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Yao Y, Ding J, Ju H, Yang L, Liu Y, Liang Y, Yuan Y, Li T, Lei X. Efficacy comparison of optimal natural orifice specimen extraction for robotic middle rectal cancer resection in women: transanal or transvaginal orifice. World J Surg Oncol 2025; 23:22. [PMID: 39856731 PMCID: PMC11762907 DOI: 10.1186/s12957-024-03630-z] [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: 11/01/2024] [Accepted: 12/17/2024] [Indexed: 01/27/2025] Open
Abstract
PURPOSE This study aimed to determine the optimal natural orifice specimen extraction (NOSE) method for robotic-assisted mid-rectal cancer resection in women. METHODS This retrospective propensity score-matched (PSM) study was to analyze the clinical data prospectively collected from female rectal cancer patients who underwent either robotic-assisted transvaginal specimen extraction (RATV) or robotic-assisted transanal specimen extraction (RATA) at our center between June 2016 and December 2022. The main outcome measures were urinary, anal, and sexual function. Disease-free survival (DFS), and overall survival (OS) were also included . RESULTS Anal function, assessed by the Wexner score, was better in the RATV group than in the RATA group (P = 0.034). Additionally, pre-menopausal women in RATV group exhibited superior anal function over those in RATA group (P = 0.031). There was no statistically significant difference in urinary function between the groups for both pre-menopausal and peri-menopausal patients (P = 0.711, P = 0.106). No difference was observed in sexual function between the two groups (P = 0.351); however, pre-menopausal patients in RATA group had better sexual function than those in RATV group (P = 0.045). Univariate logistic regression analysis showed surgical procedure was not a significant factor for the occurrence of sexual dysfunction. There were no significant difference in DFS (P = 0.845)and OS (P = 0.642) between the two groups. CONCLUSION Though the postoperative efficacy of the RATA and RATV was equivalent on urinary and sexual function, RATV is an optimal natural orifice specimen extraction for robotic middle rectal cancer resection in women based on anal function.
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Affiliation(s)
- Yao Yao
- Department of General Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China
- Gastrointestinal Surgical Institute, Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Jiarui Ding
- Jiangxi Provincial Key Laboratory of Respiratory Diseases, Jiangxi Institute of Respiratory Diseases, The Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Houqiong Ju
- Department of General Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China
- Gastrointestinal Surgical Institute, Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Lingling Yang
- Department of Gastroenterology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Yang Liu
- Department of General Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China
- Gastrointestinal Surgical Institute, Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Yahang Liang
- Department of General Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China
- Gastrointestinal Surgical Institute, Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Yuli Yuan
- Department of General Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China
- Gastrointestinal Surgical Institute, Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Taiyuan Li
- Department of General Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China.
- Gastrointestinal Surgical Institute, Nanchang University, Nanchang, Jiangxi, 330006, China.
| | - Xiong Lei
- Department of General Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China.
- Gastrointestinal Surgical Institute, Nanchang University, Nanchang, Jiangxi, 330006, China.
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Fadlallah H, El Masri J, Fakhereddine H, Youssef J, Chemaly C, Doughan S, Abou-Kheir W. Colorectal cancer: Recent advances in management and treatment. World J Clin Oncol 2024; 15:1136-1156. [PMID: 39351451 PMCID: PMC11438855 DOI: 10.5306/wjco.v15.i9.1136] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 06/11/2024] [Accepted: 07/29/2024] [Indexed: 08/29/2024] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide, and the second most common cause of cancer-related death. In 2020, the estimated number of deaths due to CRC was approximately 930000, accounting for 10% of all cancer deaths worldwide. Accordingly, there is a vast amount of ongoing research aiming to find new and improved treatment modalities for CRC that can potentially increase survival and decrease overall morbidity and mortality. Current management strategies for CRC include surgical procedures for resectable cases, and radiotherapy, chemotherapy, and immunotherapy, in addition to their combination, for non-resectable tumors. Despite these options, CRC remains incurable in 50% of cases. Nonetheless, significant improvements in research techniques have allowed for treatment approaches for CRC to be frequently updated, leading to the availability of new drugs and therapeutic strategies. This review summarizes the most recent therapeutic approaches for CRC, with special emphasis on new strategies that are currently being studied and have great potential to improve the prognosis and lifespan of patients with CRC.
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Affiliation(s)
- Hiba Fadlallah
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Jad El Masri
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Hiam Fakhereddine
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Joe Youssef
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Chrystelle Chemaly
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Samer Doughan
- Department of Surgery, American University of Beirut Medical Center, Beirut 1107-2020, Lebanon
| | - Wassim Abou-Kheir
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
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Radić J, Nikolić I, Kolarov-Bjelobrk I, Vasiljević T, Djurić A, Vidović V, Kožik B. Prognostic and Predictive Significance of Primary Tumor Localization and HER2 Expression in the Treatment of Patients with KRAS Wild-Type Metastatic Colorectal Cancer: Single-Centre Experience from Serbia. J Pers Med 2024; 14:879. [PMID: 39202071 PMCID: PMC11355236 DOI: 10.3390/jpm14080879] [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: 07/03/2024] [Revised: 08/02/2024] [Accepted: 08/15/2024] [Indexed: 09/03/2024] Open
Abstract
The treatment of patients with metastatic colorectal cancer (mCRC) is complex and is impacted by the location of the primary tumor (LPT). Our study aims to emphasize the importance of LPT as a prognostic and predictive marker as well as to examine the significance of HER2 overexpression in patients with mCRC, particularly in relation to the response to Epidermal Growth Factor Receptor Antibody treatment (anti-EGFR therapy). In this study, 181 patients with Kirsten RAS (KRAS) wild-type mCRC who received anti-EGFR therapy were included. Among them, 101 had left colon cancer (LCC) and 80 had right colon cancer (RCC). Results demonstrated that patients with KRAS wild-type LCC had better median overall survival (OS) (43 vs. 33 months, p = 0.005) and progression-free survival (PFS) (6 vs. 3 months, p < 0.001) compared to those with RCC. Multivariate analysis identified mucinous adenocarcinoma (p < 0.001), RCC location (p = 0.022), perineural invasion (p = 0.034), and tumors at the resection margin (p = 0.001) as independent predictors of OS, while mucinous adenocarcinoma (p = 0.001) and RCC location (p = 0.004) independently correlated with significantly shorter PFS. In addition, human epidermal growth factor receptor 2 (HER2) positive expression was significantly associated with worse PFS compared to HER2 negative results (p < 0.001). In conclusion, LPT is an important marker for predicting outcomes in the treatment of wild-type mCRC using anti-EGFR therapy, since patients with RCC have a statistically significantly shorter PFS and OS. Further investigation is needed to understand the role of HER2 overexpression in wild-type mCRC, as these patients also exhibit shorter survival.
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Affiliation(s)
- Jelena Radić
- Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia; (J.R.); (I.N.); (I.K.-B.); (T.V.)
- Department of Medical Oncology, Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia; (A.D.); (V.V.)
| | - Ivan Nikolić
- Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia; (J.R.); (I.N.); (I.K.-B.); (T.V.)
- Department of Medical Oncology, Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia; (A.D.); (V.V.)
| | - Ivana Kolarov-Bjelobrk
- Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia; (J.R.); (I.N.); (I.K.-B.); (T.V.)
- Department of Medical Oncology, Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia; (A.D.); (V.V.)
| | - Tijana Vasiljević
- Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia; (J.R.); (I.N.); (I.K.-B.); (T.V.)
- Department of Pathology and Laboratory Diagnostic, Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia
| | - Aleksandar Djurić
- Department of Medical Oncology, Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia; (A.D.); (V.V.)
| | - Vladimir Vidović
- Department of Medical Oncology, Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia; (A.D.); (V.V.)
| | - Bojana Kožik
- Laboratory for Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences, National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia
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Zhang Y, Yang Y, Qi X, Cui P, Kang Y, Liu H, Wei Z, Wang H. SLC14A1 and TGF-β signaling: a feedback loop driving EMT and colorectal cancer metachronous liver metastasis. J Exp Clin Cancer Res 2024; 43:208. [PMID: 39061061 PMCID: PMC11282742 DOI: 10.1186/s13046-024-03114-8] [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: 12/01/2023] [Accepted: 07/01/2024] [Indexed: 07/28/2024] Open
Abstract
BACKGROUND Colorectal cancer (CRC) metachronous liver metastasis is a significant clinical challenge, largely attributable to the late detection and the intricate molecular mechanisms that remain poorly understood. This study aims to elucidate the role of Solute Carrier Family 14 Member 1 (SLC14A1) in the pathogenesis and progression of CRC metachronous liver metastasis. METHODS We conducted a comprehensive analysis of CRC patient data from The Cancer Genome Atlas and GSE40967 databases, focusing on the differential expression of genes associated with non-metachronous liver metastasis and metachronous liver metastasis. Functional assays, both in vitro and in vivo, were performed to assess the biological impact of SLC14A1 modulation in CRC cells. Gene set enrichment analysis, molecular assays and immunohistochemical analyses on clinical specimens were employed to unravel the underlying mechanisms through which SLC14A1 exerts its effects. RESULTS SLC14A1 was identified as a differentially expressed gene, with its overexpression significantly correlating with poor relapse-free and overall survival. Mechanistically, elevated SLC14A1 levels enhanced CRC cell invasiveness and migratory abilities, corroborated by upregulated TGF-β/Smad signaling and Epithelial-Mesenchymal Transition. SLC14A1 interacted with TβRII and stabilized TβRII protein, impeding its Smurf1-mediated K48-linked ubiquitination and degradation, amplifying TGF-β/Smad signaling. Furthermore, TGF-β1 reciprocally elevated SLC14A1 mRNA expression, with Snail identified as a transcriptional regulator, binding downstream of SLC14A1's transcription start site, establishing a positive feedback loop. Clinically, SLC14A1, phosphorylated Smad2, and Snail were markedly upregulated in CRC patients with metachronous liver metastasis, underscoring their potential as prognostic markers. CONCLUSIONS Our findings unveil SLC14A1 as a critical regulator in CRC metachronous liver metastasis, providing novel insights into the molecular crosstalk between SLC14A1 and TGF-β/Smad signaling. These discoveries not only enhance our understanding of CRC metachronous liver metastasis pathogenesis, but also highlight SLC14A1 as a promising target for therapeutic intervention and predictive marker.
