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Hu C, Chen Y, Yin X, Xu R, Yin C, Wang C, Zhao Y. Pancreatic endocrine and exocrine signaling and crosstalk in physiological and pathological status. Signal Transduct Target Ther 2025; 10:39. [PMID: 39948335 PMCID: PMC11825823 DOI: 10.1038/s41392-024-02098-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 10/20/2024] [Accepted: 12/03/2024] [Indexed: 02/16/2025] Open
Abstract
The pancreas, an organ with dual functions, regulates blood glucose levels through the endocrine system by secreting hormones such as insulin and glucagon. It also aids digestion through the exocrine system by secreting digestive enzymes. Complex interactions and signaling mechanisms between the endocrine and exocrine functions of the pancreas play a crucial role in maintaining metabolic homeostasis and overall health. Compelling evidence indicates direct and indirect crosstalk between the endocrine and exocrine parts, influencing the development of diseases affecting both. From a developmental perspective, the exocrine and endocrine parts share the same origin-the "tip-trunk" domain. In certain circumstances, pancreatic exocrine cells may transdifferentiate into endocrine-like cells, such as insulin-secreting cells. Additionally, several pancreatic diseases, including pancreatic cancer, pancreatitis, and diabetes, exhibit potential relevance to both endocrine and exocrine functions. Endocrine cells may communicate with exocrine cells directly through cytokines or indirectly by regulating the immune microenvironment. This crosstalk affects the onset and progression of these diseases. This review summarizes the history and milestones of findings related to the exocrine and endocrine pancreas, their embryonic development, phenotypic transformations, signaling roles in health and disease, the endocrine-exocrine crosstalk from the perspective of diseases, and potential therapeutic targets. Elucidating the regulatory mechanisms of pancreatic endocrine and exocrine signaling and provide novel insights for the understanding and treatment of diseases.
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Grants
- National High Level Hospital Clinical Research Funding (2022, 2022-PUMCH-D-001, to YZ), CAMS Innovation Fund for Medical Sciences (2021, 2021-I2M-1-002, to YZ), National Nature Science Foundation of China (2021, 82102810, to CW, the Fundamental Research Funds for the Central Universities(3332023123)
- cNational High Level Hospital Clinical Research Funding (2022, 2022-PUMCH-D-001, to YZ), CAMS Innovation Fund for Medical Sciences (2021, 2021-I2M-1-002, to YZ), National Nature Science Foundation of China (2021, 82102810, to CW, the Fundamental Research Funds for the Central Universities(3332023123)
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Affiliation(s)
- Chenglin Hu
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Yuan Chen
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Xinpeng Yin
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Ruiyuan Xu
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Chenxue Yin
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Chengcheng Wang
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China.
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China.
- National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Beijing, PR China.
- Institute of Clinical Medicine, Peking Union Medical College Hospital, Beijing, PR China.
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China.
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China.
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China.
- National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Beijing, PR China.
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Gong J, Li X, Feng Z, Lou J, Pu K, Sun Y, Hu S, Zhou Y, Song T, Shangguan M, Zhang K, Lu W, Dong X, Wu J, Zhu H, He Q, Xu H, Wu Y. Sorcin can trigger pancreatic cancer-associated new-onset diabetes through the secretion of inflammatory cytokines such as serpin E1 and CCL5. Exp Mol Med 2024; 56:2535-2547. [PMID: 39516378 PMCID: PMC11612510 DOI: 10.1038/s12276-024-01346-4] [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: 11/18/2023] [Revised: 07/28/2024] [Accepted: 08/19/2024] [Indexed: 11/16/2024] Open
Abstract
A rise in blood glucose is an early warning sign of underlying pancreatic cancer (PC) and may be an indicator of genetic events in PC progression. However, there is still a lack of mechanistic research on pancreatic cancer-associated new-onset diabetes (PCAND). In the present study, we identified a gene SRI, which possesses a SNP with the potential to distinguish PCAND and Type 2 diabetes mellitus (T2DM), by machine learning on the basis of the UK Biobank database. In vitro and in vivo, sorcin overexpression induced pancreatic β-cell dysfunction. Sorcin can form a positive feedback loop with STAT3 to increase the transcription of serpin E1 and CCL5, which may directly induce β-cell dysfunction. In 88 biopsies, the expression of sorcin was elevated in PC tissues, especially in PCAND samples. Furthermore, plasma serpin E1 levels are higher in peripheral blood samples from PCAND patients than in those from T2DM patients. In conclusion, sorcin may be the key driver in PCAND, and further study on the sorcin-STAT3-serpin E1/CCL5 signaling axis may help us better understand the pathogenesis of PCAND and identify potential biomarkers.
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Affiliation(s)
- Jiali Gong
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
- Department of Surgery, Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China
| | - Xiawei Li
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
- Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA
| | - Zengyu Feng
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jianyao Lou
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Kaiyue Pu
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yongji Sun
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
- Department of Surgery, Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China
| | - Sien Hu
- Department of Surgery, Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China
| | - Yizhao Zhou
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Tianyu Song
- Department of Surgery, Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China
| | - Meihua Shangguan
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Kai Zhang
- School of Public Health and Eye Center The Second Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Wenjie Lu
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xin Dong
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jian Wu
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- School of Public Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Institute of Wenzhou, Zhejiang University, Wenzhou, Zhejiang, China
| | - Hong Zhu
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
- Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou, Zhejiang, China
| | - Qiaojun He
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
- Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou, Zhejiang, China.
| | - Hongxia Xu
- Innovation Institute for Artificial Intelligence in Medicine and Liangzhu Laboratory, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.
| | - Yulian Wu
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China.
- Department of Surgery, Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China.
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Sun Y, Hu C, Hu S, Xu H, Gong J, Wu Y, Fan Y, Lv C, Song T, Lou J, Zhang K, Wu J, Li X, Wu Y. Predicting Pancreatic Cancer in New-Onset Diabetes Cohort Using a Novel Model With Integrated Clinical and Genetic Indicators: A Large-Scale Prospective Cohort Study. Cancer Med 2024; 13:e70388. [PMID: 39526476 PMCID: PMC11551786 DOI: 10.1002/cam4.70388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 09/30/2024] [Accepted: 10/20/2024] [Indexed: 11/16/2024] Open
Abstract
INTRODUCTION Individuals who develop new-onset diabetes have been identified as a high-risk cohort for pancreatic cancer (PC), exhibiting an incidence rate nearly 8 times higher than the general population. Hence, the targeted screening of this specific cohort presents a promising opportunity for early pancreatic cancer detection. We aimed to develop and validate a novel model capable of identifying high-risk individuals among those with new-onset diabetes. METHODS Employing the UK Biobank cohort, we focused on those developing new-onset diabetes during follow-up. Genetic and clinical characteristics available at registration were considered as candidate predictors. We conducted univariate regression analysis to identify potential indicators and used a 5-fold cross-validation method to select optimal predictors for model development. Five machine learning algorithms were used for model development. RESULTS Among 12,735 patients with new-onset diabetes, 100 (0.8%) were diagnosed with PC within 2 years. The final model (area under the curve, 0.897; 95% confidence interval, 0.865-0.929) included 5 clinical predictors and 24 single nucleotide polymorphisms. Two threshold cut-offs were established: 1.28% and 5.26%. The recommended 1.28% cut-off, based on model performance, reduces definitive testing to 13% of the total population while capturing 76% of PC cases. The high-risk threshold is 5.26%. Utilizing this threshold, only 2% of the population needs definitive testing, capturing nearly half of PC cases. CONCLUSIONS We, for the first time, combined clinical and genetic data to develop and validate a model to determine the risk of pancreatic cancer in patients with new-onset diabetes using machine learning algorithms. By reducing the number of unnecessary tests while ensuring that a substantial proportion of high-risk patients are identified, this tool has the potential to improve patient outcomes and optimize healthcare sources.
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Affiliation(s)
- Yongji Sun
- Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
| | - Chaowen Hu
- Polytechnic InstituteZhejiang UniversityHangzhouZhejiangChina
| | - Sien Hu
- Department of General SurgeryHangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical UniversityZhejiangHangzhouChina
| | - Hongxia Xu
- Innovation Institute for Artificial Intelligence in MedicineZhejiang UniversityHangzhouChina
| | - Jiali Gong
- Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer InstituteSecond Affiliated Hospital, Zhejiang University School of MedicineHangzhouZhejiangChina
- Cancer CenterZhejiang UniversityHangzhouZhejiangChina
| | - Yixuan Wu
- Department of EpidemiologyHarvard T.H. Chan School of Public HealthBostonMassachusettsUSA
| | - Yiqun Fan
- Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer InstituteSecond Affiliated Hospital, Zhejiang University School of MedicineHangzhouZhejiangChina
- Cancer CenterZhejiang UniversityHangzhouZhejiangChina
| | - Changming Lv
- Department of Surgery, Fourth Affiliated Hospital, International Institutes of MedicineZhejiang University School of MedicineZhejiangChina
- Institute of WenzhouZhejiang UniversityZhejiangChina
| | - Tianyu Song
- Department of Surgery, Fourth Affiliated Hospital, International Institutes of MedicineZhejiang University School of MedicineZhejiangChina
- Institute of WenzhouZhejiang UniversityZhejiangChina
| | - Jianyao Lou
- Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer InstituteSecond Affiliated Hospital, Zhejiang University School of MedicineHangzhouZhejiangChina
- Cancer CenterZhejiang UniversityHangzhouZhejiangChina
| | - Kai Zhang
- School of Public Health and Eye CenterThe Second Affiliated Hospital, Zhejiang UniversityHangzhouChina
| | - Jian Wu
- Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Innovation Institute for Artificial Intelligence in MedicineZhejiang UniversityHangzhouChina
- Cancer CenterZhejiang UniversityHangzhouZhejiangChina
- Department of Surgery, Fourth Affiliated Hospital, International Institutes of MedicineZhejiang University School of MedicineZhejiangChina
- Institute of WenzhouZhejiang UniversityZhejiangChina
| | - Xiawei Li
- Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer InstituteSecond Affiliated Hospital, Zhejiang University School of MedicineHangzhouZhejiangChina
- Cancer CenterZhejiang UniversityHangzhouZhejiangChina
- School of Public HealthZhejiang University School of MedicineZhejiangHangzhouChina
| | - Yulian Wu
- Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer InstituteSecond Affiliated Hospital, Zhejiang University School of MedicineHangzhouZhejiangChina
- Cancer CenterZhejiang UniversityHangzhouZhejiangChina
- Department of Surgery, Fourth Affiliated Hospital, International Institutes of MedicineZhejiang University School of MedicineZhejiangChina
- Institute of WenzhouZhejiang UniversityZhejiangChina
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Koning T, Calaf GM. Genes Related to Motility in an Ionizing Radiation and Estrogen Breast Cancer Model. BIOLOGY 2024; 13:849. [PMID: 39596804 PMCID: PMC11591951 DOI: 10.3390/biology13110849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 10/16/2024] [Accepted: 10/18/2024] [Indexed: 11/29/2024]
Abstract
Breast cancer is a major global health concern as it is the primary cause of cancer death for women. Environmental radiation exposure and endogenous factors such as hormones increase breast cancer risk, and its development and spread depend on cell motility and migration. The expression of genes associated with cell motility, such as ADAM12, CYR61, FLRT2, SLIT2, VNN1, MYLK, MAP1B, and TUBA1A, was analyzed in an experimental breast cancer model induced by radiation and estrogen. The results showed that TUBA1A, SLIT2, MAP1B, MYLK, and ADAM12 gene expression increased in the irradiated Alpha3 cell line but not in the control or the malignant Tumor2 cell line. Bioinformatic analysis indicated that FLERT2, SLIT2, VNN1, MAP1B, MYLK, and TUBA1A gene expressions were found to be higher in normal tissue than in tumor tissue of breast cancer patients. However, ADAM12 and CYR61 expressions were found to be higher in tumors than in normal tissues, and they had a negative correlation with ESR1 gene expression. Concerning ESR2 gene expression, there was a negative correlation with CYR61, but there was a positive correlation with FLRT2, MYLK, MAP1B, and VNN1. Finally, a decreased survival rate was observed in patients exhibiting high expression levels of TUBA1A and MAP1B. These genes also showed a negative ER status, an important parameter for endocrine therapy. The genes related to motility were affected by ionizing radiation, confirming its role in the initiation process of breast carcinogenesis. In conclusion, the relationship between the patient's expression of hormone receptors and genes associated with cell motility presents a novel prospect for exploring therapeutic strategies.
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Affiliation(s)
| | - Gloria M. Calaf
- Instituto de Alta Investigación, Universidad de Tarapacá, Arica 1000000, Chile;
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Pasternak-Mnich K, Kujawa J, Agier J, Kozłowska E. Impact of photobiomodulation therapy on pro-inflammation functionality of human peripheral blood mononuclear cells - a preliminary study. Sci Rep 2024; 14:23111. [PMID: 39367102 PMCID: PMC11452683 DOI: 10.1038/s41598-024-74533-y] [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: 02/10/2024] [Accepted: 09/26/2024] [Indexed: 10/06/2024] Open
Abstract
Research into the efficacy of photobiomodulation therapy (PBMT) in reducing inflammation has been ongoing for years, but standards for irradiation methodology still need to be developed. This study aimed to test whether PBMT stimulates in vitro human peripheral blood mononuclear cells (PBMCs) to synthesize pro-inflammatory cytokines, including chemokines. PBMCs were irradiated with laser radiation at two wavelengths simultaneously (λ = 808 nm in continuous emission and λ = 905 nm in pulsed emission). The laser radiation energy was dosed in one dose as a whole (5 J, 15 J, 20 J) or in a fractionated way (5 J + 15 J and 15 J + 5 J) with a frequency of 500, 1,500 and 2,000 Hz. The surface power densities were 177, 214 and 230 mW/cm2, respectively. A pro-inflammatory effect was observed at both the transcript and protein levels for IL-1β after PBMT at the energy doses 5 J and 20 J (ƒ=500 Hz) and only at the transcript level after application of PBMT at energy doses of 20 J (ƒ= 1,500; ƒ=2,000 Hz) and 5 + 15 J (ƒ=500 Hz). An increase in CCL2 and CCL3 mRNA expression was observed after PBMT at 5 + 15 J (ƒ=1,500 Hz) and 15 + 5 J (ƒ=2,000 Hz) and CCL3 concentration after application of an energy dose of 15 J (frequency of 500 Hz). Even though PBMT can induce mRNA synthesis and stimulate PBMCs to produce selected pro-inflammatory cytokines and chemokines, it is necessary to elucidate the impact of the simultaneous emission of two wavelengths on the inflammatory response mechanisms.
