of this systematic review is to identify a molecular signature that is predictive of colon cancer downstaging and/or downgrading after neoadjuvant therapy. Among the hundreds analysed in the available studies, only 19 messenger-RNAs (mRNAs) and six micro-RNAs (miRNAs) were differentially expressed in responders versus non-responders in two or more independent studies. Therefore, a mRNA/miRNA signature can be designed accordingly, with limitations caused by the retrospective nature of these studies, the heterogeneity in study designs and the downgrading/downstaging assessment criteria. This signature can be proposed to tailor neoadjuvant therapy regimens on an individual basis.
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Affiliation(s)
- Alberto Izzotti
- Department of Experimental Medicine, University of Genova, 16132 Genova, Italy;
- IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy;
- Correspondence: ; Tel.: +39-010-353-8522
| | | | - Marta Geretto
- Department of Experimental Medicine, University of Genova, 16132 Genova, Italy;
| | | | - Sara Schenone
- Department of Health Sciences, University of Genova, 16132 Genova, Italy; (S.S.); (E.D.M.)
| | - Emilio Di Maria
- Department of Health Sciences, University of Genova, 16132 Genova, Italy; (S.S.); (E.D.M.)
- Unit of Medical Genetics, Galliera Hospital, 16128 Genoa, Italy
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22
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Holm M, Joenväärä S, Saraswat M, Tohmola T, Ristimäki A, Renkonen R, Haglund C. Preoperative Radiotherapy Leads to Significant Differences in the Plasma Protein Profile of Rectal Cancer Patients. Oncology 2020; 98:493-500. [PMID: 32294655 DOI: 10.1159/000505697] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Accepted: 12/31/2019] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Colorectal cancer (CRC) is the third most common cancer worldwide, accounting for 10% of the global cancer burden. Rectal cancer accounts for around 30% of CRC cases, and patients with resectable rectal cancer are often given preoperative radiotherapy (PRT) to reduce the rate of local recurrence. The human plasma proteome is an exceptionally complex proteome and ideal to study due to its ability to reflect the presence of diseases such as cancer and the ease of obtaining blood samples. Previous proteomic studies involving rectal cancer patients have mostly focused on the identification of proteins involved in resistance to radiotherapy. OBJECTIVE The aim of this study was to investigate the overall effects of PRT on plasma protein expression in rectal cancer patients, as there is a lack of such studies. METHODS Here, we have used mass spectrometry and subsequent statistical analyses to analyze the plasma samples of 30 rectal cancer patients according to PRT status (positive or negative) and tumor stage (II or III). RESULTS AND CONCLUSIONS We discovered 42 proteins whose levels differed significantly between stage II and III rectal cancer patients who did or did not receive PRT. This study shows that PRT, although localized to the pelvis, leads to measurable, tumor stage-specific changes in plasma protein expression. Future studies of plasma proteins should, when relevant, take this into account and be aware of the widespread effects that PRT has on the plasma proteome.