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Affiliation(s)
- Yixun Zhang
- Department of Colorectal Surgery, Cancer Hospital Affiliated to Shanxi Medical University, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Taiyuan, China
| | - Yumeng Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, No.10 Xitoutiao, You An Men Wai, Beijing, 100069, China
- Laboratory for Clinical Medicine, Capital Medical University, No.10 Xitoutiao, You An Men Wai, Beijing, China
| | - Xuan Qi
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, No.10 Xitoutiao, You An Men Wai, Beijing, 100069, China
- Laboratory for Clinical Medicine, Capital Medical University, No.10 Xitoutiao, You An Men Wai, Beijing, China
| | - Peng Cui
- Department of General Surgery, State Key Lab of Digestive Health, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yi Kang
- Department of Gastroenterology, Cancer Hospital Affiliated to Shanxi Medical University, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Taiyuan, China
| | - Haiyi Liu
- Department of Colorectal Surgery, Cancer Hospital Affiliated to Shanxi Medical University, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Taiyuan, China
| | - Zhigang Wei
- Hepatobiliary and Pancreatic Surgery and Liver Transplantation Center, First Hospital of Shanxi Medical University, 85 Jiefang Nan Lu, Taiyuan, 030001, Shanxi, China.
| | - Haibo Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, No.10 Xitoutiao, You An Men Wai, Beijing, 100069, China.
- Laboratory for Clinical Medicine, Capital Medical University, No.10 Xitoutiao, You An Men Wai, Beijing, China.
- Beijing Laboratory of Oral Health, Capital Medical University, No.10 Xitoutiao, You An Men Wai, Beijing, China.
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Hu SS, Han Y, Tan TY, Chen H, Gao JW, Wang L, Yang MH, Zhao L, Wang YQ, Ding YQ, Wang S. SLC25A21 downregulation promotes KRAS-mutant colorectal cancer progression by increasing glutamine anaplerosis. JCI Insight 2023; 8:e167874. [PMID: 37937641 PMCID: PMC10721270 DOI: 10.1172/jci.insight.167874] [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: 12/09/2022] [Accepted: 09/20/2023] [Indexed: 11/09/2023] Open
Abstract
Emerging evidence shows that KRAS-mutant colorectal cancer (CRC) depends on glutamine (Gln) for survival and progression, indicating that targeting Gln metabolism may be a promising therapeutic strategy for KRAS-mutant CRC. However, the precise mechanism by which Gln metabolism reprogramming promotes and coordinates KRAS-mutant CRC progression remains to be fully investigated. Here, we discovered that solute carrier 25 member 21 (SLC25A21) expression was downregulated in KRAS-mutant CRC, and that SLC25A21 downregulation was correlated with poor survival of KRAS-mutant CRC patients. SLC25A21 depletion selectively accelerated the growth, invasion, migration, and metastasis of KRAS-mutant CRC cells in vitro and in vivo, and inhibited Gln-derived α-ketoglutarate (α-KG) efflux from mitochondria, thereby potentiating Gln replenishment, accompanied by increased GTP availability for persistent KRAS activation in KRAS-mutant CRC. The restoration of SLC25A21 expression impaired the KRAS-mutation-mediated resistance to cetuximab in KRAS-mutant CRC. Moreover, the arrested α-KG efflux that occurred in response to SLC25A21 depletion inhibited the activity of α-KG-dependent DNA demethylases, resulting in a further decrease in SLC25A21 expression. Our studies demonstrate that SLC25A21 plays a significant role as a tumor suppressor in KRAS-mutant CRC by antagonizing Gln-dependent anaplerosis to limit GTP availability for KRAS activation, which suggests potential alternative therapeutic strategies for KRAS-mutant CRC.
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Affiliation(s)
- Sha-Sha Hu
- Department of Pathology, Nanfang Hospital, and
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yue Han
- Department of Pathology, Nanfang Hospital, and
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Tian-Yuan Tan
- Department of Pathology, Nanfang Hospital, and
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Hui Chen
- Department of Pathology, Nanfang Hospital, and
| | - Jia-Wen Gao
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Lan Wang
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Min-Hui Yang
- Department of Pathology, Nanfang Hospital, and
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Li Zhao
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yi-Qing Wang
- Department of Pathology, Nanfang Hospital, and
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yan-Qing Ding
- Department of Pathology, Nanfang Hospital, and
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Shuang Wang
- Department of Pathology, Nanfang Hospital, and
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
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Ko B, Hanna M, Yu M, Grady WM. Epigenetic Alterations in Colorectal Cancer. EPIGENETICS AND HUMAN HEALTH 2023:331-361. [DOI: 10.1007/978-3-031-42365-9_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Impact of Preoperative Chemotherapy Features on Patient Outcomes after Hepatectomy for Initially Unresectable Colorectal Cancer Liver Metastases: A LiverMetSurvey Analysis. Cancers (Basel) 2022; 14:cancers14174340. [PMID: 36077874 PMCID: PMC9454829 DOI: 10.3390/cancers14174340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 08/30/2022] [Accepted: 08/31/2022] [Indexed: 11/16/2022] Open
Abstract
Background: Prognostic factors have been extensively reported after resection of colorectal liver metastases (CLM); however, specific analyses of the impact of preoperative systemic anticancer therapy (PO-SACT) features on outcomes is lacking. Methods: For this real-world evidence study, we used prospectively collected data within the international surgical LiverMetSurvey database from all patients with initially-irresectable CLM. The main outcome was Overall Survival (OS) after surgery. Disease-free (DFS) and hepatic-specific relapse-free survival (HS-RFS) were secondary outcomes. PO-SACT features included duration (cumulative number of cycles), choice of the cytotoxic backbone (oxaliplatin- or irinotecan-based), fluoropyrimidine (infusional or oral) and addition or not of targeted monoclonal antibodies (anti-EGFR or anti-VEGF). Results: A total of 2793 patients in the database had received PO-SACT for initially irresectable diseases. Short (<7 or <13 cycles in 1st or 2nd line) PO-SACT duration was independently associated with longer OS (HR: 0.85 p = 0.046), DFS (HR: 0.81; p = 0.016) and HS-RFS (HR: 0.80; p = 0.05). All other PO-SACT features yielded basically comparable results. Conclusions: In this international cohort, provided that PO-SACT allowed conversion to resectability in initially irresectable CLM, surgery performed as soon as technically feasible resulted in the best outcomes. When resection was achieved, our findings indicate that the choice of PO-SACT regimen had a marginal if any, impact on outcomes.
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Metformin inhibits the development and metastasis of colorectal cancer. Med Oncol 2022; 39:136. [PMID: 35780231 DOI: 10.1007/s12032-022-01722-y] [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: 12/08/2021] [Accepted: 03/29/2022] [Indexed: 10/17/2022]
Abstract
Metformin is a commonly used drug for the treatment of diabetes. Accumulating evidence suggests that it exerts anti-cancer effects in many cancers, including colorectal cancer. However, the underlying molecular mechanisms of colorectal cancer metastasis remain unclear. Colorectal cancer cell lines were treated with metformin, and cell proliferation, invasion, and migration were analyzed in vitro. The relationship between metformin and the AMPK-mTOR axis was assessed by Western blot analysis and transfection with small interfering RNA. A colorectal cancer xenograft mouse model was used to observe the effects of metformin on liver metastasis. Immunohistochemical analysis was performed on liver metastatic tumors. In in vitro experiments, metformin significantly inhibited the proliferation, migration, and invasion only in HCT116 and SW837 cells, but not in HCT8 and Lovo cells. Only in HCT116 and SW837, a change in AMPK-mTOR expression was observed in a dose-dependent manner. In colorectal cancer xenograft mice, the liver metastatic rate (10% vs. 50%, p = 0.05) and the number of liver metastatic nodules (0.1/body vs. 1.2/body, p = 0.04) were significantly lower in the metformin group. Tumor proliferation and EMT were decreased and apoptosis was promoted only in metastatic liver tumors of mice treated with metformin. The molecular mechanism of the anti-cancer effects of metformin involves repression of mTOR pathways via AMPK activation. Moreover, the differences in metformin sensitivity depend on the response of the AMPK-mTOR pathway to metformin. Our study provides a theoretical basis for the anti-metastatic treatment of colorectal cancer using metformin.