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Affiliation(s)
- Kamila Pasternak-Mnich
- Department of Medical Rehabilitation, Faculty of Health Sciences, Medical University of Lodz, 251 Pomorska St, Lodz, 92-213, Poland.
| | - Jolanta Kujawa
- Department of Medical Rehabilitation, Faculty of Health Sciences, Medical University of Lodz, 251 Pomorska St, Lodz, 92-213, Poland
| | - Justyna Agier
- Department of Microbiology, Genetics and Experimental Immunology, Lodz Centre of Molecular Studies on Civilisation Diseases, Medical University of Lodz, Lodz, 92-215, Poland
| | - Elżbieta Kozłowska
- Department of Microbiology, Genetics and Experimental Immunology, Lodz Centre of Molecular Studies on Civilisation Diseases, Medical University of Lodz, Lodz, 92-215, Poland
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Xu J, Song Y, Zhou B, Yuan S, Gao S. Prognostic and diagnostic value of circulating IGFBP2 in pancreatic cancer. Open Med (Wars) 2024; 19:20230893. [PMID: 39221034 PMCID: PMC11365464 DOI: 10.1515/med-2023-0893] [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: 01/29/2023] [Revised: 12/24/2023] [Accepted: 01/05/2024] [Indexed: 09/04/2024] Open
Abstract
Insulin-like growth factor binding protein 2 (IGFBP2) is overexpressed in tumor tissues of several malignancies, including pancreatic cancer. Because of its role in tumor progression, IGFBP2 has been investigated as a tumor biomarker. However, little is known about its utility in pancreatic cancer. Plasma IGFBP2 levels were determined using enzyme-linked immunosorbent assay in 75 patients with pancreatic ductal adenocarcinoma (PDAC), 73 matched healthy controls, and 17 chronic pancreatitis patients. Our results showed that the plasma IGFPB2 level was significantly higher in PDAC patients than in patients with chronic pancreatitis and healthy controls. At a cut-off value of 333.9 ng/mL, the specificity and sensitivity were 78.08 and 65.33%, respectively. IGFBP2 level alone did not outperform carbohydrate antigen 19-9 (CA19-9) in diagnostic accuracy, but it successfully identified 9 out of 24 PDAC patients who were misidentified by CA19-9. The combination of IGFBP2 and CA19-9 was more accurate in the detection of PDAC than CA19-9 alone. IGFBP2 was more accurate than the other in discriminating between chronic pancreatitis and PDAC. Plasma IGFBP2, rather than CA19-9, was higher in the new-onset diabetes, lymph node involvement, and distant metastasis subgroups. IGFBP2 level was notably higher in stage IV cases than in stage I/II or stage III disease. However, CA19-9 did not show a difference between stages. After adjusting for lymph node involvement and distant metastasis, plasma IGFBP2 was identified as an independent prognostic marker for PDAC. The median survival time for patients with an IGFBP2 level ≥333.9 ng/mL was significantly shorter than that for patients with an IGFBP2 level <333.9 ng/mL. Marked elevation of plasma IGFBP2 in PDAC is associated with poorer survival. IGFBP2 may be considered as a supplementary biomarker for the diagnosis and prognostic prediction in Chinese pancreatic cancer patients.
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Affiliation(s)
- Jie Xu
- Senior Ward, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
| | - Yuning Song
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
| | - Bodong Zhou
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
| | - Shuai Yuan
- Senior Ward, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
| | - Song Gao
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
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Xu L, Wang Z, Liu S, Wei Z, Yu J, Li J, Li J, Yao W, Gu Z. CRISPR/Cas9-mediated knockout of the Vanin-1 gene in the Leghorn Male Hepatoma cell line and its effects on lipid metabolism. Anim Biosci 2024; 37:437-450. [PMID: 37946431 PMCID: PMC10915194 DOI: 10.5713/ab.23.0162] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 06/12/2023] [Accepted: 09/18/2023] [Indexed: 11/12/2023] Open
Abstract
OBJECTIVE Vanin-1 (VNN1) is a pantetheinase that catalyses the hydrolysis of pantetheine to produce pantothenic acid and cysteamine. Our previous studies have shown that the VNN1 is specifically expressed in chicken liver which negatively regulated by microRNA-122. However, the functions of the VNN1 in lipid metabolism in chicken liver haven't been elucidated. METHODS First, we detected the VNN1 mRNA expression in 4-week chickens which were fasted 24 hours. Next, knocked out VNN1 via CRISPR/Cas9 system in the chicken Leghorn Male Hepatoma cell line. Detected the lipid deposition via oil red staining and analysis the content of triglycerides (TG), low-density lipoprotein-C (LDL-C), and highdensity lipoprotein-C (HDL-C) after VNN1 knockout in Leghorn Male Hepatoma cell line. Then we captured various differentially expressed genes (DEGs) between VNN1-modified LMH cells and original LMH cells by RNA-seq. RESULTS Firstly, fasting-induced expression of VNN1. Meanwhile, we successfully used the CRISPR/Cas9 system to achieve targeted mutations of the VNN1 in the chicken LMH cell line. Moreover, the expression level of VNN1 mRNA in LMH-KO-VNN1 cells decreased compared with that in the wild-type LMH cells (p<0.0001). Compared with control, lipid deposition was decreased after knockout VNN1 via oil red staining, meanwhile, the contents of TG and LDL-C were significantly reduced, and the content of HDL-C was increased in LMH-KO-VNN1 cells. Transcriptome sequencing showed that there were 1,335 DEGs between LMH-KO-VNN1 cells and original LMH cells. Of these DEGs, 431 were upregulated, and 904 were downregulated. Gene ontology analyses of all DEGs showed that the lipid metabolism-related pathways, such as fatty acid biosynthesis and long-chain fatty acid biosynthesis, were enriched. KEGG pathway analyses showed that "lipid metabolism pathway", "energy metabolism", and "carbohydrate metabolism" were enriched. A total of 76 DEGs were involved in these pathways, of which 29 genes were upregulated (such as cytochrome P450 family 7 subfamily A member 1, ELOVL fatty acid elongase 2, and apolipoprotein A4) and 47 genes were downregulated (such as phosphoenolpyruvate carboxykinase 1) by VNN1 knockout in the LMH cells. CONCLUSION These results suggest that VNN1 plays an important role in coordinating lipid metabolism in the chicken liver.
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Affiliation(s)
- Lu Xu
- School of Biology and Food Engineering, Changshu Institute of Technology, Changshu, 215500,
China
| | - Zhongliang Wang
- School of Biology and Food Engineering, Changshu Institute of Technology, Changshu, 215500,
China
- College of Animal Science & Technology, Nanjing Agriculture University, Nanjing, 210000,
China
| | - Shihao Liu
- School of Biology and Food Engineering, Changshu Institute of Technology, Changshu, 215500,
China
| | - Zhiheng Wei
- School of Biology and Food Engineering, Changshu Institute of Technology, Changshu, 215500,
China
| | - Jianfeng Yu
- School of Biology and Food Engineering, Changshu Institute of Technology, Changshu, 215500,
China
| | - Jun Li
- School of Biology and Food Engineering, Changshu Institute of Technology, Changshu, 215500,
China
| | - Jie Li
- School of Biology and Food Engineering, Changshu Institute of Technology, Changshu, 215500,
China
- College of Animal Science & Technology, Nanjing Agriculture University, Nanjing, 210000,
China
| | - Wen Yao
- College of Animal Science & Technology, Nanjing Agriculture University, Nanjing, 210000,
China
| | - Zhiliang Gu
- School of Biology and Food Engineering, Changshu Institute of Technology, Changshu, 215500,
China
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8
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Yu H, Cui Y, Guo F, Zhu Y, Zhang X, Shang D, Dong D, Xiang H. Vanin1 (VNN1) in chronic diseases: Future directions for targeted therapy. Eur J Pharmacol 2024; 962:176220. [PMID: 38042463 DOI: 10.1016/j.ejphar.2023.176220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Revised: 11/19/2023] [Accepted: 11/20/2023] [Indexed: 12/04/2023]
Abstract
Vanin1 (VNN1) is an exogenous enzyme with pantetheinase activity that mainly exerts physiological functions through enzyme catalysis products, including pantothenic acid and cysteamine. In recent years, the crosstalk between VNN1 and metabolism and oxidative stress has attracted much attention. As a result of the ability of VNN1 to affect multiple metabolic pathways and oxidative stress to exacerbate or alleviate pathological processes, it has become a key component of disease progression. This review discusses the functions of VNN1 in glucolipid metabolism, cysteamine metabolism, and glutathione metabolism to provide perspectives on VNN1-targeted therapy for chronic diseases.
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Affiliation(s)
- Hao Yu
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, 116011, China; College of Pharmacy, Dalian Medical University, 116044, China
| | - Yuying Cui
- Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China; Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116044, China
| | - Fangyue Guo
- Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China; Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116044, China
| | - YuTong Zhu
- Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China; Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116044, China
| | - Xiaonan Zhang
- Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China; Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116044, China
| | - Dong Shang
- Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China; Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116044, China; Department of General Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China
| | - Deshi Dong
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, 116011, China.
| | - Hong Xiang
- Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.
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9
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Binang HB, Perera CJ, Apte MV. Role of Pancreatic Tumour-Derived Exosomes and Their Cargo in Pancreatic Cancer-Related Diabetes. Int J Mol Sci 2023; 24:10203. [PMID: 37373351 DOI: 10.3390/ijms241210203] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 06/10/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
One of the most common and deadly types of pancreatic cancer (PC) is pancreatic ductal adenocarcinoma (PDAC), with most patients succumbing to the disease within one year of diagnosis. Current detection strategies do not address asymptomatic PC; therefore, patients are diagnosed at an advanced stage when curative treatment is often no longer possible. In order to detect PC in asymptomatic patients earlier, the risk factors that could serve as reliable markers need to be examined. Diabetic mellitus (DM) is a significant risk factor for this malignancy and can be both a cause and consequence of PC. Typically, DM caused by PC is known as new-onset, pancreatogenic, pancreoprivic, or pancreatic cancer-related diabetes (PCRD). Although PCRD is quite distinct from type 2 DM (T2DM), there are currently no biomarkers that differentiate PCRD from T2DM. To identify such biomarkers, a better understanding of the mechanisms mediating PCRD is essential. To this end, there has been a growing research interest in recent years to elucidate the role of tumour-derived exosomes and their cargo in the pathogenesis of PCRD. Exosomes derived from tumours can be recognized for their specificity because they reflect the characteristics of their parent cells and are important in intercellular communication. Their cargo consists of proteins, lipids, and nucleic acids, which can be transferred to and alter the behaviour of recipient cells. This review provides a concise overview of current knowledge regarding tumour-derived exosomes and their cargo in PCRD and discusses the potential areas worthy of further study.
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Affiliation(s)
- Helen B Binang
- Pancreatic Research Group, South Western Sydney Clinical Campuses, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW 2052, Australia
- Ingham Institute for Applied Medical Research, Sydney, NSW 2170, Australia
| | - Chamini J Perera
- Pancreatic Research Group, South Western Sydney Clinical Campuses, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW 2052, Australia
- Ingham Institute for Applied Medical Research, Sydney, NSW 2170, Australia
| | - Minoti V Apte
- Pancreatic Research Group, South Western Sydney Clinical Campuses, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW 2052, Australia
- Ingham Institute for Applied Medical Research, Sydney, NSW 2170, Australia
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10
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Chianese U, Papulino C, Ali A, Ciardiello F, Cappabianca S, Altucci L, Carafa V, Benedetti R. FASN multi-omic characterization reveals metabolic heterogeneity in pancreatic and prostate adenocarcinoma. J Transl Med 2023; 21:32. [PMID: 36650542 PMCID: PMC9847120 DOI: 10.1186/s12967-023-03874-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 01/02/2023] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) and prostate cancer (PCa) are among the most prevalent malignant tumors worldwide. There is now a comprehensive understanding of metabolic reprogramming as a hallmark of cancer. Fatty acid synthase (FASN) is a key regulator of the lipid metabolic network, providing energy to favor tumor proliferation and development. Whereas the biological role of FASN is known, its response and sensitivity to inhibition have not yet been fully established in these two cancer settings. METHODS To evaluate the association between FASN expression, methylation, prognosis, and mutational profile in PDAC and PCa, we interrogated public databases and surveyed online platforms using TCGA data. The STRING database was used to investigate FASN interactors, and the Gene Set Enrichment Analysis platform Reactome database was used to perform an enrichment analysis using data from RNA sequencing public databases of PDAC and PCa. In vitro models using PDAC and PCa cell lines were used to corroborate the expression of FASN, as shown by Western blot, and the effects of FASN inhibition on cell proliferation/cell cycle progression and mitochondrial respiration were investigated with MTT, colony formation assay, cell cycle analysis and MitoStress Test. RESULTS The expression of FASN was not modulated in PDAC compared to normal pancreatic tissues, while it was overexpressed in PCa, which also displayed a different level of promoter methylation. Based on tumor grade, FASN expression decreased in advanced stages of PDAC, but increased in PCa. A low incidence of FASN mutations was found for both tumors. FASN was overexpressed in PCa, despite not reaching statistical significance, and was associated with a worse prognosis than in PDAC. The biological role of FASN interactors correlated with lipid metabolism, and GSEA indicated that lipid-mediated mitochondrial respiration was enriched in PCa. Following validation of FASN overexpression in PCa compared to PDAC in vitro, we tested TVB-2640 as a FASN inhibitor. PCa proliferation arrest was modulated by FASN inhibition in a dose- and time-dependent manner, whereas PDAC proliferation was not altered. In line with this finding, mitochondrial respiration was found to be more affected in PCa than in PDAC. FASN inhibition interfered with metabolic signaling causing lipid accumulation and affecting cell viability with an impact on the replicative processes. CONCLUSIONS FASN exhibited differential expression patterns in PDAC and PCa, suggesting a different evolution during cancer progression. This was corroborated by the fact that both tumors responded differently to FASN inhibition in terms of proliferative potential and mitochondrial respiration, indicating that its use should reflect context specificity.