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Affiliation(s)
- Matilda Holm
- Department of Surgery, Faculty of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland, .,Department of Pathology, Faculty of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland, .,Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland, .,Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland,
| | - Sakari Joenväärä
- Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.,HUSLAB, Helsinki University Hospital, Helsinki, Finland
| | - Mayank Saraswat
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Tiialotta Tohmola
- Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.,HUSLAB, Helsinki University Hospital, Helsinki, Finland.,Department of Biosciences, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
| | - Ari Ristimäki
- Department of Pathology, Faculty of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,HUSLAB, Helsinki University Hospital, Helsinki, Finland
| | - Risto Renkonen
- Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.,HUSLAB, Helsinki University Hospital, Helsinki, Finland
| | - Caj Haglund
- Department of Surgery, Faculty of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,HUSLAB, Helsinki University Hospital, Helsinki, Finland
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23
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Park IJ, Yu YS, Mustafa B, Park JY, Seo YB, Kim GD, Kim J, Kim CM, Noh HD, Hong SM, Kim YW, Kim MJ, Ansari AA, Buonaguro L, Ahn SM, Yu CS. A Nine-Gene Signature for Predicting the Response to Preoperative Chemoradiotherapy in Patients with Locally Advanced Rectal Cancer. Cancers (Basel) 2020; 12:cancers12040800. [PMID: 32225122 PMCID: PMC7226472 DOI: 10.3390/cancers12040800] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 03/22/2020] [Accepted: 03/25/2020] [Indexed: 12/21/2022] Open
Abstract
Preoperative chemoradiotherapy (PCRT) and subsequent surgery is the standard multimodal treatment for locally advanced rectal cancer (LARC), albeit PCRT response varies among the individuals. This creates a dire necessity to identify a predictive model to forecast treatment response outcomes and identify patients who would benefit from PCRT. In this study, we performed a gene expression study using formalin-fixed paraffin-embedded (FFPE) tumor biopsy samples from 156 LARC patients (training cohort n = 60; validation cohort n = 96); we identified the nine-gene signature (FGFR3, GNA11, H3F3A, IL12A, IL1R1, IL2RB, NKD1, SGK2, and SPRY2) that distinctively differentiated responders from non-responders in the training cohort (accuracy = 86.9%, specificity = 84.8%, sensitivity = 81.5%) as well as in an independent validation cohort (accuracy = 81.0%, specificity = 79.4%, sensitivity = 82.3%). The signature was independent of all pathological and clinical features and was robust in predicting PCRT response. It is readily applicable to the clinical setting using FFPE samples and Food and Drug Administration (FDA) approved hardware and reagents. Predicting the response to PCRT may aid in tailored therapies for respective responders to PCRT and improve the oncologic outcomes for LARC patients.
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Affiliation(s)
- In Ja Park
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea;
| | - Yun Suk Yu
- CbsBioscience Inc., Daejeon 34036, Korea; (Y.S.Y.); (J.Y.P.); (Y.B.S.); (G.-D.K.); (J.K.); (C.M.K.); (H.D.N.)
| | - Bilal Mustafa
- Department of Health Sciences and Technology, Gachon Advanced Institute for Health Sciences and Technology, Gachon University, Incheon 21565, Korea;
| | - Jin Young Park
- CbsBioscience Inc., Daejeon 34036, Korea; (Y.S.Y.); (J.Y.P.); (Y.B.S.); (G.-D.K.); (J.K.); (C.M.K.); (H.D.N.)
| | - Yong Bae Seo
- CbsBioscience Inc., Daejeon 34036, Korea; (Y.S.Y.); (J.Y.P.); (Y.B.S.); (G.-D.K.); (J.K.); (C.M.K.); (H.D.N.)
| | - Gun-Do Kim
- CbsBioscience Inc., Daejeon 34036, Korea; (Y.S.Y.); (J.Y.P.); (Y.B.S.); (G.-D.K.); (J.K.); (C.M.K.); (H.D.N.)
- Department of Microbiology, College of Natural Sciences, Pukyong National University, Busan 48513, Korea
| | - Jinpyo Kim
- CbsBioscience Inc., Daejeon 34036, Korea; (Y.S.Y.); (J.Y.P.); (Y.B.S.); (G.-D.K.); (J.K.); (C.M.K.); (H.D.N.)
| | - Chang Min Kim
- CbsBioscience Inc., Daejeon 34036, Korea; (Y.S.Y.); (J.Y.P.); (Y.B.S.); (G.-D.K.); (J.K.); (C.M.K.); (H.D.N.)
| | - Hyun Deok Noh
- CbsBioscience Inc., Daejeon 34036, Korea; (Y.S.Y.); (J.Y.P.); (Y.B.S.); (G.-D.K.); (J.K.); (C.M.K.); (H.D.N.)
| | - Seung-Mo Hong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea;
- Asan Institute for Life Science, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (Y.W.K.); (M.-J.K.)
| | - Yeon Wook Kim
- Asan Institute for Life Science, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (Y.W.K.); (M.-J.K.)
| | - Mi-Ju Kim
- Asan Institute for Life Science, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (Y.W.K.); (M.-J.K.)