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Cai Y, Chen Z, Liang Y, Liao Y, Wu Y, Huang J, Huang Z, Li R, Chen J. Cleavage factor Im 25 as a potential biomarker for prognosis of colorectal cancer. Transl Cancer Res 2022; 10:5267-5279. [PMID: 35116376 PMCID: PMC8797961 DOI: 10.21037/tcr-21-1441] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 10/29/2021] [Indexed: 12/24/2022]
Abstract
Background Cleavage factor Im 25 (CFIm25) affects the prognosis and progression of cancer by regulating alternative polyadenylation; however, its role in colorectal cancer remains unclear. Methods A standard EnVision tissue microarray was used to evaluate the expression of CFIm25 by immunohistochemistry in 363 patients with colorectal cancer. The correlation between CFIm25 expression and clinicopathological characteristics was analyzed using the χ2 test. Univariate analysis was used to study the relationship between clinicopathological characteristics and patient prognosis. Multivariate analysis was performed using the Cox regression model to identify independent prognostic factors for patients with colorectal cancer. Results Statistical analysis revealed that CFIm25 expression was significantly associated with vascular invasion (P=0.000), serous invasion (P=0.007), pT stage (P=0.016), and clinical stage (P=0.007). Age, vascular invasion, nerve invasion, serosal invasion, differentiation, clinical stage, recurrence, and CFIm25 expression were significantly correlated with the survival time of colorectal cancer patients (P<0.05). The mean overall survival rate in colorectal cancer patients with decreased CFIm25 expression was only 88.53 months, compared with 110.69 months in the high expression group (P=0.000). Decreased CFIm25 expression indicated a worse prognosis in patients with colorectal cancer. Further analysis by the Cox multivariate model showed that CFIm25 (HR, 0.543; 95% CI: 0.372–0.792; P=0.002) and serosa invasion (HR, 1.470; 95% CI: 1.032–2.094; P=0.033) are independent prognostic factors for colorectal cancer. Conclusions Decreased CFIm25 expression indicates a worse prognosis of colorectal cancer patients and could be a novel target for the treatment of colorectal cancer in the future. Keywords Polyadenylation; survival analysis; colorectal cancer (CRC); CFIm25
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Affiliation(s)
- Yubo Cai
- Department of Pathology, Jiangmen Central Hospital, Jiangmen, China
| | - Zequn Chen
- Department of Gastrointestinal Surgery, Maoming People's Hospital, Maoming, China
| | - Yutong Liang
- Department of Pathology, Jiangmen Central Hospital, Jiangmen, China
| | - Yuehua Liao
- Department of Pathology, Jiangmen Central Hospital, Jiangmen, China
| | - Yuanwei Wu
- Department of Pathology, Jiangmen Central Hospital, Jiangmen, China
| | - Junqiang Huang
- Department of Pathology, Jiangmen Central Hospital, Jiangmen, China
| | - Zhizhen Huang
- Department of Pathology, Jiangmen Central Hospital, Jiangmen, China
| | - Ronggang Li
- Department of Pathology, Jiangmen Central Hospital, Jiangmen, China
| | - Jiewei Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
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Shinji S, Yamada T, Matsuda A, Sonoda H, Ohta R, Iwai T, Takeda K, Yonaga K, Masuda Y, Yoshida H. Recent advances in the treatment of colorectal cancer: A review. J NIPPON MED SCH 2022; 89:246-254. [DOI: 10.1272/jnms.jnms.2022_89-310] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Seiichi Shinji
- Departments of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School
| | - Takeshi Yamada
- Departments of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School
| | - Akihisa Matsuda
- Departments of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School
| | - Hiromichi Sonoda
- Departments of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School
| | - Ryo Ohta
- Departments of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School
| | - Takuma Iwai
- Departments of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School
| | - Koki Takeda
- Departments of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School
| | - Kazuhide Yonaga
- Departments of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School
| | - Yuka Masuda
- Departments of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School
| | - Hiroshi Yoshida
- Departments of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School
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Wesdorp NJ, Bolhuis K, Roor J, van Waesberghe JHTM, van Dieren S, van Amerongen MJ, Chapelle T, Dejong CHC, Engelbrecht MRW, Gerhards MF, Grunhagen D, van Gulik TM, Hermans JJ, de Jong KP, Klaase JM, Liem MSL, van Lienden KP, Molenaar IQ, Patijn GA, Rijken AM, Ruers TM, Verhoef C, de Wilt JHW, Swijnenburg RJ, Punt CJA, Huiskens J, Kazemier G. The Prognostic Value of Total Tumor Volume Response Compared With RECIST1.1 in Patients With Initially Unresectable Colorectal Liver Metastases Undergoing Systemic Treatment. ANNALS OF SURGERY OPEN 2021; 2:e103. [PMID: 37637880 PMCID: PMC10455281 DOI: 10.1097/as9.0000000000000103] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 09/17/2021] [Indexed: 01/20/2023] Open
Abstract
Objectives Compare total tumor volume (TTV) response after systemic treatment to Response Evaluation Criteria in Solid Tumors (RECIST1.1) and assess the prognostic value of TTV change and RECIST1.1 for recurrence-free survival (RFS) in patients with colorectal liver-only metastases (CRLM). Background RECIST1.1 provides unidimensional criteria to evaluate tumor response to systemic therapy. Those criteria are accepted worldwide but are limited by interobserver variability and ignore potentially valuable information about TTV. Methods Patients with initially unresectable CRLM receiving systemic treatment from the randomized, controlled CAIRO5 trial (NCT02162563) were included. TTV response was assessed using software specifically developed together with SAS analytics. Baseline and follow-up computed tomography (CT) scans were used to calculate RECIST1.1 and TTV response to systemic therapy. Different thresholds (10%, 20%, 40%) were used to define response of TTV as no standard currently exists. RFS was assessed in a subgroup of patients with secondarily resectable CRLM after induction treatment. Results A total of 420 CT scans comprising 7820 CRLM in 210 patients were evaluated. In 30% to 50% (depending on chosen TTV threshold) of patients, discordance was observed between RECIST1.1 and TTV change. A TTV decrease of >40% was observed in 47 (22%) patients who had stable disease according to RECIST1.1. In 118 patients with secondarily resectable CRLM, RFS was shorter for patients with less than 10% TTV decrease compared with patients with more than 10% TTV decrease (P = 0.015), while RECIST1.1 was not prognostic (P = 0.821). Conclusions TTV response assessment shows prognostic potential in the evaluation of systemic therapy response in patients with CRLM.
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Affiliation(s)
- Nina J. Wesdorp
- From the Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Karen Bolhuis
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Joran Roor
- Department of Health, SAS Institute B.V., Huizen, The Netherlands
| | - Jan-Hein T. M. van Waesberghe
- Department of Radiology and Molecular Imaging, Cancer Center Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Susan van Dieren
- Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Martin J. van Amerongen
- Department of Medical Imaging, Radboud University Medical Center, Radboud University Nijmegen, Nijmegen, The Netherlands
| | - Thiery Chapelle
- Department of Hepatobiliary, Transplantation, and Endocrine Surgery, Antwerp University Hospital, Antwerp, Belgium
| | - Cornelis H. C. Dejong
- Department of Surgery, Maastricht University Medical Center, Maastricht, The Netherlands
- Department of Surgery, Universitätsklinikum Aachen, Aachen, Germany
| | - Marc R. W. Engelbrecht
- Department of Radiology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Michael F. Gerhards
- Department of Surgery, Onze Lieve Vrouwe Gasthuis Hospital, Amsterdam, The Netherlands
| | - Dirk Grunhagen
- Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus University Medical Center Cancer Institute, Rotterdam, The Netherlands
| | - Thomas M. van Gulik
- Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - John J. Hermans
- Department of Medical Imaging, Radboud University Medical Center, Radboud University Nijmegen, Nijmegen, The Netherlands
| | - Koert P. de Jong
- Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Joost M. Klaase
- Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Mike S. L. Liem
- Department of Surgery, Medical Spectrum Twente, Enschede, The Netherlands
| | - Krijn P. van Lienden
- Department of Interventional Radiology, St Antonius Hospital, Nieuwegein, The Netherlands
| | - I. Quintus Molenaar
- Department of Surgery, Regional Academic Cancer Center Utrecht, University Medical Center Utrecht and St Antonius Hospital, Nieuwegein, The Netherlands
| | - Gijs A. Patijn
- Department of Surgery, Isala Hospital, Zwolle, The Netherlands
| | - Arjen M. Rijken
- Department of Surgery, Amphia Hospital, Breda, The Netherlands
| | - Theo M. Ruers
- Department of Surgery, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Cornelis Verhoef
- Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus University Medical Center Cancer Institute, Rotterdam, The Netherlands
| | - Johannes H. W. de Wilt
- Department of Surgery, Radboud University Medical Center, Radboud University Nijmegen, Nijmegen, The Netherlands
| | - Rutger-Jan Swijnenburg
- Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Cornelis J. A. Punt
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
- Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Joost Huiskens
- Department of Health, SAS Institute B.V., Huizen, The Netherlands
| | - Geert Kazemier
- From the Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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12
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Chen H, Sun B, Sun H, Xu L, Wu G, Tu Z, Cheng X, Fan X, Mai Z, Tang Q, Wang X, Chen T. Bak instead of Bax plays a key role in metformin-induced apoptosis s in HCT116 cells. Cell Death Dis 2021; 7:363. [PMID: 34811352 PMCID: PMC8608863 DOI: 10.1038/s41420-021-00755-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 10/25/2021] [Accepted: 11/03/2021] [Indexed: 12/13/2022]
Abstract
Metformin (Met) exhibits anticancer ability in various cancer cell lines. This report aims to explore the exact molecular mechanism of Met-induced apoptosis in HCT116 cells, a human colorectal cancer cell line. Met-induced reactive oxygen species (ROS) increase and ROS-dependent cell death accompanied by plasma membrane blistering, mitochondrial swelling, loss of mitochondrial membrane potential, and release of cytochrome c. Western blotting analysis showed that Met upregulated Bak expression but downregulated Bax expression. Most importantly, silencing Bak instead of Bax inhibited Met-induced loss of mitochondrial membrane potential, indicating the key role of Bak in Met-induced apoptosis. Live-cell fluorescence resonance energy transfer (FRET) analysis showed that Met unlocked the binding of Mcl-1 to Bak, and enhanced the binding of Bim to Bak and subsequent Bak homo-oligomerization. Western blotting analysis showed that Met enhanced AMPK phosphorylation and Bim expression, and compound C, an inhibitor of AMPK, inhibited Met-induced Bim upregulation. Although Met increased the expression of Bcl-xL, overexpression of Bcl-xL did not prevent Met-induced apoptosis. In summary, our data demonstrate for the first time that Met promotes ROS-dependent apoptosis by regulating the Mcl-1-Bim-Bak axis.
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Affiliation(s)
- Hongce Chen
- grid.263785.d0000 0004 0368 7397MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, 510631 Guangzhou, China
| | - Beini Sun
- grid.263785.d0000 0004 0368 7397MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, 510631 Guangzhou, China
| | - Han Sun
- grid.263785.d0000 0004 0368 7397MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, 510631 Guangzhou, China
| | - Lingjun Xu
- grid.412601.00000 0004 1760 3828Department of Pain Management, The First Affiliated Hospital of Jinan University, 510632 Guangzhou, China
| | - Guihao Wu
- grid.412601.00000 0004 1760 3828Department of Pain Management, The First Affiliated Hospital of Jinan University, 510632 Guangzhou, China
| | - Zhuang Tu
- grid.263785.d0000 0004 0368 7397MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, 510631 Guangzhou, China
| | - Xuecheng Cheng
- grid.263785.d0000 0004 0368 7397MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, 510631 Guangzhou, China
| | - Xuhong Fan
- grid.412601.00000 0004 1760 3828Department of Pain Management, The First Affiliated Hospital of Jinan University, 510632 Guangzhou, China
| | - Zihao Mai
- grid.263785.d0000 0004 0368 7397MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, 510631 Guangzhou, China
| | - Qiling Tang
- grid.263785.d0000 0004 0368 7397MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, 510631 Guangzhou, China
| | - Xiaoping Wang
- Department of Pain Management, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, China.
| | - Tongsheng Chen
- MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, 510631, Guangzhou, China. .,SCNU Qingyuan Institute of Science and Technology Innovation Co., Ltd., South China Normal University, 511500, Qingyuan, China.