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Affiliation(s)
- Ugo Chianese
- grid.9841.40000 0001 2200 8888Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, L. De Crecchio 7, 80138 Naples, Italy
| | - Chiara Papulino
- grid.9841.40000 0001 2200 8888Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, L. De Crecchio 7, 80138 Naples, Italy
| | - Ahmad Ali
- grid.9841.40000 0001 2200 8888Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, L. De Crecchio 7, 80138 Naples, Italy
| | - Fortunato Ciardiello
- grid.9841.40000 0001 2200 8888Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, L. De Crecchio 7, 80138 Naples, Italy
| | - Salvatore Cappabianca
- grid.9841.40000 0001 2200 8888Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, L. De Crecchio 7, 80138 Naples, Italy
| | - Lucia Altucci
- grid.9841.40000 0001 2200 8888Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, L. De Crecchio 7, 80138 Naples, Italy ,grid.428067.f0000 0004 4674 1402Biogem Institute of Molecular and Genetic Biology, 83031 Ariano Irpino, Italy ,grid.429047.c0000 0004 6477 0469IEOS, Institute for Endocrinology and Oncology “Gaetano Salvatore”, 80131 Naples, Italy
| | - Vincenzo Carafa
- grid.9841.40000 0001 2200 8888Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, L. De Crecchio 7, 80138 Naples, Italy ,grid.428067.f0000 0004 4674 1402Biogem Institute of Molecular and Genetic Biology, 83031 Ariano Irpino, Italy
| | - Rosaria Benedetti
- grid.9841.40000 0001 2200 8888Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, L. De Crecchio 7, 80138 Naples, Italy
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11
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Li L, Yu XJ, Gao L, Cheng L, Sun B, Wang G. Diabetic Ferroptosis and Pancreatic Cancer: Foe or Friend? Antioxid Redox Signal 2022; 37:1206-1221. [PMID: 35996983 DOI: 10.1089/ars.2022.0101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Significance: Pancreatic cancer and diabetes have a reciprocal causation relationship. As a potential risk factor, diabetes increases morbidity and promotes pancreatic cancer progression. The main mechanisms include islet dysfunction-induced systemic metabolic disorder, pancreatic stellate cell activation, and immunosuppression. Ferroptosis is regarded as regulated cell death, which participates in chemotherapy resistance and is refractory to radiation therapy and immunotherapy. Diabetes-induced ferroptosis causes many complications, but the underlying mechanism of diabetes-related ferroptosis in pancreatic cancer has not been discussed. Recent Advances: Ferroptosis alleviates pancreatic intraepithelial neoplasia (PanIN) progression by activating chronic inflammation. The specific drugs that cause ferroptosis achieve tumor suppression by inducing lipid peroxidation. Ferroptosis plays pro and con roles in cancer. Both the ferroptosis inhibitor and inducer exhibit antitumor effects through killing cancer cells or directly affecting tumor growth. Diabetes-induced ferroptosis contributes to tumor cell death by different components, including tumor cells, fibroblasts, immune cells, and adipocytes. A better understanding of its role in modulating the tumor microenvironment will reveal diabetes-associated ferroptotic features in cancer development, which can be used to figure out possible treatment strategies for cancer patients with hyperglycemia. Critical Issues: We demonstrate the potential roles of diabetes-related ferroptosis in pancreatic cancer progression and discuss ferroptosis-related antitumor effects and therapeutics for pancreatic cancer treatment. Future Directions: Further studies are required to highlight mechanisms of diabetes-mediated ferroptosis in pancreatic cancer tumorigenesis and progression. The antitumor effects of ferroptosis regulators combined with chemotherapy, targeted therapy, or immunotherapy in diabetic patients should be investigated. We hope that pancreatic cancer patients with diabetes will benefit from ferroptosis-related therapies. Antioxid. Redox Signal. 37, 1206-1221.
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Affiliation(s)
- Le Li
- Department of Pancreatic and Biliary Surgery and The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xing-Jia Yu
- Department of Centric Operating Room, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Lei Gao
- Department of Pancreatic and Biliary Surgery and The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Long Cheng
- Department of Pancreatic and Biliary Surgery and The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Bei Sun
- Department of Pancreatic and Biliary Surgery and The First Affiliated Hospital of Harbin Medical University, Harbin, China.,Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Gang Wang
- Department of Pancreatic and Biliary Surgery and The First Affiliated Hospital of Harbin Medical University, Harbin, China
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12
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Kalantari S, Kazemi B, Roudi R, Zali H, D'Angelo A, Mohamadkhani A, Madjd Z, Pourshams A. RNA-sequencing for transcriptional profiling of whole blood in early stage and metastatic pancreatic cancer patients. Cell Biol Int 2022; 47:238-249. [PMID: 36229929 DOI: 10.1002/cbin.11924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 09/21/2022] [Indexed: 11/10/2022]
Abstract
We investigated the transcriptional profile of whole blood in early and metastatic stages of pancreatic cancer (PaC) patients to identify potential diagnostic factors for early diagnosis. Blood samples from 18 participants (6 healthy individuals, 6 patients in early stage (I/II) PaC, and 6 patients in metastatic PaC) were analyzed by RNA-sequencing. The expression levels of identified genes were subsequently compared with their expression in pancreatic tumor tissues based on TCGA data reported in UALCAN and GEPIA2 databases. Overall, 331 and 724 genes were identified as differentially expressed genes in early and metastatic stages, respectively. Of these, 146 genes were shared by early and metastatic stages. Upregulation of PTCD3 and UBA52 genes and downregulation of A2M and ARID1B genes in PaC patients were observed from early stage to metastasis. TCGA database showed increasing trend in expression levels of these genes from stage I to IV in pancreatic tumor tissue. Finally, we found that low expression of PTCD3, A2M, and ARID1B genes and high expression of UBA52 gene were positively correlated with PaC patients survival. We identified a four-gene set (PTCD3, UBA52, A2M, and ARID1B) expressed in peripheral blood of early stage and metastatic PaC patients that may be useful for PaC early diagnosis.
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Affiliation(s)
- Sima Kalantari
- Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bahram Kazemi
- Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Raheleh Roudi
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Hakimeh Zali
- Proteomics Research Center, Shahid Beheshti University of Medical Science, Tehran, Iran.,Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alberto D'Angelo
- Department of Biology and Biochemistry, University of Bath, Bath, UK
| | - Ashraf Mohamadkhani
- Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Madjd
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Akram Pourshams
- Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.,Digestive Oncology Research Center, Digestive Diseases Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
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13
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Tang K, Chen Q, Liu Y, Wang L, Lu W. Combination of Metformin and Sorafenib Induces Ferroptosis of Hepatocellular Carcinoma Through p62-Keap1-Nrf2 Pathway. J Cancer 2022; 13:3234-3243. [PMID: 36118519 PMCID: PMC9475364 DOI: 10.7150/jca.76618] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 08/21/2022] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal cancers in the world. Sorafenib is the first small-molecule multi-kinase inhibitors approved by FDA for treatment of advanced HCC. Metformin has been demonstrated to have benefit for preventing cancer progression. In human recurrent HCCs, NF-E2-related factor 2 (Nrf2) was overexpressed and associated with poor survival. Nrf2 related signaling pathway plays central role to mediate cellular resistance to sorafenib through protecting HCC cells from ferroptosis. The effect of Combination treatment for HCC cells and the intrinsic mechanism have not been reported. In this study, metformin augmented the anti-tumor effect of sorafenib for HCC through ferroptosis induction by inhibiting Nrf2 related pathway. Based on the results of Nrf2 knockdown and p62 knockdown study, the combination of sorafenib and metformin suppressed proliferation of HCC cells through p62-Keap1-Nrf2/HO1 signaling way. Size of xenografts treated with the combination of sorafenib and metformin was smaller than other groups in vivo. Moreover, the combination treatment greatly induced ferroptosis in HCC cells through inhibiting Nrf2 expression. Based on our findings, the combination treatment suppressed proliferation of HCC cells through ferroptosis induction, by p62-Keap1-Nrf2/HO1 signaling way.
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Affiliation(s)
- Kezhong Tang
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, #88 Jiefang Road, Hangzhou 310009, PR China
| | - Qing Chen
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, #88 Jiefang Road, Hangzhou 310009, PR China
| | - Yanmo Liu
- Department of Pharmacy, Affiliated Sir RunRun Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310009, PR China
| | - Lantian Wang
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, #88 Jiefang Road, Hangzhou 310009, PR China
| | - Wenjie Lu
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, #88 Jiefang Road, Hangzhou 310009, PR China
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14
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Mosallaei M, Ehtesham N, Rahimirad S, Saghi M, Vatandoost N, Khosravi S. PBMCs: a new source of diagnostic and prognostic biomarkers. Arch Physiol Biochem 2022; 128:1081-1087. [PMID: 32293207 DOI: 10.1080/13813455.2020.1752257] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
There are various types of molecular biomarkers that are derived from distinct starting materials. Although many indirect biomarkers are found in blood, their detection remains a challenging issue because of the high degree of fragmentation, minute quantity and a vast amount of non-specific background. The present review points out the sensitivity and specificity of peripheral blood mononuclear cells (PBMCs) as an intact source of biomarkers in a variety of diseases. Multiple recent studies that have used PBMCs as a source of biomarkers reveal the alteration of mRNAs/microRNAs (miRNAs) signature and methylation profile in many kinds of disorders; for instance, dysregulation of mRNAs/miRNAs in schizophrenia, diabetes and different types of cancers and change in the methylation status of LINE-1 in neoplasms. In conclusion with a strong probability, PBMCs mimic conditions of some tissues which are in contact with them like the tumour cells, hence providing a non-invasive and suitable source of biomarkers.
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Affiliation(s)
- Meysam Mosallaei
- Department of Genetics and Molecular biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Naeim Ehtesham
- Department of Genetics and Molecular biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shima Rahimirad
- Department of Genetics and Molecular biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mostafa Saghi
- AJA Cancer Epidemiology Research and Treatment Center (AJA-CERTC), AJA university of medical sciences, Tehran, Iran
| | - Nasim Vatandoost
- Department of Genetics and Molecular biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sharifeh Khosravi
- Department of Genetics and Molecular biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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15
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Park S, Kim OH, Lee K, Park IB, Kim NH, Moon S, Im J, Sharma SP, Oh BC, Nam S, Lee DH. Plasma and urinary extracellular vesicle microRNAs and their related pathways in diabetic kidney disease. Genomics 2022; 114:110407. [PMID: 35716820 DOI: 10.1016/j.ygeno.2022.110407] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 04/22/2022] [Accepted: 06/10/2022] [Indexed: 11/30/2022]
Abstract
To explore extracellular vesicle microRNAs (EV miRNAs) and their target mRNAs in relation to diabetic kidney disease (DKD), we performed paired plasma and urinary EV small RNA sequencing (n = 18) in patients with type 2 diabetes and DKD (n = 5) and healthy subjects (n = 4) and metabolic network analyses using our own miRNA and public mRNA datasets. We found 13 common differentially expressed EV miRNAs in both fluids and 17 target mRNAs, including RRM2, NT5E, and UGDH. Because succinate dehydrogenase B was suggested to interact with proteins encoded by these three genes, we measured urinary succinate and adenosine in a validation study (n = 194). These two urinary metabolite concentrations were associated with DKD progression. In addition, renal expressions of NT5E and UGDH proteins were increased in db/db mice with DKD compared to control mice. In conclusion, we profiled DKD-related EV miRNAs in plasma and urine samples and found their relevant target pathways.
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Affiliation(s)
- Sungjin Park
- Department of Genome Medicine and Science, AI Convergence Center for Medical Science, Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Republic of Korea
| | - Ok-Hee Kim
- Department of Physiology, Lee Gil Ya Cancer and Diabetes Institute, College of Medicine, Gachon University, Incheon, Republic of Korea
| | - Kiyoung Lee
- Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea; Department of Internal Medicine, Gachon University College of Medicine, Incheon, Republic of Korea
| | - Ie Byung Park
- Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea; Department of Internal Medicine, Gachon University College of Medicine, Incheon, Republic of Korea
| | - Nan Hee Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Seongryeol Moon
- Department of Health Sciences and Technology, Gachon Advanced Institute for Health Sciences and Technology (GAIHST), Gachon University, Incheon, Republic of Korea
| | - Jaebeen Im
- Department of Health Sciences and Technology, Gachon Advanced Institute for Health Sciences and Technology (GAIHST), Gachon University, Incheon, Republic of Korea
| | - Satya Priya Sharma
- Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea
| | - Byung-Chul Oh
- Department of Physiology, Lee Gil Ya Cancer and Diabetes Institute, College of Medicine, Gachon University, Incheon, Republic of Korea
| | - Seungyoon Nam
- Department of Genome Medicine and Science, AI Convergence Center for Medical Science, Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Republic of Korea; Department of Health Sciences and Technology, Gachon Advanced Institute for Health Sciences and Technology (GAIHST), Gachon University, Incheon, Republic of Korea.
| | - Dae Ho Lee
- Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea; Department of Internal Medicine, Gachon University College of Medicine, Incheon, Republic of Korea; Department of Health Sciences and Technology, Gachon Advanced Institute for Health Sciences and Technology (GAIHST), Gachon University, Incheon, Republic of Korea.
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16
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Evans RM, Wei Z. Interorgan crosstalk in pancreatic islet function and pathology. FEBS Lett 2022; 596:607-619. [PMID: 35014695 DOI: 10.1002/1873-3468.14282] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 12/16/2021] [Accepted: 12/28/2021] [Indexed: 12/14/2022]
Abstract
Pancreatic β cells secrete insulin in response to glucose, a process that is regulated at multiple levels, including a network of input signals from other organ systems. Impaired islet function contributes to the pathogenesis of type 2 diabetes mellitus (T2DM), and targeting inter-organ communications, such as GLP-1 signalling, to enhance β-cell function has been proven to be a successful therapeutic strategy in the last decade. In this review, we will discuss recent advances in inter-organ communication from the metabolic, immune and neural system to pancreatic islets, their biological implication in normal pancreas endocrine function and their role in the (mal)adaptive responses of islet to nutrition-induced stress.
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Affiliation(s)
- Ronald M Evans
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Zong Wei
- Department of Physiology and Biomedical Engineering, Mayo Clinic Arizona, Scottsdale, AZ, USA
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17
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Yang J, Fang W, Wu W, Tian Z, Gao R, Yu L, Chen D, Weng X, Zhu S, Yang C. A Novel Diagnostic Biomarker, PZP, for Detecting Colorectal Cancer in Type 2 Diabetes Mellitus Patients Identified by Serum-Based Mass Spectrometry. Front Mol Biosci 2021; 8:736272. [PMID: 34917649 PMCID: PMC8670180 DOI: 10.3389/fmolb.2021.736272] [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: 07/05/2021] [Accepted: 11/16/2021] [Indexed: 12/19/2022] Open
Abstract
Background: Growing evidence has confirmed that populations with type 2 diabetes mellitus (T2DM) have an increasing risk of developing colorectal cancer (CRC). Thus, convenient and effective screening strategies for CRC should be developed for the T2DM population to increase the detection rate of CRC. Methods: Twenty serum samples extracted from five healthy participants, five T2DM patients, five CRC patients and five T2DM patients with CRC (T2DM + CRC) were submitted to data-independent acquisition mass spectrometry (DIA-MS) analysis to discover unique differentially altered proteins (DAPs) for CRC in patients with T2DM. Then, the diagnostic value of pregnancy zone protein (PZP) was validated by ELISA analysis in the validated cohort. Results: Based on DIA-MS analysis, we found eight unique proteins specific to T2DM patients with CRC. Among these proteins, four proteins showed different expression between the T2DM + CRC and T2DM groups, and PZP exhibited the largest difference. Next, the diagnostic value of serum PZP was validated by ELISA analysis with an AUC of 0.713. Moreover, the combination of PZP, CA199 and CEA exhibited encouraging diagnostic value, and the AUC reached 0.916. Conclusion: Overall, our current research implied that PZP could be regarded as a newfound serum biomarker for CRC medical diagnosis in T2DM patients.