| | - Adnan Ahmad Ansari
- Department of Industrial and Environmental Engineering, Graduate School of Environment, Gachon University, Incheon 21565, Korea;
| | - Luigi Buonaguro
- Cancer Immunoregulation Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, “Fondazione Pascale”-IRCCS, 80131 Naples, Italy;
| | - Sung-Min Ahn
- Department of Genome Medicine and Science, College of Medicine, Gachon University, Incheon 21565, Korea
- Correspondence: (S.-M.A.); (C.-S.Y.); Tel.: +82-010-3648-7437 (S.-M.A.); +82-2-3010-3494 (C.-S.Y.)
| | - Chang-Sik Yu
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea;
- Correspondence: (S.-M.A.); (C.-S.Y.); Tel.: +82-010-3648-7437 (S.-M.A.); +82-2-3010-3494 (C.-S.Y.)
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24
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Cantor DI, Cheruku HR, Westacott J, Shin JS, Mohamedali A, Ahn SB. Proteomic investigations into resistance in colorectal cancer. Expert Rev Proteomics 2020; 17:49-65. [PMID: 31914823 DOI: 10.1080/14789450.2020.1713103] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Introduction: Despite advances in screening and treatment options, colorectal cancer (CRC) remains one of the most prevalent and lethal cancer subtypes. Resistance to cytotoxic or targeted therapy has remained a constant challenge to the treatment and long-term management of patients, attracting intense worldwide investigation since the 1950s. Through extensive investigations into the proteomic mechanisms and functions that convey resistance to therapy/s, researchers have become able to implicate alterations in several signaling pathways that provide and sustain resistance to treatment.Areas covered: In this review, we summarize how protein alterations are associated with resistance to therapy, with particular emphasis on CRC. An overview of the mechanisms of therapeutic resistance is described, highlighting recent studies which endeavor to elucidate the proteomic changes that are associated with the acquisition and promulgation of therapeutic resistance.Expert opinion: While cancers such as CRC have been intensively studied for decades, unresponsiveness and the resistance to therapy remain critical obstacles in the treatment of patients. Due to the inherent biological and clinical heterogeneity of individual CRCs, proteomic methods stand to become powerful tools to provide biological insights that may guide therapeutic strategies with the ultimate goal of refining emergent immunotherapeutic treatments.
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Affiliation(s)
- David I Cantor
- Australian Proteome Analysis Facility, Macquarie University, Sydney, Australia
| | | | - Jack Westacott
- Faculty of Science and Engineering, Macquarie University, Sydney, Australia
| | - Joo-Shik Shin
- Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and Faculty of Medicine, University of Sydney, Sydney, Australia
| | - Abidali Mohamedali
- Faculty of Science and Engineering, Macquarie University, Sydney, Australia
| | - Seong Boem Ahn
- Faculty of Health and Medical Sciences, Macquarie University, Sydney, Australia
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25
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Alves Martins BA, de Bulhões GF, Cavalcanti IN, Martins MM, de Oliveira PG, Martins AMA. Biomarkers in Colorectal Cancer: The Role of Translational Proteomics Research. Front Oncol 2019; 9:1284. [PMID: 31828035 PMCID: PMC6890575 DOI: 10.3389/fonc.2019.01284] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2019] [Accepted: 11/05/2019] [Indexed: 12/11/2022] Open
Abstract
Colorectal cancer is one of the most common cancers in the world, and it is one of the leading causes of cancer-related death. Despite recent progress in the development of screening programs and in the management of patients with colorectal cancer, there are still many gaps to fill, ranging from the prevention and early diagnosis to the determination of prognosis factors and treatment of metastatic disease, to establish a personalized approach. The genetic profile approach has been increasingly used in the decision-making process, especially in the choice of targeted therapies and in the prediction of drug response, but there are still few validated biomarkers of colorectal cancer for clinical practice. The discovery of non-invasive, sensitive, and specific biomarkers is an urgent need, and translational proteomics play a key role in this process, as they enable better comprehension of colorectal carcinogenesis, identification of potential markers, and subsequent validation. This review provides an overview of recent advances in the search for colorectal cancer biomarkers through proteomics studies according to biomarker function and clinical application.