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13
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Ghani MA, Fereydooni A, Chen E, Letzen B, Laage-Gaupp F, Nezami N, Deng Y, Gan G, Thakur V, Lin M, Papademetris X, Schernthaner RE, Huber S, Chapiro J, Hong K, Georgiades C. Identifying enhancement-based staging markers on baseline MRI in patients with colorectal cancer liver metastases undergoing intra-arterial tumor therapy. Eur Radiol 2021; 31:8858-8867. [PMID: 34061209 DOI: 10.1007/s00330-021-08058-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/07/2021] [Accepted: 05/06/2021] [Indexed: 12/17/2022]
Abstract
OBJECTIVES To determine if three-dimensional whole liver and baseline tumor enhancement features on MRI can serve as staging biomarkers and help predict survival of patients with colorectal cancer liver metastases (CRCLM) more accurately than one-dimensional and non-enhancement-based features. METHODS This retrospective study included 88 patients with CRCLM, treated with transarterial chemoembolization or Y90 transarterial radioembolization between 2001 and 2014. Semi-automated segmentations of up to three dominant lesions were performed on pre-treatment MRI to calculate total tumor volume (TTV) and total liver volumes (TLV). Quantitative 3D analysis was performed to calculate enhancing tumor volume (ETV), enhancing tumor burden (ETB, calculated as ETV/TLV), enhancing liver volume (ELV), and enhancing liver burden (ELB, calculated as ELV/TLV). Overall and enhancing tumor diameters were also measured. A modified Kaplan-Meier method was used to determine appropriate cutoff values for each metric. The predictive value of each parameter was assessed by Kaplan-Meier survival curves and univariable and multivariable cox proportional hazard models. RESULTS All methods except whole liver (ELB, ELV) and one-dimensional/non-enhancement-based methods were independent predictors of survival. Multivariable analysis showed a HR of 2.1 (95% CI 1.3-3.4, p = 0.004) for enhancing tumor diameter, HR 1.7 (95% CI 1.1-2.8, p = 0.04) for TTV, HR 2.3 (95% CI 1.4-3.9, p < 0.001) for ETV, and HR 2.4 (95% CI 1.4-4.0, p = 0.001) for ETB. CONCLUSIONS Tumor enhancement of CRCLM on baseline MRI is strongly associated with patient survival after intra-arterial therapy, suggesting that enhancing tumor volume and enhancing tumor burden are better prognostic indicators than non-enhancement-based and one-dimensional-based markers. KEY POINTS • Tumor enhancement of colorectal cancer liver metastases on MRI prior to treatment with intra-arterial therapies is strongly associated with patient survival. • Three-dimensional, enhancement-based imaging biomarkers such as enhancing tumor volume and enhancing tumor burden may serve as the basis of a novel prognostic staging system for patients with liver-dominant colorectal cancer metastases.
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Affiliation(s)
- Mansur A Ghani
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, 333 Cedar St, New Haven, CT, USA
| | - Arash Fereydooni
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, 333 Cedar St, New Haven, CT, USA
| | - Evan Chen
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, 333 Cedar St, New Haven, CT, USA
| | - Brian Letzen
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, 333 Cedar St, New Haven, CT, USA
| | - Fabian Laage-Gaupp
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, 333 Cedar St, New Haven, CT, USA
| | - Nariman Nezami
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, 333 Cedar St, New Haven, CT, USA.,Russel H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital, Baltimore, MD, USA.,Interventional Radiology and Image-Guided Medicine, Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA, USA
| | - Yanhong Deng
- Yale Center for Analytical Science, Yale School of Public Health, New Haven, CT, USA
| | - Geliang Gan
- Yale Center for Analytical Science, Yale School of Public Health, New Haven, CT, USA
| | - Vinayak Thakur
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, 333 Cedar St, New Haven, CT, USA
| | - MingDe Lin
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, 333 Cedar St, New Haven, CT, USA
| | - Xenophon Papademetris
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, 333 Cedar St, New Haven, CT, USA.,Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Ruediger E Schernthaner
- Russel H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital, Baltimore, MD, USA.,Department of Diagnostic and Interventional Radiology, Hospital Landstraße, Vienna, Austria
| | - Steffen Huber
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, 333 Cedar St, New Haven, CT, USA
| | - Julius Chapiro
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, 333 Cedar St, New Haven, CT, USA. .,Russel H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital, Baltimore, MD, USA.
| | - Kelvin Hong
- Russel H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Christos Georgiades
- Russel H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital, Baltimore, MD, USA
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14
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Verter E, Sadot E. ASO Author Reflections: Neutrophil-to-Lymphocyte Ratio Predicts Recurrence Pattern in Patients with Resectable Colorectal Liver Metastases. Ann Surg Oncol 2021; 28:4330-4331. [PMID: 33900503 DOI: 10.1245/s10434-021-10009-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 03/24/2021] [Indexed: 11/18/2022]
Affiliation(s)
- Eden Verter
- Department of Surgery, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Eran Sadot
- Department of Surgery, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel. .,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
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15
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Verter E, Berger Y, Perl G, Peretz I, Tovar A, Morgenstern S, Brenner B, Benchimol D, Kashtan H, Sadot E. Neutrophil-to-Lymphocyte Ratio Predicts Recurrence Pattern in Patients with Resectable Colorectal Liver Metastases. Ann Surg Oncol 2021; 28:4320-4329. [PMID: 33886020 DOI: 10.1245/s10434-021-10000-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 02/19/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Studies have suggested that neutrophil-to-lymphocyte ratio (NLR) has value as a predictor of long-term outcomes in various cancer types. Its prognostic potential in patients with CRLM has not been thoroughly investigated. This original, retrospective study assessed the relationship between the preoperative NLR, survival outcomes, and recurrence patterns in patients after colorectal liver metastasis resection (CRLM). METHODS The prospectively maintained database of a tertiary medical center was queried for all patients who underwent CRLM resection between 2005 and 2017. Patients were divided into two groups: NLR <3 (normal) or >3 (high). Recurrence risk was analysed using Fine and Gray correction for competing risk method and cause specific analyses. RESULTS The cohort included 231 patients of whom 53 (23%) had a high neutrophil-to-lymphocyte ratio. At presentation, 35% had synchronous disease and 48% had a solitary metastasis; median tumor size was 2 cm. Patients with a high NLR had a significantly higher rate of simultaneous colorectal resection (P = 0.01). A high NLR was independently associated with worse OS (P = 0.02), worse DFS (P = 0.03), and higher risk of recurrence (P = 0.048), specifically recurrence with an extrahepatic pattern (P = 0.03). CONCLUSIONS A high preoperative NLR was independently associated with poorer survival outcomes and extrahepatic recurrence pattern. The NLR appears to have prognostic importance in CRLM and may serve as a surrogate marker of aggressive systemic disease after resection. These findings warrant external validation, preferably in a prospective design.
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Affiliation(s)
- Eden Verter
- Department of Surgery, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yael Berger
- Department of Surgery, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Gali Perl
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel
| | - Idit Peretz
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel
| | - Ana Tovar
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Institute of Pathology, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel
| | - Sara Morgenstern
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Institute of Pathology, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel
| | - Baruch Brenner
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel
| | - Daniel Benchimol
- Department of Surgery, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Hanoch Kashtan
- Department of Surgery, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Eran Sadot
- Department of Surgery, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel. .,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
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16
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Wesdorp NJ, van Goor VJ, Kemna R, Jansma EP, van Waesberghe JHTM, Swijnenburg RJ, Punt CJA, Huiskens J, Kazemier G. Advanced image analytics predicting clinical outcomes in patients with colorectal liver metastases: A systematic review of the literature. Surg Oncol 2021; 38:101578. [PMID: 33866191 DOI: 10.1016/j.suronc.2021.101578] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 03/30/2021] [Accepted: 04/01/2021] [Indexed: 12/26/2022]
Abstract
BACKGROUND To better select patients with colorectal liver metastases (CRLM) for an optimal selection of treatment strategy (i.e. local, systemic or combined treatment) new prognostic models are warranted. In the last decade, radiomics has emerged as a field to create predictive models based on imaging features. This systematic review aims to investigate the current state and potential of radiomics to predict clinical outcomes in patients with CRLM. METHODS A comprehensive literature search was conducted in the electronic databases of PubMed, Embase, and Cochrane Library, according to PRISMA guidelines. Original studies reporting on radiomics predicting clinical outcome in patients diagnosed with CRLM were included. Clinical outcomes were defined as response to systemic treatment, recurrence of disease, and survival (overall, progression-free, disease-free). Primary outcome was the predictive performance of radiomics. A narrative synthesis of the results was made. Methodological quality was assessed using the radiomics quality score. RESULTS In 11 out of 14 included studies, radiomics was predictive for response to treatment, recurrence of disease, survival, or a combination of outcomes. Combining clinical parameters and radiomic features in multivariate modelling often improved the predictive performance. Different types of individual features were found prognostic. Noticeable were the contrary levels of heterogeneous and homogeneous features in patients with good response. The methodological quality as assessed by the radiomics quality score varied considerably between studies. CONCLUSION Radiomics appears a promising non-invasive method to predict clinical outcome and improve personalized decision-making in patients with CRLM. However, results were contradictory and difficult to compare. Standardized prospective studies are warranted to establish the added value of radiomics in patients with CRLM.
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Affiliation(s)
- N J Wesdorp
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Surgery, Cancer Center Amsterdam, De Boelelaan, 1117, Amsterdam, Netherlands.
| | - V J van Goor
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Surgery, Cancer Center Amsterdam, De Boelelaan, 1117, Amsterdam, Netherlands
| | - R Kemna
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Surgery, Cancer Center Amsterdam, De Boelelaan, 1117, Amsterdam, Netherlands
| | - E P Jansma
- Amsterdam UMC, University of Amsterdam, Department of Epidemiology and Biostatistics, Cancer Center Amsterdam, De Boelelaan, 1117, Amsterdam, Netherlands
| | - J H T M van Waesberghe
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Radiology and Molecular Imaging, Cancer Center Amsterdam, De Boelelaan, 1117, Amsterdam, Netherlands
| | - R J Swijnenburg
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Surgery, Cancer Center Amsterdam, Meibergdreef 9, Amsterdam, Netherlands
| | - C J A Punt
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Department of Epidemiology, Utrecht, the Netherlands
| | - J Huiskens
- SAS Institute B.V., Flevolaan 69, Huizen, the Netherlands
| | - G Kazemier
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Surgery, Cancer Center Amsterdam, De Boelelaan, 1117, Amsterdam, Netherlands
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17
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Liu B, Huang G, Xie X, Zhao Q, Su L, Liu M, Li X, Long J, Kuang M, Xie X. Feasibility and outcomes of percutaneous radiofrequency ablation for intrahepatic recurrent hepatocellular carcinoma after liver transplantation: a single-center experience. Int J Hyperthermia 2020; 37:1202-1209. [PMID: 33100042 DOI: 10.1080/02656736.2020.1834154] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Affiliation(s)
- Baoxian Liu
- Division of Interventional Ultrasound, Department of Medical Ultrasound, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Guangliang Huang
- Division of Interventional Ultrasound, Department of Medical Ultrasound, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaohua Xie
- Division of Interventional Ultrasound, Department of Medical Ultrasound, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qiang Zhao
- Department of Organ Transplantation, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Liya Su
- Division of Interventional Ultrasound, Department of Medical Ultrasound, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ming Liu
- Division of Interventional Ultrasound, Department of Medical Ultrasound, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoju Li
- Division of Interventional Ultrasound, Department of Medical Ultrasound, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jianting Long
- Department of Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ming Kuang
- Division of Interventional Ultrasound, Department of Medical Ultrasound, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoyan Xie
- Division of Interventional Ultrasound, Department of Medical Ultrasound, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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18
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Ma ZH, Wang YP, Zheng WH, Ma J, Bai X, Zhang Y, Wang YH, Chi D, Fu XB, Hua XD. Prognostic factors and therapeutic effects of different treatment modalities for colorectal cancer liver metastases. World J Gastrointest Oncol 2020; 12:1177-1194. [PMID: 33133385 PMCID: PMC7579728 DOI: 10.4251/wjgo.v12.i10.1177] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 08/18/2020] [Accepted: 09/14/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the most common malignant tumors in China, and the liver is the most common metastatic site in patients with advanced CRC. Hepatectomy is the gold standard treatment for colorectal liver metastases. For patients who cannot undergo radical resection of liver metastases for various reasons, ablation therapy, interventional therapy, and systemic chemotherapy can be used to improve their quality of life and prolong their survival time.