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Affiliation(s)
- Jiayue Yang
- Department of Endocrinology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Weigang Fang
- Department of Gastroenterology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Wenjun Wu
- Department of Endocrinology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Zhen Tian
- Department of Clinical Laboratory, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Rong Gao
- Department of Clinical Laboratory, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Lu Yu
- Department of Endocrinology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Dayang Chen
- Department of Gastroenterology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Xiaohua Weng
- Department of Endocrinology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Shengwei Zhu
- Department of Endocrinology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Cheng Yang
- Department of Gastroenterology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
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Perera CJ, Falasca M, Chari ST, Greenfield JR, Xu Z, Pirola RC, Wilson JS, Apte MV. Role of Pancreatic Stellate Cell-Derived Exosomes in Pancreatic Cancer-Related Diabetes: A Novel Hypothesis. Cancers (Basel) 2021; 13:cancers13205224. [PMID: 34680372 PMCID: PMC8534084 DOI: 10.3390/cancers13205224] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 09/27/2021] [Accepted: 10/14/2021] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating condition characterised by vague symptomatology and delayed diagnosis. About 30% of PDAC patients report a history of new onset diabetes, usually diagnosed within 3 years prior to the diagnosis of cancer. Thus, new onset diabetes, which is also known as pancreatic cancer-related diabetes (PCRD), could be a harbinger of PDAC. Diabetes is driven by progressive β cell loss/dysfunction and insulin resistance, two key features that are also found in PCRD. Experimental studies suggest that PDAC cell-derived exosomes carry factors that are detrimental to β cell function and insulin sensitivity. However, the role of stromal cells, particularly pancreatic stellate cells (PSCs), in the pathogenesis of PCRD is not known. PSCs are present around the earliest neoplastic lesions and around islets. Given that PSCs interact closely with cancer cells to drive cancer progression, it is possible that exosomal cargo from both cancer cells and PSCs plays a role in modulating β cell function and peripheral insulin resistance. Identification of such mediators may help elucidate the mechanisms of PCRD and aid early detection of PDAC. This paper discusses the concept of a novel role of PSCs in the pathogenesis of PCRD.
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Affiliation(s)
- Chamini J. Perera
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Health, UNSW Sydney, Sydney 2052, Australia; (C.J.P.); (Z.X.); (R.C.P.); (J.S.W.)
- Ingham Institute for Applied Medical Research, Sydney 2170, Australia
| | - Marco Falasca
- Metabolic Signalling Group, Curtin Health Innovation Research Institute, Curtin Medical School, Curtin University, Perth 6102, Australia;
| | - Suresh T. Chari
- M.D Anderson Cancer Centre, Department of Gastroenterology, Hepatology and Nutrition, University of Texas, Houston, TX 75083, USA;
| | - Jerry R. Greenfield
- St Vincent Clinical School, Faculty of Medicine and Health, UNSW Sydney, Sydney 2052, Australia;
- Healthy Ageing, Garvan Institute of Medical Research, Darlinghurst 2830, Australia
- Department of Diabetes and Endocrinology, St Vincent’s Hospital, Darlinghurst 3065, Australia
| | - Zhihong Xu
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Health, UNSW Sydney, Sydney 2052, Australia; (C.J.P.); (Z.X.); (R.C.P.); (J.S.W.)
- Ingham Institute for Applied Medical Research, Sydney 2170, Australia
| | - Romano C. Pirola
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Health, UNSW Sydney, Sydney 2052, Australia; (C.J.P.); (Z.X.); (R.C.P.); (J.S.W.)
| | - Jeremy S. Wilson
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Health, UNSW Sydney, Sydney 2052, Australia; (C.J.P.); (Z.X.); (R.C.P.); (J.S.W.)
- Ingham Institute for Applied Medical Research, Sydney 2170, Australia
| | - Minoti V. Apte
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Health, UNSW Sydney, Sydney 2052, Australia; (C.J.P.); (Z.X.); (R.C.P.); (J.S.W.)
- Ingham Institute for Applied Medical Research, Sydney 2170, Australia
- Correspondence: ; Tel.: +61-2-87389029
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19
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Duan X, Wang W, Pan Q, Guo L. Type 2 Diabetes Mellitus Intersects With Pancreatic Cancer Diagnosis and Development. Front Oncol 2021; 11:730038. [PMID: 34485159 PMCID: PMC8415500 DOI: 10.3389/fonc.2021.730038] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 07/30/2021] [Indexed: 12/12/2022] Open
Abstract
The relationship between type 2 diabetes mellitus (T2DM) and pancreatic cancer (PC) is complex. Diabetes is a known risk factor for PC, and new-onset diabetes (NOD) could be an early manifestation of PC that may be facilitate the early diagnosis of PC. Metformin offers a clear benefit of inhibiting PC, whereas insulin therapy may increase the risk of PC development. No evidence has shown that novel hypoglycemic drugs help or prevent PC. In this review, the effects of T2DM on PC development are summarized, and novel strategies for the prevention and treatment of T2DM and PC are discussed.
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Affiliation(s)
- Xiaoye Duan
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Weihao Wang
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Qi Pan
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Lixin Guo
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
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20
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Roy A, Sahoo J, Kamalanathan S, Naik D, Mohan P, Kalayarasan R. Diabetes and pancreatic cancer: Exploring the two-way traffic. World J Gastroenterol 2021; 27:4939-4962. [PMID: 34497428 PMCID: PMC8384733 DOI: 10.3748/wjg.v27.i30.4939] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 06/16/2021] [Accepted: 07/07/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) is often associated with a poor prognosis. Long-standing diabetes mellitus is considered as an important risk factor for its development. This risk can be modified by the use of certain antidiabetic medications. On the other hand, new-onset diabetes can signal towards an underlying PC in the elderly population. Recently, several attempts have been made to develop an effective clinical tool for PC screening using a combination of history of new-onset diabetes and several other clinical and biochemical markers. On the contrary, diabetes affects the survival after treatment for PC. We describe this intimate and complex two-way relationship of diabetes and PC in this review by exploring the underlying pathogenesis.
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Affiliation(s)
- Ayan Roy
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
- Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, Jodhpur 342005, India
| | - Jayaprakash Sahoo
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Sadishkumar Kamalanathan
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Dukhabandhu Naik
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Pazhanivel Mohan
- Department of Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Raja Kalayarasan
- Department of Surgical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
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21
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Zhou W, Wang Y, Gao H, Jia Y, Xu Y, Wan X, Zhang Z, Yu H, Yan S. Identification of Key Genes Involved in Pancreatic Ductal Adenocarcinoma with Diabetes Mellitus Based on Gene Expression Profiling Analysis. Pathol Oncol Res 2021; 27:604730. [PMID: 34257566 PMCID: PMC8262175 DOI: 10.3389/pore.2021.604730] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 02/26/2021] [Indexed: 12/12/2022]
Abstract
This study aimed to identify key genes involved in the progression of diabetic pancreatic ductal adenocarcinoma (PDAC). Two gene expression datasets (GSE74629 and GSE15932) were obtained from Gene Expression Omnibus. Then, differentially expressed genes (DEGs) between diabetic PDAC and non-diabetic PDAC were identified, followed by a functional analysis. Subsequently, gene modules related to DM were extracted by weighed gene co-expression network analysis. The protein-protein interaction (PPI) network for genes in significant modules was constructed and functional analyses were also performed. After that, the optimal feature genes were screened by support vector machine (SVM) recursive feature elimination and SVM classification model was built. Finally, survival analysis was conducted to identify prognostic genes. The correlations between prognostic genes and other clinical factors were also analyzed. Totally, 1546 DEGs with consistent change tendencies were identified and functional analyses showed they were strongly correlated with metabolic pathways. Furthermore, there were two significant gene modules, in which RPS27A and UBA52 were key genes. Functional analysis of genes in two gene modules revealed that these genes primarily participated in oxidative phosphorylation pathway. Additionally, 21 feature genes were closely related with diabetic PDAC and the corresponding SVM classifier markedly distinguished diabetic PDAC from non-diabetic PDAC patients. Finally, decreased KIF22 and PYGL levels had good survival outcomes for PDAC. Four genes (RPS27A, UBA52, KIF22 and PYGL) might be involved in the pathogenesis of diabetic PDAC. Furthermore, KIF22 and PYGL acted as prognostic biomarkers for diabetic PDAC.
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Affiliation(s)
- Weiyu Zhou
- Department of Endocrinology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yujing Wang
- Department of Endocrinology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hongmei Gao
- Department of Neurology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Ying Jia
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yuanxin Xu
- Department of Endocrinology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiaojing Wan
- Department of Endocrinology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhiying Zhang
- Department of Endocrinology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Haiqiao Yu
- Department of Endocrinology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shuang Yan
- Department of Endocrinology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
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Yang J, Yang C, Shen H, Wu W, Tian Z, Xu Q, Cao C, Ye S, Ban L, Tong X, Mei J. Discovery and validation of PZP as a novel serum biomarker for screening lung adenocarcinoma in type 2 diabetes mellitus patients. Cancer Cell Int 2021; 21:162. [PMID: 33691685 PMCID: PMC7945354 DOI: 10.1186/s12935-021-01861-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Accepted: 03/01/2021] [Indexed: 12/11/2022] Open
Abstract
Background Patients with type 2 diabetes mellitus (T2DM) have an increased risk of suffering from various malignancies. This study aimed to identify specific biomarkers that can detect lung adenocarcinoma (LAC) in T2DM patients for the early diagnosis of LAC. Methods The clinical information of hospitalized T2DM patients diagnosed with various cancers was collected by reviewing medical records in Wuxi People’s Hospital Affiliated to Nanjing Medical University from January 1, 2015, to June 30, 2020. To discover diagnostic biomarkers for early-stage LAC in the T2DM population, 20 samples obtained from 5 healthy controls, 5 T2DM patients, 5 LAC patients and 5 T2DM patients with LAC (T2DM + LAC) were subjected to sequential windowed acquisition of all theoretical fragment ion mass spectrum (SWATH-MS) analysis to identify specific differentially-expressed proteins (DEPs) for LAC in patients with T2DM. Then, these results were validated by parallel reaction monitoring MS (PRM-MS) and ELISA analyses. Results Lung cancer was the most common malignant tumor in patients with T2DM, and LAC accounted for the majority of cases. Using SWATH-MS analysis, we found 13 proteins to be unique in T2DM patients with early LAC. Two serum proteins were further validated by PRM-MS analysis, namely, pregnancy-zone protein (PZP) and insulin-like growth factor binding protein 3 (IGFBP3). Furthermore, the diagnostic values of these proteins were validated by ELISA, and PZP was validated as a novel serum biomarker for screening LAC in T2DM patients. Conclusions Our findings indicated that PZP could be used as a novel serum biomarker for the identification of LAC in T2DM patients, which will enhance auxiliary diagnosis and assist in the selection of surgical treatment at an early stage. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-021-01861-8.
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Affiliation(s)
- Jiayue Yang
- Department of Endocrinology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China
| | - Cheng Yang
- Department of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China
| | - Hong Shen
- Department of Endocrinology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China
| | - Wenjun Wu
- Department of Endocrinology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China
| | - Zhen Tian
- Department of Clinical Laboratory, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China
| | - Qinghua Xu
- Department of Endocrinology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China
| | - Cuiping Cao
- Department of Endocrinology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China
| | - Shugao Ye
- Department of Chest Surgery, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China
| | - Le Ban
- Department of Chest Surgery, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China
| | - Xin Tong
- Department of Clinical Laboratory, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China
| | - Jie Mei
- Department of Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, No. 299 Qingyang Road, Wuxi, 214023, China.
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23
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Brown ML, Schneyer A. A Decade Later: Revisiting the TGFβ Family's Role in Diabetes. Trends Endocrinol Metab 2021; 32:36-47. [PMID: 33261990 DOI: 10.1016/j.tem.2020.11.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 11/02/2020] [Accepted: 11/03/2020] [Indexed: 12/16/2022]
Abstract
In 2010, we published a review summarizing the role of the transforming growth factor-beta (TGFβ) family of proteins in diabetes. At that time there were still many outstanding questions that needed to be answered. In this updated review, we revisit the topic and provide new evidence that supports findings from previous studies included in the 2010 review and adds to the knowledge base with new findings and information. The most substantial contributions in the past 10 years have been in the areas of human data, the investigation of TGFβ family members other than activin [e.g., bone morphogenetic proteins (BMPs), growth and differentiation factor 11 (GDF11), nodal], and the expansion of β-cell number through various mechanisms including transdifferentiation, which was previously believed to not be possible.
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Affiliation(s)
| | - Alan Schneyer
- Fairbanks Pharmaceuticals, Inc., Springfield, MA 01199, USA
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24
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Kazemi B, Kalantari S, Pourshams A, Roudi R, Zali H, Bandehpour M, Kalantari A, Ghanbari R, D'Angelo A, Madjd Z. Identification of potential common molecular factors of pancreatic cancer and diabetes mellitus using microarray data analysis combined with bioinformatics techniques and experimental validation. BIOMEDICAL AND BIOTECHNOLOGY RESEARCH JOURNAL (BBRJ) 2021. [DOI: 10.4103/bbrj.bbrj_122_21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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25
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Mizuno S, Nakai Y, Ishigaki K, Saito K, Oyama H, Hamada T, Suzuki Y, Inokuma A, Kanai S, Noguchi K, Sato T, Hakuta R, Saito T, Takahara N, Kogure H, Isayama H, Koike K. Screening Strategy of Pancreatic Cancer in Patients with Diabetes Mellitus. Diagnostics (Basel) 2020; 10:diagnostics10080572. [PMID: 32784500 PMCID: PMC7460163 DOI: 10.3390/diagnostics10080572] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 08/04/2020] [Accepted: 08/07/2020] [Indexed: 12/18/2022] Open
Abstract
The incidence of pancreatic cancer (PCa) is increasing worldwide and has become one of the leading causes of cancer-related death. Screening for high risk populations is fundamental to overcome this intractable malignancy. Diabetes mellitus (DM) is classically known as a risk factor for PCa. Recently the reverse causality is in the spotlight, that is to say, DM is considered to be a manifestation of PCa. Numbers of epidemiological studies clarified that new-onset DM (≤2-year duration) was predominant in PCa patients and the relative risk for PCa inversely correlated with duration of DM. Among patients with new-onset DM, elder onset, weight loss, and rapid exacerbation of glycemic control were reported to be promising risk factors and signs, and the model was developed by combining these factors. Several pilot studies disclosed the possible utility of biomarkers to discriminate PCa-associated DM from type 2 DM. However, there is no reliable biomarkers to be used in the practice. We previously reported the application of a multivariate index for PCa based on the profile of plasma free amino acids (PFAAs) among diabetic patients. We are further investigating on the PFAA profile of PCa-associated DM, and it can be useful for developing the novel biomarker in the near future.