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Affiliation(s)
| | - Gabriel Fonseca de Bulhões
- UniCeub—Centro Universitário Do Distrito Federal, Translational Medicine Group, School of Medicine, Brasilia, Brazil
| | - Igor Norat Cavalcanti
- UniCeub—Centro Universitário Do Distrito Federal, Translational Medicine Group, School of Medicine, Brasilia, Brazil
| | | | | | - Aline Maria Araújo Martins
- Medical Sciences Postgraduate Program, School of Medicine, University of Brasilia, Brasília, Brazil
- UniCeub—Centro Universitário Do Distrito Federal, Translational Medicine Group, School of Medicine, Brasilia, Brazil
- Metabolomics and Bioanalysis Center, San Pablo CEU University, Madrid, Spain
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26
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Giusti L, Angeloni C, Lucacchini A. Update on proteomic studies of formalin-fixed paraffin-embedded tissues. Expert Rev Proteomics 2019; 16:513-520. [DOI: 10.1080/14789450.2019.1615452] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Affiliation(s)
- Laura Giusti
- School of Pharmacy, University of Camerino, Camerino, Italy
| | | | - Antonio Lucacchini
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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Nagamine A, Araki T, Nagano D, Miyazaki M, Yamamoto K. L-Lactate dehydrogenase B may be a predictive marker for sensitivity to anti-EGFR monoclonal antibodies in colorectal cancer cell lines. Oncol Lett 2019; 17:4710-4716. [PMID: 30944657 DOI: 10.3892/ol.2019.10075] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 01/31/2019] [Indexed: 01/19/2023] Open
Abstract
Recently, proteins derived from cancer cells have been widely investigated as biomarkers for predicting the efficacy of chemotherapy. In this study, to identify a sensitive biomarker for the efficacy of anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR mAbs), proteins derived from 6 colorectal cancer (CRC) cell lines with different sensitivities to cetuximab, an anti-EGFR mAb, were analyzed. Cytoplasmic and membrane proteins extracted from each CRC cell line were digested using trypsin and analyzed comprehensively using mass spectrometry. As a result, 148 and 146 peaks from cytoplasmic proteins and 363 and 267 peaks from membrane proteins were extracted as specific peaks for cetuximab-resistant and -sensitive CRC cell lines, respectively. By analyzing the proteins identified from the peptide peaks, cytoplasmic L-lactate dehydrogenase B (LDHB) was detected as a marker of cetuximab sensitivity, and it was confirmed that LDHB expression was increased in cetuximab-resistant CRC cell lines. Furthermore, LDHB expression levels were significantly upregulated with the acquisition of resistance to cetuximab in cetuximab-sensitive CRC cell lines. In conclusion, LDHB was identified as an important factor affecting cetuximab sensitivity using comprehensive proteome analysis for the first time.
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Affiliation(s)
- Ayumu Nagamine
- Department of Clinical Pharmacology and Therapeutics, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.,Department of Pharmacy, Gunma University Hospital, Maebashi, Gunma 371-8511, Japan
| | - Takuya Araki
- Department of Clinical Pharmacology and Therapeutics, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.,Department of Pharmacy, Gunma University Hospital, Maebashi, Gunma 371-8511, Japan
| | - Daisuke Nagano
- Department of Clinical Pharmacology and Therapeutics, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Mitsue Miyazaki
- Division of Endocrinology Metabolism and Signal Research, Gunma University Initiative for Advanced Research and Institute for Molecular and Cellular Regulation, Maebashi, Gunma 371-8511, Japan
| | - Koujirou Yamamoto
- Department of Clinical Pharmacology and Therapeutics, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.,Department of Pharmacy, Gunma University Hospital, Maebashi, Gunma 371-8511, Japan
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Chauvin A, Boisvert FM. Clinical Proteomics in Colorectal Cancer, a Promising Tool for Improving Personalised Medicine. Proteomes 2018; 6:proteomes6040049. [PMID: 30513835 PMCID: PMC6313903 DOI: 10.3390/proteomes6040049] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 11/22/2018] [Accepted: 11/29/2018] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer is the third most common and the fourth most lethal cancer worldwide. In most of cases, patients are diagnosed at an advanced or even metastatic stage, thus explaining the high mortality. The lack of proper clinical tests and the complicated procedures currently used for detecting this cancer, as well as for predicting the response to treatment and the outcome of a patient's resistance in guiding clinical practice, are key elements driving the search for biomarkers. In the present overview, the different biomarkers (diagnostic, prognostic, treatment resistance) discovered through proteomics studies in various colorectal cancer study models (blood, stool, biopsies), including the different proteomic techniques used for the discovery of these biomarkers, are reviewed, as well as the various tests used in clinical practice and those currently in clinical phase. These studies define the limits and perspectives related to proteomic biomarker research for personalised medicine in colorectal cancer.