AIM To explore the prognostic factors and treatments of liver metastases of CRC.
METHODS A retrospective analysis was conducted on 87 patients with liver metastases from CRC treated at the Liaoning Cancer Hospital and Institute between January 2005 and March 2011. According to different treatments, the patients were divided into the following four groups: Surgical resection group (36 patients); ablation group (23 patients); intervention group (15 patients); and drug group (13 patients). The clinicopathological data and postoperative survival of the four groups were analyzed. The Kaplan-Meier method was used for survival analysis, and the Cox proportional hazards regression model was used for multivariate analysis.
RESULTS The median survival time of the 87 patients was 38.747 ± 3.062 mo, and the 1- and 3-year survival rates were 87.5% and 53.1%, respectively. The Cox proportional hazards model showed that the following factors were independent factors affecting prognosis: The degree of tumor differentiation, the number of metastases, the size of metastases, and whether the metastases are close to great vessels. The results of treatment factor analysis showed that the effect of surgical treatment was better than that of drugs, intervention, or ablation alone, and the median survival time was 48.83 ± 4.36 mo. The drug group had the worst prognosis, with a median survival time of only 13.5 ± 0.7 mo (P < 0.05). For patients with liver metastases of CRC near the great vessels, the median survival time (27.3 mo) of patients undergoing surgical resection was better than that of patients using other treatments (20.6 mo) (P < 0.05).
CONCLUSION Patients with a low degree of primary tumor differentiation, multiple liver metastases (number of tumors > 4), and maximum diameter of liver metastases > 5 cm have a poor prognosis. Among drug therapy, intervention, ablation, and surgical treatment options, surgical treatment is the first choice for liver metastases. When liver metastases are close to great vessels, surgical treatment is significantly better than drug therapy, intervention, and ablation alone.
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Affiliation(s)
- Zuo-Hong Ma
- Department of Hepatopancreatobiliary Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang 110042, Liaoning Province, China
| | - Yong-Peng Wang
- Department of Hepatopancreatobiliary Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang 110042, Liaoning Province, China
| | - Wen-Heng Zheng
- Department of Medical Imaging, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang 110042, Liaoning Province, China
| | - Ji Ma
- Department of Pathology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang 110042, Liaoning Province, China
| | - Xue Bai
- Department of Hepatopancreatobiliary Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang 110042, Liaoning Province, China
| | - Yong Zhang
- Department of Pathology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang 110042, Liaoning Province, China
| | - Yuan-He Wang
- Department of Hepatopancreatobiliary Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang 110042, Liaoning Province, China
| | - Da Chi
- Department of Hepatopancreatobiliary Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang 110042, Liaoning Province, China
| | - Xi-Bo Fu
- Department of Hepatopancreatobiliary Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang 110042, Liaoning Province, China
| | - Xiang-Dong Hua
- Department of Hepatopancreatobiliary Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang 110042, Liaoning Province, China
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Song X, Shen L, Tong J, Kuang C, Zeng S, Schoen RE, Yu J, Pei H, Zhang L. Mcl-1 inhibition overcomes intrinsic and acquired regorafenib resistance in colorectal cancer. Theranostics 2020; 10:8098-8110. [PMID: 32724460 PMCID: PMC7381732 DOI: 10.7150/thno.45363] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 06/19/2020] [Indexed: 12/11/2022] Open
Abstract
Intrinsic and acquired resistance to targeted therapies is a significant clinical problem in cancer. We previously showed that resistance to regorafenib, a multi-kinase inhibitor for treating colorectal cancer (CRC) patients, can be caused by mutations in the tumor suppressor FBW7, which block degradation of the pro-survival Bcl-2 family protein Mcl-1. We tested if Mcl-1 inhibition can be used to develop a precision combination therapy for overcoming regorafenib resistance. METHODS Small-molecule Mcl-1 inhibitors were tested on CRC cells with knock-in (KI) of a non-degradable Mcl-1. Effects of Mcl-1 inhibitors on regorafenib sensitivity were determined in FBW7-mutant and -wild-type (WT) CRC cells and tumors, and in those with acquired regorafenib resistance due to enriched FBW7 mutations. Furthermore, translational potential was explored by establishing and analyzing FBW7-mutant and -WT patient-derived organoid (PDO) and xenograft (PDX) tumor models. RESULTS We found that highly potent and specific Mcl-1 inhibitors such as S63845 overcame regorafenib resistance by restoring apoptosis in multiple regorafenib-resistant CRC models. Mcl-1 inhibition re-sensitized CRC tumors with intrinsic and acquired regorafenib resistance in vitro and in vivo, including those with FBW7 mutations. Importantly, Mcl-1 inhibition also sensitized FBW7-mutant PDO and PDX models to regorafenib. In contrast, Mcl-1 inhibition had no effect in FBW7-WT CRCs. CONCLUSIONS Our results demonstrate that Mcl-1 inhibitors can overcome intrinsic and acquired regorafenib resistance in CRCs by restoring apoptotic response. FBW7 mutations might be a potential biomarker predicting for response to the regorafenib/Mcl-1 inhibitor combination.
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Affiliation(s)
- Xiangping Song
- UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P.R. China
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Lin Shen
- UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P.R. China
| | - Jingshan Tong
- UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | | | - Shan Zeng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P.R. China
| | - Robert E. Schoen
- UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213. USA
| | - Jian Yu
- UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213. USA
| | - Haiping Pei
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P.R. China
| | - Lin Zhang
- UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
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20
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Dong D, Zhang J, Zhang R, Li F, Li Y, Jia Y. Multiprobe Assay for Clinical SEPT9 Methylation Based on the Carbon Dot-Modified Liquid-Exfoliated Graphene Field Effect Transistor with a Potential to Present a Methylation Panorama. ACS OMEGA 2020; 5:16228-16237. [PMID: 32656445 PMCID: PMC7346271 DOI: 10.1021/acsomega.0c02022] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 06/11/2020] [Indexed: 05/11/2023]
Abstract
The hypermethylation in the promoter region of the SEPT9 gene is associated with the development of colorectal cancer (CRC). Although its clinical significance for early diagnosis and screening of CRC has been demonstrated, the tedious operations in the conventional DNA methylation (DNAm) detection hinder its wide application. Herein, an electronic method for determining SEPT9 methylation in CRC patients is proposed by using the carbon dot-modified liquid exfoliated graphene field effect transistor (CDs-LEG-FET) as the DNAm sensor, the specifically designed probes to capture the SEPT9 gene and the immunologic recognition to recognize 5-methylcytosine (5mC) positions on the anchored sequences. The identification and nanomorphology of the as-prepared materials and devices are executed first by the characterizations of UV-vis, Raman, atomic force microscopy, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and electronic measurements. Then, the role of CDs in enhancing DNAm sensitivity of CD-LEG-FET is manifested by comparing it with that of CD-free LEG-FET. Third, the captured SEPT9 genes on CD-LEG-FETs by different probes are evaluated, and the optimized temperature for hybridizing the target ssDNA sequences is determined to be 48 °C. Furthermore, the detection sensitivity for the low-quantity of DNA samples is demonstrated to be as low as 2 ng. Finally, the methylation degree of the tumor and corresponding noncancerous tissue DNA samples were examined by the proposed electric method and methylight assay in parallel. The diagnostic value of the electrical assay is confirmed by using the receiver operating characteristic curves; meanwhile, the superiority of the CD-LEG-FET platform is found to present a methylation panorama of the target gene.
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Affiliation(s)
- Dong Dong
- Department
of Laboratory, Tianjin’s Clinical Research Center for Cancer,
Key Laboratory of Cancer Prevention and Therapy, National Clinical
Research Center for Cancer, Tianjin Medical
University Cancer Institute and Hospital, Tianjin 300060, China
| | - Jizhao Zhang
- College
of Electronic Information and Optical Engineering, Nankai University, Tianjin 300071, China
| | - Runshi Zhang
- Department
of Laboratory, Tianjin’s Clinical Research Center for Cancer,
Key Laboratory of Cancer Prevention and Therapy, National Clinical
Research Center for Cancer, Tianjin Medical
University Cancer Institute and Hospital, Tianjin 300060, China
| | - Fang Li
- College
of Electronic Information and Optical Engineering, Nankai University, Tianjin 300071, China
| | - Yueguo Li
- Department
of Laboratory, Tianjin’s Clinical Research Center for Cancer,
Key Laboratory of Cancer Prevention and Therapy, National Clinical
Research Center for Cancer, Tianjin Medical
University Cancer Institute and Hospital, Tianjin 300060, China
| | - Yunfang Jia
- College
of Electronic Information and Optical Engineering, Nankai University, Tianjin 300071, China
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21
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Herrero de la Parte B, García-Alonso I, Mar-Medina C, Iturrizaga S, Saiz-López A, Hernández-Farto L, Del Campo-Clemente C, Echevarría-Uraga JJ. Ultrasound Tumor Size Assessment, Histology and Serum Enzyme Analysis in a Rat Model of Colorectal Liver Cancer. ULTRASOUND IN MEDICINE & BIOLOGY 2020; 46:1504-1512. [PMID: 32178957 DOI: 10.1016/j.ultrasmedbio.2020.02.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 02/11/2020] [Accepted: 02/14/2020] [Indexed: 06/10/2023]
Abstract
During tumor development, tissue necrosis appears as a natural phenomenon directly associated with an increase in tumor size. The aim of this study was to assess the use of ultrasound (US) for predicting natural tumor necrosis in a rat liver implant model of colorectal cancer. To achieve this goal, we sought to establish a correlation between US-measured tumor volume, serum enzyme levels and histopathological findings, particularly those regarding necrosis phenomena in liver implants. Under US guidance, CC531 colorectal cancer cells were injected into the left liver lobe of WAG/RijHsd rats. Twenty-eight days after cell inoculation, tumor volume was measured by US, and rats were sacrificed to obtain samples of tumor tissue as well as blood serum. In hematoxylin and eosin-stained tumor samples, the percentage of tumor that was necrotic was estimated. The association between percentage tumor necrosis and US-measured tumor volume was assessed by univariate logistic regression analysis, and a linear regression equation was obtained. Serum enzyme levels did not differ significantly between tumor-bearing and tumor-free rats. Tumor implants appeared as well-defined hyper-echoic regions with a mean volume of 0.61 ± 0.39 mL and tumor necrosis percentage of 8.6 ± 7.7%. Linear regression analysis revealed a very strong relationship (Pearson correlation coefficient r = 0.911) between US-measured tumor volume and tumor necrosis percentage; the regression equation was tumor necrosis percentage = 21 × US-measured tumor volume (in mL) - 3.1. The study found US to be a useful tool in animal-based trials. Tumors inside the liver (ranging in volume from 0.24-1.37 mL) can be observed by US, and moreover, US-measured tumor volume on day 28 can be used to estimate tumor necrosis occurring as the natural evolution of tumor implants.