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Affiliation(s)
- Suguru Mizuno
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (S.M.); (K.I.); (K.S.); (H.O.); (T.H.); (Y.S.); (A.I.); (S.K.); (K.N.); (T.S.); (R.H.); (T.S.); (N.T.); (H.K.); (K.K.)
| | - Yousuke Nakai
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (S.M.); (K.I.); (K.S.); (H.O.); (T.H.); (Y.S.); (A.I.); (S.K.); (K.N.); (T.S.); (R.H.); (T.S.); (N.T.); (H.K.); (K.K.)
- Department of Endoscopy and Endoscopic Surgery, The University of Tokyo Hospital, Tokyo 113-8655, Japan
- Correspondence: ; Tel.: +81-3-3815-5411; Fax: +81-3-5800-8812
| | - Kazunaga Ishigaki
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (S.M.); (K.I.); (K.S.); (H.O.); (T.H.); (Y.S.); (A.I.); (S.K.); (K.N.); (T.S.); (R.H.); (T.S.); (N.T.); (H.K.); (K.K.)
| | - Kei Saito
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (S.M.); (K.I.); (K.S.); (H.O.); (T.H.); (Y.S.); (A.I.); (S.K.); (K.N.); (T.S.); (R.H.); (T.S.); (N.T.); (H.K.); (K.K.)
| | - Hiroki Oyama
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (S.M.); (K.I.); (K.S.); (H.O.); (T.H.); (Y.S.); (A.I.); (S.K.); (K.N.); (T.S.); (R.H.); (T.S.); (N.T.); (H.K.); (K.K.)
| | - Tsuyoshi Hamada
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (S.M.); (K.I.); (K.S.); (H.O.); (T.H.); (Y.S.); (A.I.); (S.K.); (K.N.); (T.S.); (R.H.); (T.S.); (N.T.); (H.K.); (K.K.)
| | - Yukari Suzuki
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (S.M.); (K.I.); (K.S.); (H.O.); (T.H.); (Y.S.); (A.I.); (S.K.); (K.N.); (T.S.); (R.H.); (T.S.); (N.T.); (H.K.); (K.K.)
| | - Akiyuki Inokuma
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (S.M.); (K.I.); (K.S.); (H.O.); (T.H.); (Y.S.); (A.I.); (S.K.); (K.N.); (T.S.); (R.H.); (T.S.); (N.T.); (H.K.); (K.K.)
| | - Sachiko Kanai
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (S.M.); (K.I.); (K.S.); (H.O.); (T.H.); (Y.S.); (A.I.); (S.K.); (K.N.); (T.S.); (R.H.); (T.S.); (N.T.); (H.K.); (K.K.)
| | - Kensaku Noguchi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (S.M.); (K.I.); (K.S.); (H.O.); (T.H.); (Y.S.); (A.I.); (S.K.); (K.N.); (T.S.); (R.H.); (T.S.); (N.T.); (H.K.); (K.K.)
| | - Tatsuya Sato
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (S.M.); (K.I.); (K.S.); (H.O.); (T.H.); (Y.S.); (A.I.); (S.K.); (K.N.); (T.S.); (R.H.); (T.S.); (N.T.); (H.K.); (K.K.)
| | - Ryunosuke Hakuta
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (S.M.); (K.I.); (K.S.); (H.O.); (T.H.); (Y.S.); (A.I.); (S.K.); (K.N.); (T.S.); (R.H.); (T.S.); (N.T.); (H.K.); (K.K.)
- Department of Endoscopy and Endoscopic Surgery, The University of Tokyo Hospital, Tokyo 113-8655, Japan
| | - Tomotaka Saito
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (S.M.); (K.I.); (K.S.); (H.O.); (T.H.); (Y.S.); (A.I.); (S.K.); (K.N.); (T.S.); (R.H.); (T.S.); (N.T.); (H.K.); (K.K.)
| | - Naminatsu Takahara
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (S.M.); (K.I.); (K.S.); (H.O.); (T.H.); (Y.S.); (A.I.); (S.K.); (K.N.); (T.S.); (R.H.); (T.S.); (N.T.); (H.K.); (K.K.)
| | - Hirofumi Kogure
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (S.M.); (K.I.); (K.S.); (H.O.); (T.H.); (Y.S.); (A.I.); (S.K.); (K.N.); (T.S.); (R.H.); (T.S.); (N.T.); (H.K.); (K.K.)
| | - Hiroyuki Isayama
- Department of Gastroenterology, Graduate School of Medicine, Juntendo University, Tokyo 113-8431, Japan;
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (S.M.); (K.I.); (K.S.); (H.O.); (T.H.); (Y.S.); (A.I.); (S.K.); (K.N.); (T.S.); (R.H.); (T.S.); (N.T.); (H.K.); (K.K.)
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Sahni S, Krisp C, Molloy MP, Nahm C, Maloney S, Gillson J, Gill AJ, Samra J, Mittal A. PSMD11, PTPRM and PTPRB as novel biomarkers of pancreatic cancer progression. Biochim Biophys Acta Gen Subj 2020; 1864:129682. [PMID: 32663515 DOI: 10.1016/j.bbagen.2020.129682] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 06/25/2020] [Accepted: 07/09/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) has the lowest survival rate of all major cancers. Surgery is the only curative intent therapy, but the majority of patients experience disease relapse. Thus, patients who do not benefit from highly morbid surgical resection needs to be identified and offered palliative chemotherapy instead. In this pilot study, we aimed to identify differentially regulated proteins in plasma and plasma derived microparticles from PDAC patients with poor and good prognosis. METHODS Plasma and plasma derived microparticle samples were obtained before surgical resection from PDAC patients. Sequential Windowed Acquisition of all Theoretical fragment ion spectra - Mass Spectrometry (SWATH-MS) proteomic analysis was performed to identify and quantify proteins in these samples. Statistical analysis was performed to identify biomarkers for poor prognosis. RESULTS A total of 482 and 1024 proteins were identified from plasma and microparticle samples, respectively, by SWATH-MS analysis. Statistical analysis of the data further identified nine and six differentially (log2ratio > 1, p < .05) expressed proteins in plasma and microparticles, respectively. Protein tyrosine phosphatases, PTPRM and PTPRB, were decreased in plasma of patients with poor PDAC prognosis, while proteasomal subunit PSMD11 was increased in microparticles of patients with poor prognosis. CONCLUSION AND GENERAL SIGNIFICANCE A novel blood-based biomarker signature for PDAC prognosis was identified.
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Affiliation(s)
- Sumit Sahni
- Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Australia; Australian Pancreatic Centre, St Leonards, Sydney, Australia.
| | - Christoph Krisp
- Australian Proteome Analysis Facility (APAF), Macquarie University, Sydney, NSW, Australia; Institute of Clinical Chemistry and Laboratory Medicine, Mass Spectrometric Proteomics, University Medical Center Hamburg - Eppendorf, Hamburg, Germany
| | - Mark P Molloy
- Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Australian Proteome Analysis Facility (APAF), Macquarie University, Sydney, NSW, Australia; Bowel Cancer and Biomarker Research Laboratory, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
| | - Christopher Nahm
- Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Australia; Australian Pancreatic Centre, St Leonards, Sydney, Australia
| | - Sarah Maloney
- Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Australia
| | - Josef Gillson
- Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Australia; Australian Pancreatic Centre, St Leonards, Sydney, Australia
| | - Anthony J Gill
- Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW 2065, Australia; NSW Health Pathology, Dept of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
| | - Jaswinder Samra
- Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Australian Pancreatic Centre, St Leonards, Sydney, Australia; Upper GI Surgical Unit, Royal North Shore Hospital and North Shore Private Hospital, Australia
| | - Anubhav Mittal
- Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Australian Pancreatic Centre, St Leonards, Sydney, Australia; Upper GI Surgical Unit, Royal North Shore Hospital and North Shore Private Hospital, Australia.
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Principe DR, Rana A. Updated risk factors to inform early pancreatic cancer screening and identify high risk patients. Cancer Lett 2020; 485:56-65. [PMID: 32389710 DOI: 10.1016/j.canlet.2020.04.022] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 04/06/2020] [Accepted: 04/23/2020] [Indexed: 02/07/2023]
Abstract
Pancreatic adenocarcinoma (PDAC) is associated with poor clinical outcomes and incomplete responses to conventional therapy. Therefore, there is an unmet clinical need to better understand the predisposing factors for pancreatic cancer in hopes of providing early screening to high-risk patients. While select risk factors such as age, race, and family history, or predisposing syndromes are unavoidable, there are several new and established risk factors that allow for intervention, namely by counseling patients to make the appropriate lifestyle modifications. Here, we discuss the best-studied risk factors for PDAC such as tobacco use and chronic pancreatitis, as well as newly emerging risk factors including select nutritional deficits, bacterial infections, and psychosocial factors. As several of these risk factors appear to be additive or synergistic, by understanding their relationships and offering coordinated, multidisciplinary care to high-risk patients, it may be possible to reduce pancreatic cancer incidence and improve clinical outcomes through early detection.
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Affiliation(s)
- Daniel R Principe
- Medical Scientist Training Program, University of Illinois College of Medicine, Chicago, IL, USA; Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL, USA.
| | - Ajay Rana
- Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL, USA; Jesse Brown VA Medical Center, Chicago, IL, USA.
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28
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Sirtl S, Oehrle B, Mayerle J, Goni E. [Diabetes and pancreatic cancer - state of the art]. MMW Fortschr Med 2020; 162:42-46. [PMID: 32342372 DOI: 10.1007/s15006-020-0428-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Affiliation(s)
- Simon Sirtl
- Medizinische Klinik und Poliklinik II, Klinikum der Ludwig-Maximilians, Universität München, Deutschland
| | - Bettina Oehrle
- Medizinische Klinik und Poliklinik II, Klinikum der Ludwig-Maximilians, Universität München, Deutschland
| | - Julia Mayerle
- Medizinische Klinik und Poliklinik II, Klinikum der Ludwig-Maximilians-Universität München Campus Großhadern, Marchioninistr. 15, D-81377, München, Deutschland.
| | - Elisabetta Goni
- Medizinische Klinik und Poliklinik II, Klinikum der Ludwig-Maximilians, Universität München, Deutschland
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29
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Tramontano AC, Chen Y, Watson TR, Eckel A, Sheehan DF, Peters MLB, Pandharipande PV, Hur C, Kong CY. Pancreatic cancer treatment costs, including patient liability, by phase of care and treatment modality, 2000-2013. Medicine (Baltimore) 2019; 98:e18082. [PMID: 31804317 PMCID: PMC6919520 DOI: 10.1097/md.0000000000018082] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES Our study provides phase-specific cost estimates for pancreatic cancer based on stage and treatment. We compare treatment costs between the different phases and within the stage and treatment modality subgroups. METHODS Our cohort included 20,917 pancreatic cancer patients from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database diagnosed between 2000 and 2011. We allocated costs into four phases of care-staging (or surgery), initial, continuing, and terminal- and calculated the total, cancer-attributable, and patient-liability costs in 2018 US dollars. We fit linear regression models using log transformation to determine whether costs were predicted by age and calendar year. RESULTS Monthly cost estimates were high during the staging and surgery phases, decreased over the initial and continuing phases, and increased during the three-month terminal phase. Overall, the linear regression models showed that cancer-attributable costs either remained stable or increased by year, and either were unaffected by age or decreased with older age; continuing phase costs for stage II patients increased with age. CONCLUSIONS Our estimates demonstrate that pancreatic cancer costs can vary widely by stage and treatment received. These cost estimates can serve as an important baseline foundation to guide resource allocation for cancer care and research in the future.
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Affiliation(s)
| | - Yufan Chen
- Institute for Technology Assessment, Massachusetts General Hospital, Boston, MA
| | - Tina R. Watson
- Institute for Technology Assessment, Massachusetts General Hospital, Boston, MA
| | - Andrew Eckel
- Institute for Technology Assessment, Massachusetts General Hospital, Boston, MA
| | - Deirdre F. Sheehan
- Institute for Technology Assessment, Massachusetts General Hospital, Boston, MA
| | - Mary Linton B. Peters
- Institute for Technology Assessment, Massachusetts General Hospital, Boston, MA
- Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, MA
- Harvard Medical School, Boston, MA
| | - Pari V. Pandharipande
- Institute for Technology Assessment, Massachusetts General Hospital, Boston, MA
- Harvard Medical School, Boston, MA
| | - Chin Hur
- Columbia University Medical Center, New York City, NY
| | - Chung Yin Kong
- Institute for Technology Assessment, Massachusetts General Hospital, Boston, MA
- Harvard Medical School, Boston, MA
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30
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Zhang H, Huang JJ, Wang J, Hu M, Chen XC, Sun W, Ren KF, Ji J. Surface-Mediated Stimuli-Responsive Gene Delivery Based on Breath Figure Film Combined with Matrix Metalloproteinase-Sensitive Hydrogel. ACS Biomater Sci Eng 2019; 5:6610-6616. [PMID: 33423480 DOI: 10.1021/acsbiomaterials.9b01353] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Surface-mediated gene delivery appears to be potential gene delivery modes for various applications. Still, controlled and smart delivery manners are required especially considering the need for gene therapy to deliver gene with selectivity. A surface that can effectively payload DNA, promote cell adhesion, and stimuli response is an important prerequisite. Here, we report a matrix metalloproteinase (MMP)-responsive surface-mediated gene delivery system by combining MMP-degradable hydrogel with a breath figure (BF) porous film. The MMP-degradable hydrogel containing plasmid DNA was loaded into the surface pores of the BF film as DNA reservoirs. The upper surface without hydrogel on the BF film served as footholds of integrin adhesions. MMP is one of the important endogenous signals in tumor-related pathologic changes, and MMP expressions in cancer cells are significantly higher than those in normal cells. Consequently, our surface-mediated gene delivery locally and rapidly released the payload DNA in response to cancer cells and transfected them. This work highlights the importance of the combination of stimuli-response and surface-mediated gene delivery to functional materials, showing good potential applications in the field of gene therapy.