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Affiliation(s)
- Anaïs Chauvin
- Department of Anatomy and Cell Biology, Université de Sherbrooke, 3201 Jean-Mignault, Sherbrooke, QC J1E 4K8, Canada.
| | - François-Michel Boisvert
- Department of Anatomy and Cell Biology, Université de Sherbrooke, 3201 Jean-Mignault, Sherbrooke, QC J1E 4K8, Canada.
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Zhou ZP, Wang LP, Hong ZS, Qiu CZ, Wang MZ, Chen ZX, Tang LF, Yu WS, Wang CX. Silencing GOLPH3 gene expression reverses resistance to cisplatin in HT29 colon cancer cells via multiple signaling pathways. Int J Oncol 2018; 53:1183-1192. [PMID: 30015866 DOI: 10.3892/ijo.2018.4471] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Accepted: 06/05/2018] [Indexed: 11/06/2022] Open
Abstract
Golgi phosphorylated protein (GOLPH)3 is overexpressed in colorectal cancer tissues and promotes the proliferation of colon cancer cells. A previous study by the authors demonstrated that GOLPH3 was associated with poor prognosis in colorectal cancer. However, the association between GOLPH3 gene overexpression and resistance to platinum-based drugs in colon cancer remains unknown. In the present study, the association between GOLPH3 overexpression and resistance of HT29 colon cancer cells to cisplatin and the mechanism underlying the development of chemoresistance were investigated. HT29 cells were divided into five groups. The expression of GOLPH3 mRNA was measured in the control and siRNA transfection groups. Reverse transcription-quantitative polymerase chain reaction analysis, cell proliferation, colony formation assay, tumor sphere formation and apoptosis (Annexin V) assays, western blotting and a nude mouse tumorigenicity assay were performed. HT29 cells were resistant to 10 µM cisplatin treatment, whereas the expression of GOLPH3, P-glycoprotein, phosphorylated extracellular signal-regulated kinase (pERK)1/2 and β-catenin protein was significantly upregulated compared with the control group. With cisplatin treatment, silencing GOLPH3 gene expression downregulated the expression of these proteins, reduced cell proliferation and tumorigenicity, induced apoptosis and reversed the resistance of HT29 cells to cisplatin. In addition, the change in pERK1/2 and β-catenin expression demonstrated that the mechanism of GOLPH3 overexpression involved in cisplatin resistance was associated with activation of the mitogen-activated protein kinase/ERK and Wnt/β‑catenin signaling pathways in HT29 cells. The tumorigenicity experiment in nude mice also demonstrated that silencing GOLPH3 expression increased the sensitivity of HT29 cells to cisplatin in vivo. Therefore, overexpression of GOLPH3 may be involved in the resistance of HT29 colon cancer cells to cisplatin chemotherapy by activating multiple cell signaling pathways.
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Affiliation(s)
- Zhi-Ping Zhou
- Department of General Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Lin-Pei Wang
- Department of General Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Zhong-Shi Hong
- Department of General Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Cheng-Zhi Qiu
- Department of General Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Ming-Zhen Wang
- Department of Proctology, The Fifth Hospital of Xiamen City, Xiamen, Fujian 361101, P.R. China
| | - Zhi-Xiong Chen
- Department of General Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Long-Feng Tang
- Department of General Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Wai-Shi Yu
- Department of General Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Chun-Xiao Wang
- Department of General Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
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