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Affiliation(s)
- Borja Herrero de la Parte
- Department of Surgery and Radiology and Physical Medicine, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain; Biocruces Bizkaia Health Research Institute, Barakaldo, Spain.
| | - Ignacio García-Alonso
- Department of Surgery and Radiology and Physical Medicine, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain; Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
| | - Carmen Mar-Medina
- Department of Clinical Analysis, Galdakao-Usansolo Hospital, Osakidetza Basque Health Service, Barrio Labeaga, Galdakao, Spain
| | - Sira Iturrizaga
- Department of Clinical Analysis, Galdakao-Usansolo Hospital, Osakidetza Basque Health Service, Barrio Labeaga, Galdakao, Spain
| | - Alberto Saiz-López
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain; Department of Pathology, Galdakao-Usansolo Hospital, Osakidetza Basque Health Service, Barrio Labeaga, Galdakao, Spain
| | - Leire Hernández-Farto
- Department of Pathology, Galdakao-Usansolo Hospital, Osakidetza Basque Health Service, Barrio Labeaga, Galdakao, Spain
| | - Consuelo Del Campo-Clemente
- Department of Pathology, Galdakao-Usansolo Hospital, Osakidetza Basque Health Service, Barrio Labeaga, Galdakao, Spain
| | - Jose Javier Echevarría-Uraga
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain; Department of Radiology, Galdakao-Usansolo Hospital, Osakidetza Basque Health Service, Barrio Labeaga, Galdakao, Spain
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22
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Shen CJ, Chang KY, Lin BW, Lin WT, Su CM, Tsai JP, Liao YH, Hung LY, Chang WC, Chen BK. Oleic acid-induced NOX4 is dependent on ANGPTL4 expression to promote human colorectal cancer metastasis. Am J Cancer Res 2020; 10:7083-7099. [PMID: 32641980 PMCID: PMC7330862 DOI: 10.7150/thno.44744] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Accepted: 05/20/2020] [Indexed: 12/13/2022] Open
Abstract
Background: Colorectal cancer (CRC) progression and related mortality are highly associated with metabolic disorders. However, the molecular mechanism involved in the regulation of hyperlipidemia-associated CRC metastasis remains unclear. This study aimed to investigate the effects of angiopoietin-like 4 (ANGPTL4) on NADPH oxidase 4 (NOX4) expression and reactive oxygen species (ROS) production, which might provide new targets for improving outcomes in patients with hyperlipidemia-associated CRC metastasis. Methods: The clinical relevance of relationship between NOX4 expression and ANGPTL4 was examined in CRC patients by the Oncomine and TCGA data set. Expressions of NOX4, epithelial-mesenchymal transition (EMT) markers, and gene regulation of NOX4 in free fatty acids (FFAs)-treated CRC cells were determined. The FFAs-triggered metastatic ability of CRC cells under treatments of antioxidants or knockdown of NOX4, ANGPTL4, and MMPs was evaluated in vitro and in vivo. In addition, effects of antioxidants and depletion of metastasis-associated molecules on the correlation between ROS production and FFAs-promoted CRC metastasis were also clarified. Results: In this study, we found that the induction of NOX4, followed by the increased ROS was essential for oleic acid (OA)-promoted CRC cell metastasis. The depletion of ANGPTL4 significantly inhibited c-Jun-mediated transactivation of NOX4 expression, accompanied with reduced levels of ROS, MMP-1, and MMP-9, resulting in the disruption of OA-promoted CRC cell metastasis. Moreover, knockdown of ANGPTL4, NOX4, MMP-1, and MMP-9 or the treatment of antioxidants dramatically inhibited circulating OA-enhanced tumor cell extravasation and metastatic seeding of tumor cells in lungs, indicating that the ANGPTL4/NOX4 axis was critical for dyslipidemia-associated tumor metastasis. Conclusion: The coincident expression of NOX4 and ANGPTL4 in CRC tumor specimens provides the insight into the potential therapeutic targets for the treatment of dyslipidemia-associated CRC metastasis.
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23
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Liu N, Wu C, Jia R, Cai G, Wang Y, Zhou L, Ji Q, Sui H, Zeng P, Xiao H, Liu H, Huo J, Feng Y, Deng W, Li Q. Traditional Chinese Medicine Combined With Chemotherapy and Cetuximab or Bevacizumab for Metastatic Colorectal Cancer: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Front Pharmacol 2020; 11:478. [PMID: 32372960 PMCID: PMC7187887 DOI: 10.3389/fphar.2020.00478] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 03/26/2020] [Indexed: 12/29/2022] Open
Abstract
Background Huangci Granule is a traditional Chinese medicine for treating metastatic colorectal cancer (mCRC). Objective To evaluate the efficacy and safety of Huangci Granule combination with chemotherapy and cetuximab (CET) or bevacizumab (BV) for treating mCRC. Methods We performed a randomized, controlled, and double-blind trial and recruited patients with mCRC who were planned to undergo chemotherapy combined with CET or BV. The treatment group was treated with Huangci Granule, while the control group was treated with placebo. Continuous treatment until disease progression, death, intolerable toxicity or up to 6 months. The primary endpoint was progression-free survival (PFS), and the secondary endpoint was quality of life and safety. Result 320 patients were randomly assigned to receive treatment, including 200 first-line patients and 120 second-line patients. In the first-line treatment, the median PFS was 9.59 months (95% CI, 6.94–13.25) vs 6.89 months (95% CI, 4.99–9.52) in treatment group and control group (HR, 0.69; 95% CI, 0.50–0.97; P = 0.027). Chinese medicine was an independent factor affecting the PFS. In the second-line treatment, the median PFS was 6.51 months (95% CI, 4.49–9.44) vs 4.53 months (95% CI, 3.12–6.57) in the treatment group and control group (HR, 0.65; 95% CI, 0.45–0.95; P = 0.020). Compared with the control group, “role function,” “social function,” “fatigue,” and “appetite loss” were significantly improved in the treatment (P < 0.05) and drug related grades 3 to 4 adverse events were less. Conclusion Huangci Granule combined with chemotherapy and CET or BV can prolong the PFS of mCRC, improve the quality of life, reduce adverse reactions, and have good safety.
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Affiliation(s)
- Ningning Liu
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chaojun Wu
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ru Jia
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guoxiang Cai
- Department of Colorectal Cancer Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yan Wang
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lihong Zhou
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qing Ji
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hua Sui
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Puhua Zeng
- Cancer Research Institute, Hunan Academy of Traditional Chinese Medicine, Changsha, China
| | - Haijuan Xiao
- Department of Oncology, Hospital Affiliated to Shaanxi University of Chinese Medicine, Xianyang, China
| | - Huaimin Liu
- Department of Integrated Chinese and Western Medicine, Henan Provincial Cancer Hospital, Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, China
| | - Jiege Huo
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yuanyuan Feng
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wanli Deng
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qi Li
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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24
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Ichikawa N, Kamiyama T, Yokoo H, Homma S, Maeda Y, Shinohara T, Tsuruga Y, Kazui K, Iijima H, Yoshida T, Taketomi A. Preoperative chemotherapy in colorectal cancer patients with synchronous liver metastasis. Mol Clin Oncol 2020; 12:374-383. [PMID: 32190322 PMCID: PMC7057917 DOI: 10.3892/mco.2020.1992] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 11/13/2019] [Indexed: 02/05/2023] Open
Abstract
The response to preoperative chemotherapy is useful for predicting prognosis in unresectable and resectable disease. However, the prognostic benefit of chemotherapy prior to hepatectomy in patients with colorectal carcinoma and resectable or marginally resectable liver metastases remains unclear. The present study investigated the effect of preoperative chemotherapy on the prognosis of patients with colorectal cancer and resectable or marginally resectable synchronous liver metastasis. A total of 106 patients were retrospectively reviewed, who underwent hepatectomy for colorectal metastasis. The prognosis of 64 patients who received neoadjuvant chemotherapy (NAC) were compared with the 42 patients who did not (non-NAC). Furthermore, a total of 43 patients who responded to chemotherapy were compared with the 21 who did not. Preoperative chemotherapy was administered for 5.7 months, wherein 50 patients (78%) received a single regimen, and 54 (84%) received oxaliplatin. There were more patients with <3 metastases and maximum diameters <5 cm in the non-NAC group. The median survival time was 86.0 and 71.6 months in the NAC and non-NAC groups, respectively (P=0.33). Subgroup analysis on the basis of tumor size and number showed no prognostic differences between the two groups. The median survival time was longer in responders than in non-responders (85 vs. 56 months; P=0.01). However, the median relapse-free survival was equivalent in both groups (16.4 and 10.7 months). Preoperative chemotherapy did not prolong survival. Furthermore, it did not prevent recurrence, even in clinical responders. Therefore, it should not be routinely offered to patients with resectable liver metastasis before their hepatectomy.