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Affiliation(s)
- He Zhang
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, Zhejiang, China
| | - Jun-Jie Huang
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, Zhejiang, China
| | - Jing Wang
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, Zhejiang, China
| | - Mi Hu
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, Zhejiang, China
| | - Xia-Chao Chen
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, Zhejiang, China
| | - Wei Sun
- Department of Polymer Science and Engineering, Faculty of Materials Science and Chemical Engineering, Ningbo University, Ningbo 315211, Zhejiang, China
| | - Ke-Feng Ren
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, Zhejiang, China
| | - Jian Ji
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, Zhejiang, China
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Dong WZ, Yu HT, Wang QY, Tian ZB. Temporal patterns of new-onset diabetes in pancreatic cancer. Shijie Huaren Xiaohua Zazhi 2019; 27:943-947. [DOI: 10.11569/wcjd.v27.i15.943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND ancreatic carcinoma (PCa) is a malignant tumor occurring in the exocrine glands of the pancreas. It has a hidden onset, a high degree of malignancy, and a low 5-year survival rate of less than 1%. Early clinical symptoms are often atypical and there is a lack of specific means of examination. Most of the cases have progressed to the middle and late stages of the disease and the prognosis is poor. A large number of studies have shown that diabetes is closely related to PCa, but the causal relationship between them is not clear. This study aimed to retrospectively analyze patients with PCa in order to find early diagnostic clues for PCa.
AIM To explore the relationship between PCa and new-onset diabetes.
METHODS Four hundred and sixty-three PCa patients were included in a PCa group, and 658 patients without tumour, alimentary system or non-metabolic abnormality were included in a control group. The age and course of diabetes mellitus (DM) of patients in the PCa group and control group were analyzed and compared.
RESULTS The average age of new-onset diabetes patients in the PCa group was 70.09 years (95%CI: 69.00-71.18), and the average age of patients with type 2 diabetes was 58.68 years (95%CI: 57.84-59.53); the difference was statistically significant (P < 0.01). Patients in the PCa group were divided into seven groups according to the course of diabetes. The prevalence of diabetes in the pancreatic cancer group with diabetes disease duration < 1 year, 1-2 years, and > 10 years was significantly higher than that of the control group (19.87% vs 1.52%, P < 0.01; 6.48% vs 1.67%, P < 0.05; 2.16% vs 0.91%, P < 0.05).
CONCLUSION New-onset diabetes can act as a clue for early diagnosis of PCa. Clinicians should be alert to the possibility of PCa for elderly patients with a diagnosis of DM in 2 years or great blood glucose fluctuation in short time．
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Affiliation(s)
- Wen-Zhu Dong
- Department of Gastroenterology, the 971 Hospital of Chinese PLA, Qingdao 266071, Shandong Province, China
| | - Hai-Tao Yu
- Department of Gastroenterology, the 971 Hospital of Chinese PLA, Qingdao 266071, Shandong Province, China
| | - Qun-Ying Wang
- Department of Gastroenterology, the 971 Hospital of Chinese PLA, Qingdao 266071, Shandong Province, China
| | - Zi-Bin Tian
- Department of Gastroenterology, the Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
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Bhattamisra SK, Siang TC, Rong CY, Annan NC, Sean EHY, Xi LW, Lyn OS, Shan LH, Choudhury H, Pandey M, Gorain B. Type-3c Diabetes Mellitus, Diabetes of Exocrine Pancreas - An Update. Curr Diabetes Rev 2019; 15:382-394. [PMID: 30648511 DOI: 10.2174/1573399815666190115145702] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 11/02/2018] [Accepted: 01/08/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND The incidence of diabetes is increasing steeply; the number of diabetics has doubled over the past three decades. Surprisingly, the knowledge of type 3c diabetes mellitus (T3cDM) is still unclear to the researchers, scientist and medical practitioners, leading towards erroneous diagnosis, which is sometimes misdiagnosed as type 1 diabetes mellitus (T1DM), or more frequently type 2 diabetes mellitus (T2DM). This review is aimed to outline recent information on the etiology, pathophysiology, diagnostic procedures, and therapeutic management of T3cDM patients. METHODS The literature related to T3cDM was thoroughly searched from the public domains and reviewed extensively to construct this article. Further, existing literature related to the other forms of diabetes is reviewed for projecting the differences among the different forms of diabetes. Detailed and updated information related to epidemiological evidence, risk factors, symptoms, diagnosis, pathogenesis and management is structured in this review. RESULTS T3cDM is often misdiagnosed as T2DM due to the insufficient knowledge differentiating between T2DM and T3cDM. The pathogenesis of T3cDM is explained which is often linked to the history of chronic pancreatitis, pancreatic cancer. Inflammation, and fibrosis in pancreatic tissue lead to damage both endocrine and exocrine functions, thus leading to insulin/glucagon insufficiency and pancreatic enzyme deficiency. CONCLUSION Future advancements should be accompanied by the establishment of a quick diagnostic tool through the understanding of potential biomarkers of the disease and newer treatments for better control of the diseased condition.
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Affiliation(s)
- Subrat Kumar Bhattamisra
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Tiew Chin Siang
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Chieng Yi Rong
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Naveenya Chetty Annan
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Esther Ho Yung Sean
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Lim Wen Xi
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Ong Siu Lyn
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Liew Hui Shan
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Hira Choudhury
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Manisha Pandey
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Bapi Gorain
- School of Pharmacy, Taylor's University, 1, Jalan Taylors, 47500 Subang Jaya, Selangor, Malaysia
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Pothuraju R, Rachagani S, Junker WM, Chaudhary S, Saraswathi V, Kaur S, Batra SK. Pancreatic cancer associated with obesity and diabetes: an alternative approach for its targeting. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:319. [PMID: 30567565 PMCID: PMC6299603 DOI: 10.1186/s13046-018-0963-4] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 11/14/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Pancreatic cancer (PC) is among foremost causes of cancer related deaths worldwide due to generic symptoms, lack of effective screening strategies and resistance to chemo- and radiotherapies. The risk factors associated with PC include several metabolic disorders such as obesity, insulin resistance and type 2 diabetes mellitus (T2DM). Studies have shown that obesity and T2DM are associated with PC pathogenesis; however, their role in PC initiation and development remains obscure. MAIN BODY Several biochemical and physiological factors associated with obesity and/or T2DM including adipokines, inflammatory mediators, and altered microbiome are involved in PC progression and metastasis albeit by different molecular mechanisms. Deep understanding of these factors and causal relationship between factors and altered signaling pathways will facilitate deconvolution of disease complexity as well as lead to development of novel therapies. In the present review, we focuses on the interplay between adipocytokines, gut microbiota, adrenomedullin, hyaluronan, vanin and matrix metalloproteinase affected by metabolic alteration and pancreatic tumor progression. CONCLUSIONS Metabolic diseases, such as obesity and T2DM, contribute PC development through altered metabolic pathways. Delineating key players in oncogenic development in pancreas due to metabolic disorder could be a beneficial strategy to combat cancers associated with metabolic diseases in particular, PC.
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Affiliation(s)
- Ramesh Pothuraju
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Satyanarayana Rachagani
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Wade M Junker
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.,Sanguine Diagnostics and Therapeutics, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sanjib Chaudhary
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Viswanathan Saraswathi
- Department of Cellular & Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sukhwinder Kaur
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA. .,Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. .,Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
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Sharma A, Smyrk TC, Levy MJ, Topazian MA, Chari ST. Fasting Blood Glucose Levels Provide Estimate of Duration and Progression of Pancreatic Cancer Before Diagnosis. Gastroenterology 2018; 155:490-500.e2. [PMID: 29723506 PMCID: PMC6067966 DOI: 10.1053/j.gastro.2018.04.025] [Citation(s) in RCA: 128] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 03/22/2018] [Accepted: 04/25/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS It is unclear how long pancreatic ductal adenocarcinomas (PDACs) are present before diagnosis. Patients with PDAC usually develop hyperglycemia and diabetes before the tumor is identified. If early invasive PDACs are associated with hyperglycemia, the duration of hyperglycemia should associate with the time that they have had the tumor. METHODS We collected data on patients with PDACs from medical databases in Olmsted County, Minnesota, from 2000 through 2015 and from the Mayo Clinic's tumor registry from January 1, 1976, through January 1, 2017. We compared glycemic profiles of patients with PDAC (cases) compared with patients without cancer, matched for age and sex (controls). We analyzed temporal fasting blood glucose (FBG) profiles collected for 60 months before patients received a PDAC diagnosis (index date) (n = 219) (cohort A), FBG profiles of patients with resected PDAC (n = 526) stratified by tumor volume and grade (cohort B), and temporal FBG profiles of patients with resected PDACs from whom long-term FBG data were available (n = 103) (cohort C). The primary outcome was to estimate duration of presence of invasive PDAC before its diagnosis based on hyperglycemia, defined as significantly higher (P < .05) FBG levels in cases compared with controls. RESULTS In cohort A, the mean FBG did not differ significantly between cases and controls 36 months before the index date. Hyperglycemia was first noted 36 to 30 months before PDAC diagnosis in all cases, those with or without diabetes at baseline and those with or without resection at diagnosis. FBG level increased until diagnosis of PDAC. In cohort B, the mean FBG did not differ significantly in controls vs cases with PDACs below 1.0 mL. The smallest tumor volume associated with hyperglycemia was 1.1 to 2.0 mL; FBG level increased with tumor volume. FBG varied with tumor grade: well- or moderately differentiated tumors (5.8 mL) produced the same FBG levels as smaller, poorly differentiated tumors (1.5 mL) (P < .001). In cohort C, the duration of prediagnostic hyperglycemia for cases with large-, medium-, or small-volume PDACs was 36 to 24, 24 to 12, and 12 to 0 months, respectively. PDAC resection resolved hyperglycemia, regardless of tumor location. CONCLUSIONS In a case-control study of patients with PDAC from 2 databases, we associated FBG level with time to PDAC diagnosis and tumor volume and grade. Patients are hyperglycemic for a mean period of 36 to 30 months before PDAC diagnosis; this information might be incorporated into strategies for early detection.
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35
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Irigoyen A, Jimenez-Luna C, Benavides M, Caba O, Gallego J, Ortuño FM, Guillen-Ponce C, Rojas I, Aranda E, Torres C, Prados J. Integrative multi-platform meta-analysis of gene expression profiles in pancreatic ductal adenocarcinoma patients for identifying novel diagnostic biomarkers. PLoS One 2018; 13:e0194844. [PMID: 29617451 PMCID: PMC5884535 DOI: 10.1371/journal.pone.0194844] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Accepted: 03/09/2018] [Indexed: 01/16/2023] Open
Abstract
Applying differentially expressed genes (DEGs) to identify feasible biomarkers in diseases can be a hard task when working with heterogeneous datasets. Expression data are strongly influenced by technology, sample preparation processes, and/or labeling methods. The proliferation of different microarray platforms for measuring gene expression increases the need to develop models able to compare their results, especially when different technologies can lead to signal values that vary greatly. Integrative meta-analysis can significantly improve the reliability and robustness of DEG detection. The objective of this work was to develop an integrative approach for identifying potential cancer biomarkers by integrating gene expression data from two different platforms. Pancreatic ductal adenocarcinoma (PDAC), where there is an urgent need to find new biomarkers due its late diagnosis, is an ideal candidate for testing this technology. Expression data from two different datasets, namely Affymetrix and Illumina (18 and 36 PDAC patients, respectively), as well as from 18 healthy controls, was used for this study. A meta-analysis based on an empirical Bayesian methodology (ComBat) was then proposed to integrate these datasets. DEGs were finally identified from the integrated data by using the statistical programming language R. After our integrative meta-analysis, 5 genes were commonly identified within the individual analyses of the independent datasets. Also, 28 novel genes that were not reported by the individual analyses ('gained' genes) were also discovered. Several of these gained genes have been already related to other gastroenterological tumors. The proposed integrative meta-analysis has revealed novel DEGs that may play an important role in PDAC and could be potential biomarkers for diagnosing the disease.
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Affiliation(s)
- Antonio Irigoyen
- Department of Medical Oncology, Virgen de la Salud Hospital, Toledo, Spain
| | - Cristina Jimenez-Luna
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada, Spain
| | - Manuel Benavides
- Department of Medical Oncology, Virgen de la Victoria Hospital, Malaga, Spain
| | - Octavio Caba
- Department of Health Sciences, University of Jaen, Jaen, Spain
| | - Javier Gallego
- Department of Medical Oncology, University General Hospital of Elche, Alicante, Spain
| | - Francisco Manuel Ortuño
- Department of Computer Architecture and Computer Technology, Research Center for Information and Communications Technologies, University of Granada, Granada, Spain
| | | | - Ignacio Rojas
- Department of Computer Architecture and Computer Technology, Research Center for Information and Communications Technologies, University of Granada, Granada, Spain
| | - Enrique Aranda
- Maimonides Institute of Biomedical Research (IMIBIC), Reina Sofia Hospital, University of Cordoba, Cordoba, Spain
| | - Carolina Torres
- Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, Granada, Spain
| | - Jose Prados
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada, Spain
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A novel scoring system to analyze combined effect of lifestyle factors on pancreatic cancer risk: a retrospective case-control study. Sci Rep 2017; 7:13657. [PMID: 29057932 PMCID: PMC5651911 DOI: 10.1038/s41598-017-13182-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Accepted: 09/14/2017] [Indexed: 12/12/2022] Open
Abstract
Although several risk factors for the onset of pancreatic ductal adenocarcinoma (PDAC) have been identified, currently, no scoring system to systemically evaluate the risk of PDAC has been established. In this study, we aimed to use a population of over 1200 patients to build a novel scoring system, and evaluated combined effects of risk factors for PDAC patients.A set of 4904 participants including 1274 PDAC patients and 3630 non-cancer individuals were recruited for the single-center study over 17-year period (1997~2013). Systematic logical analysis were presented for case and control groups, and a risk rating system was constructed to assess combined risk factors. Seven independent risk factors were identified with the increased risk of PDAC, were selected into the risk score. A merged risk assessment model was established, demonstrating significantly increased PDAC risk in following a number of rising scores. Individuals with scores from 1 to more than 4, the responding OR (95% CI) were 3.06 (2.57~3.65), 7.08 (5.63~8.91), 22.4 (14.2~35.4), and 31.4 (12.7~77.5), respectively. The integer-based risk score in the study can be used for risk stratification to accurately evaluate PDAC occurrence at an early stage. This scoring system provides an accurate risk assessment of PDAC risk.