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Affiliation(s)
- Nobuki Ichikawa
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan
| | - Toshiya Kamiyama
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan
| | - Hideki Yokoo
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan
| | - Shigenori Homma
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan
| | - Yoshiaki Maeda
- Department of Gastroenterological Surgery, Hokkaido Cancer Center, Sapporo, Hokkaido 003-0804, Japan
| | - Toshiki Shinohara
- Department of Gastroenterological Surgery, Hokkaido Cancer Center, Sapporo, Hokkaido 003-0804, Japan
| | - Yosuke Tsuruga
- Department of Surgery, Hokkaido Hospital, Japan Community Healthcare Organization, Sapporo, Hokkaido 062-8618, Japan
| | - Keizo Kazui
- Department of Surgery, Hokkaido Hospital, Japan Community Healthcare Organization, Sapporo, Hokkaido 062-8618, Japan
| | - Hiroaki Iijima
- Clinical Research and Medical Innovation Center, Hokkaido University Hospital, Sapporo, Hokkaido 060-8648, Japan
| | - Tadashi Yoshida
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan
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Abstract
OBJECTIVE The aim of this study was to evaluate outcomes of metastases at various time intervals after colorectal cancer (CRC) diagnosis. BACKGROUND Earlier studies have indicated a short time interval between CRC diagnosis and distant metastases to be associated with poor prognosis. The majority of studies assessed outcome from CRC diagnosis or metastasis resection rather than from metastasis diagnosis and might be subject to immortal time bias. METHODS Patients in the population-based DACHS study were stratified: metastases at/within 1 month (immediate), 2 to 6 months (early), 7 to 12 months (intermediate), and >12 months (late) after CRC diagnosis. The primary endpoint was overall survival (OS) from metastasis diagnosis. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CI). HRs were adjusted for important confounders and immortal time. RESULTS A total of 1027 patients were included. T4 (P < 0.0001) and node-positive tumors (P < 0.0001) were more frequent in the immediate group. Lung metastases (P < 0.0001) and single-site metastases (P < 0.0001) were more prevalent in the late group. In multivariable analysis, immediate metastases were not associated with poor OS compared to metastases at later time points (late vs immediate: HR 1.21; 95% CI, 0.98-1.48). Subgroup analyses revealed poor OS of late versus immediate metastases for females (1.45; 1.08-1.96), proximal colon cancer (1.54; 1.09-2.16), and N0 (1.46; 1.00-2.12) or N1 disease (1.88; 1.17-3.05). CONCLUSIONS Immediate or early metastases are not associated with unfavorable outcome compared to late metastases. These findings challenge the current notion of poor outcome for CRC with immediate or early metastases.
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Džunić M, Pejčić B, Andjelković-Apostolović M, Vrbić S, Pejčić I, Petković I. PREDICTORS OF THERAPY RESPONSE AND EARLY RECURRENCE IN PATIENTS WITH POTENTIALLY RESECTABLE COLORECTAL LIVER METASTASES TREATED WITH BEVACIZUMAB AND FOLFOX4 AS A CONVERSION THERAPY. ACTA MEDICA MEDIANAE 2019. [DOI: 10.5633/amm.2019.0310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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Conditional Survival Analysis of Metastatic Colorectal Cancer Patients Living ≥24 Months: A Single Institutional Study. Am J Clin Oncol 2019; 42:512-518. [PMID: 30973370 DOI: 10.1097/coc.0000000000000535] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
OBJECTIVES The survival of patients with metastatic colorectal cancer (CRC) has been increasing over recent decades due to improvements in chemotherapy and surgery. There is a need to refine prognostic information to more accurately predict survival as patients survive for any given length of time to assist multidisciplinary cancer management teams in treatment decisions. MATERIALS AND METHODS We performed a single center retrospective analysis of patients treated with metastatic CRC (unresectable and resectable) who survived >24 months between 2005 and 2015 (N=155). Patient tumor and treatment related variables were collected. Overall survival (OS) estimates conditional on surviving >24 months were compared with actuarial survival estimates of a cohort of patients (33,104 resected, 39,382 unresected) from the National Cancer Database (NCDB). RESULTS With a median follow-up of 44.2 months, the median OS of resected patients (n=86) was not reached. The median OS of unresected patients was 75.9 months. The conditional survival probabilities of living 1, 2, or 3 years longer after 24 months of survival are 92%, 72%, and 52%, respectively, in unresectable patients and 98%, 92%, and 89% in patients who were resected. The corresponding NCDB 1, 2, and 3 year actuarial survival was 38%, 20%, and 11% for unresected patients and 68%, 46%, and 32% for resected. CONCLUSIONS These results indicate that CRC patients who survive 24 months with metastatic colorectal cancer have an excellent prognosis and surgery may be appropriate in a subset of patients initially deemed unresectable.
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28
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Importance of autophagy in colorectal cancer: A cross-sectional study. JOURNAL OF SURGERY AND MEDICINE 2019. [DOI: 10.28982/josam.536733] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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Petrovski S, Karakolevska-Ilova M, Simeonovska-Joveva E, Serafimov A, Adzi-Andov L, Dimitrova V. Influence of the Type and Amount of Liver Resection on the Survival of the Patients with Colorectal Metastases. Open Access Maced J Med Sci 2018; 6:1046-1051. [PMID: 29983799 PMCID: PMC6026431 DOI: 10.3889/oamjms.2018.116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 05/18/2018] [Accepted: 05/23/2018] [Indexed: 12/05/2022] Open
Abstract
INTRODUCTION: Colorectal liver metastases have a poor prognosis, and only 2% have an average 5-year survival if left untreated. Despite radical resection, the average five-year survival is between 25% and 44%. AIM: To explore the experience of the Clinic in the treatment of colorectal liver metastases, comparing it with data from the literature and based on the comparison to determine the influence of the type and extensity of resection survival after radical surgical treatment of patients. METHODS: This is a retrospective study. The study comprised the period between 01.01.2006 to 31.12.2015. It included a total of 239 cases, of whom: 179 patients underwent radical interventions, 5 palliative and 55 patients underwent explorative interventions due to liver metastases. RESULTS: Radical resection of liver metastases has the impact of the patient survival, and the survival is the smallest in the patients with left hemihepatectomy and the longest in the patients with bisegmentectomy. But no specific technique and the number of resected segments influenced the survival of patients with colorectal liver metastases. CONCLUSION: In patients with colorectal liver metastases only resection has potentially curative character. The type and amount of liver resection has no influence of the survival.
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Affiliation(s)
- Stefan Petrovski
- Clinical Hospital Shtip, Surgery, Ljuben Ivanov bb, Shtip, Republic of Macedonia
| | | | | | | | | | - Violeta Dimitrova
- Clinic of General and Hepato-Pancreatic Surgery, University Hospital "Aleksandrovska", Sofia, Bulgaria
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van Dam PJ, van der Stok EP, Teuwen LA, Van den Eynden GG, Illemann M, Frentzas S, Majeed AW, Eefsen RL, Coebergh van den Braak RRJ, Lazaris A, Fernandez MC, Galjart B, Laerum OD, Rayes R, Grünhagen DJ, Van de paer M, Sucaet Y, Mudhar HS, Schvimer M, Nyström H, Kockx M, Bird NC, Vidal-Vanaclocha F, Metrakos P, Simoneau E, Verhoef C, Dirix LY, Van Laere S, Gao ZH, Brodt P, Reynolds AR, Vermeulen PB. International consensus guidelines for scoring the histopathological growth patterns of liver metastasis. Br J Cancer 2017; 117:1427-1441. [PMID: 28982110 PMCID: PMC5680474 DOI: 10.1038/bjc.2017.334] [Citation(s) in RCA: 167] [Impact Index Per Article: 20.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2017] [Revised: 06/12/2017] [Accepted: 08/30/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Liver metastases present with distinct histopathological growth patterns (HGPs), including the desmoplastic, pushing and replacement HGPs and two rarer HGPs. The HGPs are defined owing to the distinct interface between the cancer cells and the adjacent normal liver parenchyma that is present in each pattern and can be scored from standard haematoxylin-and-eosin-stained (H&E) tissue sections. The current study provides consensus guidelines for scoring these HGPs. METHODS Guidelines for defining the HGPs were established by a large international team. To assess the validity of these guidelines, 12 independent observers scored a set of 159 liver metastases and interobserver variability was measured. In an independent cohort of 374 patients with colorectal liver metastases (CRCLM), the impact of HGPs on overall survival after hepatectomy was determined. RESULTS Good-to-excellent correlations (intraclass correlation coefficient >0.5) with the gold standard were obtained for the assessment of the replacement HGP and desmoplastic HGP. Overall survival was significantly superior in the desmoplastic HGP subgroup compared with the replacement or pushing HGP subgroup (P=0.006). CONCLUSIONS The current guidelines allow for reproducible determination of liver metastasis HGPs. As HGPs impact overall survival after surgery for CRCLM, they may serve as a novel biomarker for individualised therapies.
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Affiliation(s)
- Pieter-Jan van Dam
- Translational Cancer Research Unit, GZA Hospitals (St Augustinus), Wilrijk-Antwerp, Belgium
| | - Eric P van der Stok
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Laure-Anne Teuwen
- Translational Cancer Research Unit, GZA Hospitals (St Augustinus), Wilrijk-Antwerp, Belgium
| | - Gert G Van den Eynden
- Translational Cancer Research Unit, GZA Hospitals (St Augustinus), Wilrijk-Antwerp, Belgium
| | - Martin Illemann
- The Finsen Laboratory, Rigshospitalet/BRIC, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Sophia Frentzas
- Tumour Biology Team, Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
| | - Ali W Majeed
- Hepatobiliary Surgery, Sheffield Teaching Hospitals, Sheffield, UK
| | - Rikke L Eefsen
- Department of Oncology, Naestved Hospital, Naestved, Denmark
| | | | - Anthoula Lazaris
- Department of Surgery, Cancer Research Program, McGill University Health Centre Research Institute, Montreal, QC, Canada
| | - Maria Celia Fernandez
- Departments of Surgery, Oncology and Medicine, McGill University and the McGill University Health Center Research Institute, Cancer Research Program, Montreal, QC, Canada
| | - Boris Galjart
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Ole Didrik Laerum
- The Finsen Laboratory and Department of Radiation Biology, Copenhagen University Hospital, University of Copenhagen, Denmark
| | - Roni Rayes
- Departments of Surgery, Oncology and Medicine, McGill University and the McGill University Health Center Research Institute, Cancer Research Program, Montreal, QC, Canada
| | - Dirk J Grünhagen
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Michelle Van de paer
- Translational Cancer Research Unit, GZA Hospitals (St Augustinus), Wilrijk-Antwerp, Belgium
- HistoGeneX, Sint-Bavostraat 78-80, Antwerp 2610, Belgium
| | - Yves Sucaet
- Department of Pathology, Faculty of Medicine, Vrije Universiteit Brussel, Brussels, Belgium
- Pathomation, Berchem, Belgium
| | | | - Michael Schvimer
- Institute of Pathology, Sheba Medical Center, Tel Hashomer, Israel
| | - Hanna Nyström
- Department of Surgery, Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden
| | - Mark Kockx
- HistoGeneX, Sint-Bavostraat 78-80, Antwerp 2610, Belgium
| | - Nigel C Bird
- Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK
| | | | - Peter Metrakos
- Department of Surgery, Cancer Research Program, McGill University Health Centre Research Institute, Montreal, QC, Canada
| | - Eve Simoneau
- Department of Surgery, Cancer Research Program, McGill University Health Centre Research Institute, Montreal, QC, Canada
| | - Cornelis Verhoef
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Luc Y Dirix
- Translational Cancer Research Unit, GZA Hospitals (St Augustinus), Wilrijk-Antwerp, Belgium
| | - Steven Van Laere
- Translational Cancer Research Unit, GZA Hospitals (St Augustinus), Wilrijk-Antwerp, Belgium
| | - Zu-hua Gao
- Department of Pathology and Oncology, McGill University, Montreal, QC, Canada
| | - Pnina Brodt
- Departments of Surgery, Oncology and Medicine, McGill University and the McGill University Health Center Research Institute, Cancer Research Program, Montreal, QC, Canada
| | - Andrew R Reynolds
- Tumour Biology Team, Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
- Early Clinical Development, Innovative Medicines and Early Development, AstraZeneca, Cambridge, UK
| | - Peter B Vermeulen
- Translational Cancer Research Unit, GZA Hospitals (St Augustinus), Wilrijk-Antwerp, Belgium
- Tumour Biology Team, Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
- HistoGeneX, Sint-Bavostraat 78-80, Antwerp 2610, Belgium
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Wu W, Chen J, Ding Q, Yang S, Wang J, Yu H, Lin J. Function of the macrophage-capping protein in colorectal carcinoma. Oncol Lett 2017; 14:5549-5555. [PMID: 29113183 PMCID: PMC5656019 DOI: 10.3892/ol.2017.6888] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2015] [Accepted: 07/14/2017] [Indexed: 12/13/2022] Open
Abstract
To investigate the role of macrophage-capping protein (CapG) in the development and progression of colorectal carcinoma (CRC), immunohistochemistry (IHC), Kaplan-Meier survival analysis, wound healing and Transwell migration assays were performed. The IHC results demonstrated that CapG was relatively highly expressed in CRC tissue compared with non-tumor tissue (P<0.001), and that the expression of CapG was significantly associated with the tumor site, differentiation, lymph node metastasis and clinical stage (P=0.021, P=0.036, P=0.012 and P=0.009, respectively). Wound healing and Transwell migration assays demonstrated that the reduction of CapG expression in a CRC cell line by RNA interference was associated with significantly impaired motility (P<0.001). Kaplan-Meier survival analysis revealed that the expression of CapG in tumor samples was not significantly associated with disease-free survival time. In conclusion, CapG was overexpressed in CRC and was associated with tumor progression; therefore, it may be a useful prognostic biomarker and therapeutic target in CRC.