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37
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Yan Y, Gao R, Trinh TLP, Grant MB. Immunodeficiency in Pancreatic Adenocarcinoma with Diabetes Revealed by Comparative Genomics. Clin Cancer Res 2017; 23:6363-6373. [PMID: 28684632 PMCID: PMC6022738 DOI: 10.1158/1078-0432.ccr-17-0250] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Revised: 05/22/2017] [Accepted: 07/03/2017] [Indexed: 02/06/2023]
Abstract
Purpose: Pancreatic adenocarcinomas (PAAD) often are not diagnosed until their late stages, leaving no effective treatments. Currently, immunotherapy provides a promising treatment option against this malignancy. However, a set of immunotherapy agents benefit patients with many types of cancer, but not PAAD. Sharing the origin in the same organ, diabetes and PAAD tend to occur concurrently. We aimed to identify the impact of diabetes on immunotherapy of PAAD by conducting a comparative genomics analysis.Experimental Design: We analyzed level 3 PAAD genomics data (RNAseq, miRNAseq, DNA methylation, somatic copy number, and somatic mutation) from The Cancer Genome Atlas (TCGA) and Firehose. The differential molecular profiles in PAAD with/out diabetes were performed by the differential gene expression, pathway analysis, epigenetic regulation, somatic copy-number alteration, and somatic gene mutation.Results: Differential gene expression analysis revealed a strong enrichment of immunogenic signature genes in diabetic individuals, including PD-1 and CTLA4, that were currently targetable for immunotherapy. Pathway analysis further implied that diabetic individuals were defective in immune modulation genes. Somatic copy-number aberration (SCNA) analysis showed a higher frequency of amplification and deletion occurred in the cohort without diabetes. Integrative analysis revealed strong association between differential gene expression, and epigenetic regulations, however, seemed not affected by SCNAs. Importantly, our somatic mutation analysis showed that the occurrence of diabetes in PAAD was associated with a large set of gene mutations encoding genes participating in immune modulation.Conclusions: Our analysis reveals the impact of diabetes on immunodeficiency in PAAD patients and provides novel insights into new therapeutic opportunities. Clin Cancer Res; 23(20); 6363-73. ©2017 AACR.
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Affiliation(s)
- Yuanqing Yan
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Ruli Gao
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Thao L P Trinh
- Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Maria B Grant
- Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana.
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Yao K, Wang Q, Jia J, Zhao H. A competing endogenous RNA network identifies novel mRNA, miRNA and lncRNA markers for the prognosis of diabetic pancreatic cancer. Tumour Biol 2017. [PMID: 28639886 DOI: 10.1177/1010428317707882] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Pancreatic cancer (PaC) is highly associated with diabetes mellitus (DM). However, the mechanisms are insufficient. The study aimed to uncover the underlying regulatory mechanism on diabetic PaC and find novel biomarkers for the disease prognosis. Two RNA-sequencing (RNA-seq) datasets, GSE74629 and GSE15932, as well as relevant data in TCGA were utilized. After pretreatment, differentially expressed genes (DEGs) or miRNAs (DEMs) or lncRNAs (DELs) between diabetic PaC and non-diabetic PaC patients were identified, and further examined for their correlations with clinical information. Prognostic RNAs were selected using KM curve. Optimal gene set for classification of different samples were recognized by support vector machine. Protein-protein interaction (PPI) network was constructed for DEGs based on protein databases. Interactions among three kinds of RNAs were revealed in the 'lncRNA-miRNA-mRNA' competing endogenous RNA (ceRNA) network. A group of 32 feature genes were identified that could classify diabetic PaC from non-diabetic PaC, such as CCDC33, CTLA4 and MAP4K1. This classifier had a high accuracy on the prediction. Seven lncRNAs were tied up with prognosis of diabetic PaC, especially UCA1. In addition, crucial DEMs were selected, such as hsa-miR-214 (predicted targets: MAP4K1 and CCDC33) and hsa-miR-429 (predicted targets: CTLA4). Notably, interactions of 'HOTAIR-hsa-miR-214-CCDC33' and 'CECR7-hsa-miR-429-CTLA4' were highlighted in the ceRNA network. Several biomarkers were identified for diagnosis of diabetic PaC, such as HOTAIR, CECR7, UCA1, hsa-miR-214, hsa-miR-429, CCDC33 and CTLA4. 'HOTAIR-hsa-miR-214-CCDC33' and 'CECR7-hsa-miR-429-CTLA4' regulations might be two important mechanisms for the disease progression.
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Affiliation(s)
- Kanyu Yao
- 1 Department of Emergency Surgery, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, People's Republic of China
| | - Qi Wang
- 1 Department of Emergency Surgery, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, People's Republic of China
| | - Jianhua Jia
- 2 The 253th Hospital of P.L.A., Hohhot, People's Republic of China
| | - Haiping Zhao
- 3 Department of Hepatobiliary Surgery, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, People's Republic of China
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Andersen DK, Korc M, Petersen GM, Eibl G, Li D, Rickels MR, Chari ST, Abbruzzese JL. Diabetes, Pancreatogenic Diabetes, and Pancreatic Cancer. Diabetes 2017; 66:1103-1110. [PMID: 28507210 PMCID: PMC5399609 DOI: 10.2337/db16-1477] [Citation(s) in RCA: 298] [Impact Index Per Article: 37.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 01/25/2017] [Indexed: 12/16/2022]
Abstract
The relationships between diabetes and pancreatic ductal adenocarcinoma (PDAC) are complex. Longstanding type 2 diabetes (T2DM) is a risk factor for pancreatic cancer, but increasing epidemiological data point to PDAC as also a cause of diabetes due to unknown mechanisms. New-onset diabetes is of particular interest to the oncology community as the differentiation of new-onset diabetes caused by PDAC as distinct from T2DM may allow for earlier diagnosis of PDAC. To address these relationships and raise awareness of the relationships between PDAC and diabetes, a symposium entitled Diabetes, Pancreatogenic Diabetes, and Pancreatic Cancer was held at the American Diabetes Association's 76th Scientific Sessions in June 2016. This article summarizes the data presented at that symposium, describing the current understanding of the interrelationships between diabetes, diabetes management, and pancreatic cancer, and identifies areas where additional research is needed.
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MESH Headings
- Blood Glucose/metabolism
- Carcinoma, Pancreatic Ductal/epidemiology
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/immunology
- Causality
- Diabetes Mellitus/classification
- Diabetes Mellitus/drug therapy
- Diabetes Mellitus/epidemiology
- Diabetes Mellitus/etiology
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/epidemiology
- Diabetes Mellitus, Type 2/genetics
- Diabetes Mellitus, Type 2/metabolism
- Genetic Predisposition to Disease
- Humans
- Hypoglycemic Agents/therapeutic use
- Inflammation
- Obesity/epidemiology
- Obesity/immunology
- Pancreatic Neoplasms/epidemiology
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/immunology
- Pancreatitis, Chronic/complications
- Pancreatitis, Chronic/epidemiology
- Pancreatitis, Chronic/genetics
- Pancreatitis, Chronic/immunology
- Risk Factors
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Affiliation(s)
- Dana K Andersen
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Murray Korc
- Division of Endocrinology, Department of Medicine, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, and Indiana University Melvin and Bren Simon Cancer Center and Pancreatic Cancer Signature Center, Indianapolis, IN
| | | | - Guido Eibl
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Donghui Li
- Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX
| | - Michael R Rickels
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Suresh T Chari
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN
| | - James L Abbruzzese
- Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC
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Mariani F, Roncucci L. Role of the Vanins-Myeloperoxidase Axis in Colorectal Carcinogenesis. Int J Mol Sci 2017; 18:E918. [PMID: 28448444 PMCID: PMC5454831 DOI: 10.3390/ijms18050918] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Revised: 04/20/2017] [Accepted: 04/21/2017] [Indexed: 02/06/2023] Open
Abstract
The presence of chronic inflammation in the colonic mucosa leads to an increased risk of cancer. Among proteins involved in the regulation of mucosal inflammation and that may contribute both to structural damage of the intestinal mucosa and to intestinal carcinogenesis, there are myeloperoxidase (MPO) and vanins. The infiltration of colonic mucosa by neutrophils may promote carcinogenesis through MPO, a key enzyme contained in the lysosomes of neutrophils that regulates local inflammation and the generation of reactive oxygen species (ROS) and mutagenic species. The human vanin gene family consists of three genes: vanin-1, vanin-2 and vanin-3. All vanin molecules are pantetheinases, that hydrolyze pantetheine into pantothenic acid (vitamin B5), and cysteamine, a sulfhydryl compound. Vanin-1 loss confers an increased resistance to stress and acute intestinal inflammation, while vanin-2 regulates adhesion and transmigration of activated neutrophils. The metabolic product of these enzymes has a prominent role in the inflammation processes by affecting glutathione levels, inducing ulcers through a reduction in mucosal blood flow and oxygenation, decreasing local defense mechanisms, and in carcinogenesis by damaging DNA and regulating pathways involved in cell apoptosis, metabolism and growth, as Nrf2 and HIF-1α.
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Affiliation(s)
- Francesco Mariani
- Department of Diagnostic and Clinical Medicine, and Public Health, University of Modena and Reggio Emilia, Via Del Pozzo 71, I-41125 Modena, Italy.
| | - Luca Roncucci
- Department of Diagnostic and Clinical Medicine, and Public Health, University of Modena and Reggio Emilia, Via Del Pozzo 71, I-41125 Modena, Italy.
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Han H, Valdepérez D, Jin Q, Yang B, Li Z, Wu Y, Pelaz B, Parak WJ, Ji J. Dual Enzymatic Reaction-Assisted Gemcitabine Delivery Systems for Programmed Pancreatic Cancer Therapy. ACS NANO 2017; 11:1281-1291. [PMID: 28071891 DOI: 10.1021/acsnano.6b05541] [Citation(s) in RCA: 130] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
Dual enzymatic reactions were introduced to fabricate programmed gemcitabine (GEM) nanovectors for targeted pancreatic cancer therapy. Dual-enzyme-sensitive GEM nanovectors were prepared by conjugation of matrix metalloproteinase-9 (MMP-9) detachable poly(ethylene glycol) (PEG), cathepsin B-cleavable GEM, and targeting ligand CycloRGD to CdSe/ZnS quantum dots (QDs). The GEM nanovectors decorated with a PEG corona could avoid nonspecific interactions and exhibit prolonged blood circulation time. After GEM nanovectors were accumulated in tumor tissue by the enhanced permeability and retention (EPR) effect, the PEG corona can be removed by overexpressed MMP-9 in tumor tissue and RGD would be exposed, which was capable of facilitating cellular internalization. Once internalized into pancreatic cancer cells, the elevated lysosomal cathepsin B could further promote the release of GEM. By employing dual enzymatic reactions, the GEM nanovectors could achieve prolonged circulation time while maintaining enhanced cellular internalization and effective drug release. The proposed mechanism of the dual enzymatic reaction-assisted GEM delivery system was fully investigated both in vitro and in vivo. Meanwhile, compared to free GEM, the deamination of GEM nanovectors into inactive 2',2'-difluorodeoxyuridine (dFdU) could be greatly suppressed, while the concentration of the activated form of GEM (gemcitabine triphosphate, dFdCTP) was significantly increased in tumor tissue, thus exhibiting superior tumor inhibition activity with minimal side effects.
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Affiliation(s)
- Haijie Han
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education, Department of Polymer Science and Engineering, Zhejiang University , Hangzhou, 310027, China
| | - Daniel Valdepérez
- Philipps Universität Marburg , Fachbereich Physik, Renthof 7, 35037, Marburg, Germany
| | - Qiao Jin
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education, Department of Polymer Science and Engineering, Zhejiang University , Hangzhou, 310027, China
| | - Bin Yang
- Department of Surgery, 2nd Affiliated Hospital, School of Medicine, Zhejiang University , 88 Jiefang Road, Hangzhou, Zhejiang Province, 310009, China
| | - Zuhong Li
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education, Department of Polymer Science and Engineering, Zhejiang University , Hangzhou, 310027, China
| | - Yulian Wu
- Department of Surgery, 2nd Affiliated Hospital, School of Medicine, Zhejiang University , 88 Jiefang Road, Hangzhou, Zhejiang Province, 310009, China
| | - Beatriz Pelaz
- Philipps Universität Marburg , Fachbereich Physik, Renthof 7, 35037, Marburg, Germany
| | - Wolfgang J Parak
- Philipps Universität Marburg , Fachbereich Physik, Renthof 7, 35037, Marburg, Germany
| | - Jian Ji
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education, Department of Polymer Science and Engineering, Zhejiang University , Hangzhou, 310027, China
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Hart PA, Bellin MD, Andersen DK, Bradley D, Cruz-Monserrate Z, Forsmark CE, Goodarzi MO, Habtezion A, Korc M, Kudva YC, Pandol SJ, Yadav D, Chari ST. Type 3c (pancreatogenic) diabetes mellitus secondary to chronic pancreatitis and pancreatic cancer. Lancet Gastroenterol Hepatol 2016; 1:226-237. [PMID: 28404095 DOI: 10.1016/s2468-1253(16)30106-6] [Citation(s) in RCA: 293] [Impact Index Per Article: 32.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 07/25/2016] [Accepted: 07/26/2016] [Indexed: 02/07/2023]
Abstract
Diabetes mellitus is a group of diseases defined by persistent hyperglycaemia. Type 2 diabetes, the most prevalent form, is characterised initially by impaired insulin sensitivity and subsequently by an inadequate compensatory insulin response. Diabetes can also develop as a direct consequence of other diseases, including diseases of the exocrine pancreas. Historically, diabetes due to diseases of the exocrine pancreas was described as pancreatogenic or pancreatogenous diabetes mellitus, but recent literature refers to it as type 3c diabetes. It is important to note that type 3c diabetes is not a single entity; it occurs because of a variety of exocrine pancreatic diseases with varying mechanisms of hyperglycaemia. The most commonly identified causes of type 3c diabetes are chronic pancreatitis, pancreatic ductal adenocarcinoma, haemochromatosis, cystic fibrosis, and previous pancreatic surgery. In this Review, we discuss the epidemiology, pathogenesis, and clinical relevance of type 3c diabetes secondary to chronic pancreatitis and pancreatic ductal adenocarcinoma, and highlight several important knowledge gaps.
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Affiliation(s)
- Phil A Hart
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
| | - Melena D Bellin
- Division of Pediatric Endocrinology and Schulze Diabetes Institute, University of Minnesota Medical Center, Minneapolis, MN, USA
| | - Dana K Andersen
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - David Bradley
- Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University, Wexner Medical Center, Columbus, OH, USA
| | - Zobeida Cruz-Monserrate
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Christopher E Forsmark
- Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainesville, FL, USA
| | - Mark O Goodarzi
- Division of Endocrinology, Diabetes, and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Aida Habtezion
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - Murray Korc
- Departments of Medicine, Biochemistry, and Molecular Biology, Indiana University School of Medicine, Indiana University Simon Cancer Center, Indianapolis, IN, USA; Pancreatic Cancer Signature Center, Indiana University Simon Cancer Center, Indianapolis, IN, USA
| | - Yogish C Kudva
- Division of Endocrinology and Metabolism, Mayo Clinic, Rochester, MN, USA
| | - Stephen J Pandol
- Department of Veterans Affairs, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Dhiraj Yadav
- Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh and UPMC Medical Center, Pittsburgh, PA, USA; Department of Medicine, University of Pittsburgh and UPMC Medical Center, Pittsburgh, PA, USA
| | - Suresh T Chari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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Kim BJ, Aloia TA. Cost-effectiveness of palliative surgery versus nonsurgical procedures in gastrointestinal cancer patients. J Surg Oncol 2016; 114:316-22. [PMID: 27132654 DOI: 10.1002/jso.24280] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Accepted: 04/13/2016] [Indexed: 01/04/2023]
Abstract
Palliative care is an essential component to multidisciplinary cancer care. Improved symptom control, quality of life (QOL), and survival have resulted from its utilization. Cost-effectiveness and utility analyses are significant variables that should be considered in comparing benefits and costs of medical interventions to determine if certain treatments are economically justified. This is a review on the cost-effectiveness of palliative surgery compared to other nonsurgical palliative procedures in patients with unresectable gastrointestinal cancers. J. Surg. Oncol. 2016;114:316-322. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Bradford J Kim
- Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Thomas A Aloia
- Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
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Value of Early Check-Up of Carbohydrate Antigen 19-9 Levels for Pancreatic Cancer Screening in Asymptomatic New-Onset Diabetic Patients. Pancreas 2016; 45:730-4. [PMID: 26646277 DOI: 10.1097/mpa.0000000000000538] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
OBJECTIVES We evaluated the value of carbohydrate antigen 19-9 (CA 19-9) as a pancreatic cancer (PC) screening tool in an asymptomatic new-onset diabetic patients. METHODS Medical records of asymptomatic patients newly diagnosed with diabetes mellitus (DM) were reviewed retrospectively at our hospital from January 2004 to January 2013. RESULTS In total, 2363 asymptomatic diabetic patients with CA 19-9 measurements were enrolled. Of them, 68 (2.9%) were diagnosed with PC. In the 1719 patients who had CA 19-9 measured within 1 year after the DM diagnosis, a total of 51 (3.0 %) patients developed PC and the odds ratio (OR) of PC according to higher CA 19-9 than normal upper limit, 37 IU/mL was 5.57 (P < 0.001). In 248 patients checked CA 19-9 between 1 and 2 years after DM diagnosis, PC was detected in 9 (3.6%) cases and OR of high CA 19-9 was 4.51 (P = 0.019). However, beyond 2 years, the OR for PC showed no statistical significance. The patients with high CA 19-9 levels tended to have more advanced-stage disease. CONCLUSIONS Early check-up of CA 19-9 could be a useful marker for screening for PC in asymptomatic patients with new-onset DM in the first 2 years.
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Blood expression of matrix metalloproteinases 8 and 9 and of their inducers S100A8 and S100A9 supports diagnosis and prognosis of PDAC-associated diabetes mellitus. Clin Chim Acta 2016; 456:24-30. [PMID: 26923392 DOI: 10.1016/j.cca.2016.02.018] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Accepted: 02/24/2016] [Indexed: 02/05/2023]
Abstract
BACKGROUND Based on the knowledge that matrix metalloproteinases (MMPs) and S100A8/A9 synergistically work in causing PDAC-associated type 2 diabetes mellitus (T2DM), we verified whether tissue and blood MMP8, MMP9, S100A8 and S100A9 expression might help in distinguishing PDAC among diabetics. METHODS Relative quantification of MMP8, MMP9, S100A8 and S100A9 mRNA was performed in tissues obtained from 8 PDAC, 4 chronic pancreatitis (ChrPa), 4 non-PDAC tumors and in PBMCs obtained from 30 controls, 43 T2DM, 41 ChrPa, 91 PDAC and 33 pancreatic-biliary tract tumors. RESULTS T2DM was observed in PDAC (66%), in pancreatic-biliary tract tumors (64%) and in ChrPa (70%). In diabetics, with or without PDAC, MMP9 tissue expression was increased (p<0.05). Both MMPs increased in PDAC and MMP9 increased also in pancreatic-biliary tract tumors PBMCs. In diabetics, MMP9 was independently associated with PDAC (p=0.025), but failed to enhance CA 19-9 discriminant efficacy. A highly reduced S100A9 expression, found in 7 PDAC, was significantly correlated with a reduced overall survival (p=0.015). CONCLUSIONS An increased expression of tissue and blood MMP9 reflects the presence of PDAC-associated diabetes mellitus. This finding fits with the hypothesized role of MMPs as part of the complex network linking cancer to diabetes.
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Kang M, Qin W, Buya M, Dong X, Zheng W, Lu W, Chen J, Guo Q, Wu Y. VNN1, a potential biomarker for pancreatic cancer-associated new-onset diabetes, aggravates paraneoplastic islet dysfunction by increasing oxidative stress. Cancer Lett 2016; 373:241-50. [PMID: 26845448 DOI: 10.1016/j.canlet.2015.12.031] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2015] [Revised: 12/11/2015] [Accepted: 12/25/2015] [Indexed: 12/28/2022]
Abstract
In our previous clinical microarray analysis, we were the first to report on Vanin-1 (VNN1) as a novel clinically derived biomarker of pancreatic cancer-associated new-onset diabetes (PCAND). The functional mechanisms of VNN1 in the pathogenesis of PCAND, however, are not completely understood. In the present study, we further extend our previous clinical study to include laboratory research. The functions and mechanisms of neoplastic overexpressed VNN1 in PCAND have been explored using a co-culture model. Furthermore, the serum concentrations and discrimination power of downstream molecules of VNN1 were tested in a PCAND cohort. Pancreatic ductal adenocarcinoma (PDA) overexpressed VNN1 further aggravates paraneoplastic islet dysfunction; decreases in GSH/PPAR-γ concentrations and increases in ROS/cysteamine might be primary cause of this effect. Clinical serum analyses revealed that the expression profiles of these molecules were aberrant in the PCAND group. Our results further demonstrated that PCAND is a type of paraneoplastic diabetes. As the only clinically derived biomarker for PCAND screening available today, the biological role of VNN1 in triggering oxidative stress within the pancreatic microenvironment is important. The molecules downstream of VNN1 are also potential biomarkers for PCAND screening.
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Affiliation(s)
- Muxing Kang
- Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China; Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China
| | - Wenjie Qin
- Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China; Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China
| | - Miranbieke Buya
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China
| | - Xin Dong
- Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China
| | - Wen Zheng
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China
| | - Wenjie Lu
- Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China
| | - Jian Chen
- Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China
| | - Qingqu Guo
- Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China
| | - Yulian Wu
- Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China; Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China.
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Gao W, Zhou Y, Li Q, Zhou Q, Tan L, Song Y, Zhao X, Yu M, Zheng S, Ye H, Zeng B, Lin Q, Zhou J, Liu Y, Huang H, Zhang H, Hu X, Li Z, Dai X, Chen R. Analysis of global gene expression profiles suggests a role of acute inflammation in type 3C diabetes mellitus caused by pancreatic ductal adenocarcinoma. Diabetologia 2015; 58:835-44. [PMID: 25636208 DOI: 10.1007/s00125-014-3481-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Accepted: 12/05/2014] [Indexed: 02/07/2023]
Abstract
AIMS/HYPOTHESIS Pancreatic ductal adenocarcinoma (PDAC) can cause type 3C diabetes, known as PDAC-associated diabetes mellitus (PDAC-DM), but the mechanism is unknown. This study aimed to reveal the mechanism. METHODS PDAC lesions from patients with or without PDAC-DM (n = 4 in each group) were individually profiled for 23,512 mRNAs with microarrays. Bioinformatic analysis and in vivo and in vitro assays were then conducted. RESULTS We determined that 2,778 genes were differentially expressed; over-representation of ten genes was validated with quantitative RT-PCR. The analysis of gene ontology showed that the differentially expressed secretory genes were related mainly to inflammation. High levels of a marker of inflammation (C-reactive protein [CRP]) and an inflammatory mediator (TNF super-family member 13 [TNFSF13]) were found in the serum of patients with PDAC-DM. After surgical resection of PDAC lesions, CRP and TNFSF13 levels significantly decreased (p < 0.01). Furthermore, we found that the levels of TNFSF13 in PDAC lesions and TNFSF13 and CRP in serum were significantly correlated with the diabetic status of patients with PDAC-DM (p < 0.01). Assays in vivo showed that after exposure to an inhibitor of inflammation (celecoxib), the fasting blood glucose level in the mouse model of PDAC-DM dramatically decreased from 6.9 ± 0.1 to 5.6 ± 0.1 mmol/l in 2-4 days (p < 0.01). CONCLUSIONS/INTERPRETATION We found that acute inflammation was involved in the pathogenesis of PDAC-DM. We contend that acute inflammation is a potential target for the diagnosis and treatment of PDAC-DM.
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MESH Headings
- Aged
- Animals
- Anti-Inflammatory Agents/pharmacology
- Blood Glucose/metabolism
- Carcinoma, Pancreatic Ductal/complications
- Carcinoma, Pancreatic Ductal/diagnosis
- Carcinoma, Pancreatic Ductal/drug therapy
- Carcinoma, Pancreatic Ductal/genetics
- Case-Control Studies
- Cells, Cultured
- Computational Biology
- Diabetes Mellitus/blood
- Diabetes Mellitus/diagnosis
- Diabetes Mellitus/genetics
- Diabetes Mellitus/prevention & control
- Disease Models, Animal
- Female
- Gene Expression Profiling/methods
- Genetic Association Studies
- Genetic Markers
- Humans
- Inflammation Mediators/blood
- Male
- Mice, Inbred BALB C
- Middle Aged
- Oligonucleotide Array Sequence Analysis
- Pancreatic Neoplasms/complications
- Pancreatic Neoplasms/diagnosis
- Pancreatic Neoplasms/drug therapy
- Pancreatic Neoplasms/genetics
- Pancreatitis, Chronic/blood
- Pancreatitis, Chronic/diagnosis
- Pancreatitis, Chronic/genetics
- Pancreatitis, Chronic/prevention & control
- Polymerase Chain Reaction
- Reproducibility of Results
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Affiliation(s)
- Wenchao Gao
- Department of Hepatopancreatobiliary Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, No. 107 Yanjiang Road, 510120, Guangzhou, People's Republic of China
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Caba O, Prados J, Ortiz R, Jiménez-Luna C, Melguizo C, Alvarez PJ, Delgado JR, Irigoyen A, Rojas I, Pérez-Florido J, Torres C, Perales S, Linares A, Aránega A. Transcriptional profiling of peripheral blood in pancreatic adenocarcinoma patients identifies diagnostic biomarkers. Dig Dis Sci 2014; 59:2714-2720. [PMID: 25069573 DOI: 10.1007/s10620-014-3291-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Accepted: 07/11/2014] [Indexed: 12/13/2022]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy associated with poor survival rates. Fast detection of PDAC appears to be the most relevant strategy to improve the long-term survival of patients. AIMS Our objective was to identify new markers in peripheral blood that differentiates between PDAC patients and healthy controls. METHODS Peripheral blood samples from PDAC patients (n = 18) and controls (n = 18) were analyzed by whole genome cDNA microarray hybridization. The most relevant genes were validated by quantitative real-time PCR (RT-qPCR) in the same set of samples. Finally, our gene prediction set was tested in a blinded set of new peripheral blood samples (n = 30). RESULTS Microarray studies identified 87 genes differentially expressed in peripheral blood samples from PDAC patients. Four of these genes were selected for analysis by RT-qPCR, which confirmed the previously observed changes. In our blinded validation study, the combination of CLEC4D and IRAK3 predicted the diagnosis of PDAC with 93 % accuracy, with a sensitivity of 86 % and specificity of 100 %. CONCLUSIONS Peripheral blood gene expression profiling is an useful tool for the diagnosis of PDAC. We present a validated four-gene predictor set (ANKRD22, CLEC4D, VNN1, and IRAK3) that may be useful in PDAC diagnosis.
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Affiliation(s)
- Octavio Caba
- Department of Health Sciences, University of Jaén, Jaén, Spain,
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Marengo E, Robotti E. Biomarkers for pancreatic cancer: Recent achievements in proteomics and genomics through classical and multivariate statistical methods. World J Gastroenterol 2014; 20:13325-13342. [PMID: 25309068 PMCID: PMC4188889 DOI: 10.3748/wjg.v20.i37.13325] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 06/04/2014] [Accepted: 06/26/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) is one of the most aggressive and lethal neoplastic diseases. A valid alternative to the usual invasive diagnostic tools would certainly be the determination of biomarkers in peripheral fluids to provide less invasive tools for early diagnosis. Nowadays, biomarkers are generally investigated mainly in peripheral blood and tissues through high-throughput omics techniques comparing control vs pathological samples. The results can be evaluated by two main strategies: (1) classical methods in which the identification of significant biomarkers is accomplished by monovariate statistical tests where each biomarker is considered as independent from the others; and (2) multivariate methods, taking into consideration the correlations existing among the biomarkers themselves. This last approach is very powerful since it allows the identification of pools of biomarkers with diagnostic and prognostic performances which are superior to single markers in terms of sensitivity, specificity and robustness. Multivariate techniques are usually applied with variable selection procedures to provide a restricted set of biomarkers with the best predictive ability; however, standard selection methods are usually aimed at the identification of the smallest set of variables with the best predictive ability and exhaustivity is usually neglected. The exhaustive search for biomarkers is instead an important alternative to standard variable selection since it can provide information about the etiology of the pathology by producing a comprehensive set of markers. In this review, the most recent applications of the omics techniques (proteomics, genomics and metabolomics) to the identification of exploratory biomarkers for PC will be presented with particular regard to the statistical methods adopted for their identification. The basic theory related to classical and multivariate methods for identification of biomarkers is presented and then, the most recent applications in this field are discussed.
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In Vitro and In Vivo Biological Evaluation of O-Carboxymethyl Chitosan Encapsulated Metformin Nanoparticles for Pancreatic Cancer Therapy. Pharm Res 2014; 31:3361-70. [DOI: 10.1007/s11095-014-1425-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Accepted: 05/12/2014] [Indexed: 02/08/2023]
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