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Affiliation(s)
- Wei Wu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Jingdi Chen
- 73rd Contingent, 95969 Troops, The Airborne Force of Chinese PLA, Wuhan, Hubei 430300, P.R. China
| | - Qianshan Ding
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Sheng Yang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Jianping Wang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Honggang Yu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Jun Lin
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
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Weledji EP. Centralization of Liver Cancer Surgery and Impact on Multidisciplinary Teams Working on Stage IV Colorectal Cancer. Oncol Rev 2017; 11:331. [PMID: 28814999 PMCID: PMC5538223 DOI: 10.4081/oncol.2017.331] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 12/15/2016] [Accepted: 07/17/2017] [Indexed: 12/17/2022] Open
Abstract
Surgical resection is the most effective treatment approach for colorectal liver metastases but only a minority of patients is suitable for upfront surgery. The treatment strategies of stage IV colorectal cancer have shifted towards a continuum of care in which medical and surgical treatment combinations are tailored to the clinical setting of the individual patient. The optimization of treatment through appropriate decision-making and multimodal therapy for stage IV colorectal cancer require a joint multidisciplinary meeting in a centralized liver cancer unit.
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Abstract
INTRODUCTION Colorectal cancer is a significant global health issue with over 1 million cases diagnosed annually throughout the world. 15% of patients diagnosed with colorectal cancer will have liver metastases and 60% will develop liver metastases if they have metastatic disease. Oligometastatic colorectal cancer confined to the liver represents an intermediate state in the evolution of metastatic capacity that opens the opportunity for local interventions. Areas covered: The literature supports long-term survival if patients undergo liver resection of colorectal metastases. This article reviews the liver-directed therapeutic strategies available for the management of metastatic liver disease including hepatic arterial infusion therapy, radiofrequency ablation, radiation therapy and transarterial chemoembolization. Expert commentary: Great advances have been made with the use of liver directed therapies. In the USA using hepatic arterial infusions with FUDR and Decadron along with systemic therapy, 5 year survivals after liver resection have improved. In Europe with the use of HAI of Oxaliplatin, more patients have been able to get to resection and have obtained higher survival rates, even in second line therapy. New advances in ablative therapy have improved results to get all disease treated at resection for the treatment of reccurrence.
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Affiliation(s)
- Ciara M Kelly
- a Department of Graduate Medical Education , Memorial Sloan Kettering Cancer Center , New York , USA
| | - Nancy E Kemeny
- b Memorial Sloan-Kettering Cancer Center , Weill Medical College of Cornell University , New York , USA
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Giuliani J, Bonetti A. The Pharmacological Costs of Complete Liver Resections in Unselected Advanced Colorectal Cancer Patients: Focus on Targeted Agents. A Review of Randomized Clinical Trials. J Gastrointest Cancer 2017; 47:341-350. [PMID: 27488729 DOI: 10.1007/s12029-016-9862-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND The aim of this study was to evaluate the pharmacological costs of conversion chemotherapy with targeted biological agents in an unselected population of advanced colorectal cancer (CRC) patients in order to achieve an R0 liver resection. METHODS Full reports and updates of randomized clinical trials (RCTs) that compared at least two front-line therapy regimens with targeted biological agents for advanced CRC patients were selected. The present evaluation was restricted to randomized phase II and III trials. The costs of drugs are at the Pharmacy Hospital and are expressed in euros (€). RESULTS Our study began with the evaluation of 683 abstracts. Forty-eight trials were considered appropriate for further analysis. A more in-depth evaluation looking for the trials reporting the liver resection rates following conversion chemotherapy brought to the exclusion of other 37 trials, leaving 11 randomized trials (three phase II trials, including 522 patients and eight phase III trials, including 7191 patients). The pharmacological costs of conversion therapy increased with the substitution of prolonged infusion 5-Fluorouracil by capecitabine and, to a much higher extent, with the introduction of biologicals. CONCLUSIONS Two key issues are presented in this review. First, the pharmacological costs of commonly used front line regimens based on the targeted biological agents for the treatment of advanced CRC are highly variable. Second, the performance of the published schemes, in terms of resection rates, depends on patient's selection, tumor characteristics, and on the type of the scheme.
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Affiliation(s)
- Jacopo Giuliani
- Department of Medical Oncology, Mater Salutis Hospital, AULSS 21 della Regione Veneto, Legnago, VR, Italy. .,Department of Medical Oncology, ASL 21 della Regione Veneto, Via Gianella 1, 37045, Legnago, VR, Italy.
| | - Andrea Bonetti
- Department of Medical Oncology, Mater Salutis Hospital, AULSS 21 della Regione Veneto, Legnago, VR, Italy.,Department of Medical Oncology, ASL 21 della Regione Veneto, Via Gianella 1, 37045, Legnago, VR, Italy
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Veen T, Søreide K. Can molecular biomarkers replace a clinical risk score for resectable colorectal liver metastasis? World J Gastrointest Oncol 2017; 9:98-104. [PMID: 28344745 PMCID: PMC5348630 DOI: 10.4251/wjgo.v9.i3.98] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Revised: 11/25/2016] [Accepted: 12/28/2016] [Indexed: 02/05/2023] Open
Abstract
In resectable colorectal liver metastasis (CRLM) the role and use of molecular biomarkers is still controversial. Several biomarkers have been linked to clinical outcomes in CRLM, but none have so far become routine for clinical decision making. For several reasons, the clinical risk score appears to no longer hold the same predictive value. Some of the reasons include the ever expanding indications for liver resection, which now increasingly tend to involve extrahepatic disease, such as lung metastases (both resectable and non-resectable) and the shift in indication from “what is taken out” (e.g., how much liver has to be resected) to “what is left behind” (that is, how much functional liver tissue the patient has after resection). The latter is amenable to modifications by using adjunct techniques of portal vein embolization and the associating liver partition and portal vein ligation for staged hepatectomy techniques to expand indications for liver resection. Added to this complexity is the increasing number of molecular markers, which appear to hold important prognostic and predictive information, for which some will be discussed here. Beyond characteristics of tissue-based genomic profiles will be liquid biopsies derived from circulating tumor cells and cell-free circulating tumor DNA in the blood. These markers are present in the peripheral circulation in the majority of patients with metastatic cancer disease. Circulating biomarkers may represent more readily available methods to monitor, characterize and predict cancer biology with future implications for cancer care.
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Chen P, Luo X, Nie P, Wu B, Xu W, Shi X, Chang H, Li B, Yu X, Zou Z. CQ synergistically sensitizes human colorectal cancer cells to SN-38/CPT-11 through lysosomal and mitochondrial apoptotic pathway via p53-ROS cross-talk. Free Radic Biol Med 2017; 104:280-297. [PMID: 28131902 DOI: 10.1016/j.freeradbiomed.2017.01.033] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Revised: 01/16/2017] [Accepted: 01/24/2017] [Indexed: 12/19/2022]
Abstract
Autophagy plays a key role in supporting cell survival against chemotherapy-induced apoptosis. In this study, we found the chemotherapy agent SN-38 induced autophagy in colorectal cancer (CRC) cells. However, inhibition of autophagy using a small molecular inhibitor 3-methyladenine (3-MA) and ATG5 siRNA did not increase SN-38-induced cytotoxicity in CRC cells. Notably, another autophagy inhibitor chloroquine (CQ) synergistically enhanced the anti-tumor activity of SN-38 in CRC cells with wild type (WT) p53. Subsequently, we identified a potential mechanism of this cooperative interaction by showing that CQ and SN-38 acted together to trigger reactive oxygen species (ROS) burst, upregulate p53 expression, elicit the loss of lysosomal membrane potential (LMP) and mitochondrial membrane potential (∆ψm). In addition, ROS induced by CQ plus SN-38 upregulated p53 levels by activating p38, conversely, p53 stimulated ROS. These results suggested that ROS and p53 reciprocally promoted each other's production and cooperated to induce CRC cell death. Moreover, we showed induction of ROS and p53 by the two agents provoked the loss of LMP and ∆ψm. Altogether, all results suggested that CQ synergistically sensitized human CRC cells with WT p53 to SN-38 through lysosomal and mitochondrial apoptotic pathway via p53-ROS cross-talk. Lastly, we showed that CQ could enhance CRC cells response to CPT-11 (a prodrug of SN-38) in xenograft models. Thus the combined treatment might represent an attractive therapeutic strategy for the treatment of CRC.
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Affiliation(s)
- Pinjia Chen
- Department of Oncology, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China
| | - Xiaoyong Luo
- Department of Oncology, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China
| | - Peipei Nie
- KingMed Diagnostics and KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, China
| | - Baoyan Wu
- MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, Joint Laboratory of Laser Oncology with Cancer Center of Sun Yat-sen University, College of Biophotonics, South China Normal University, No. 55 Zhongshan Road West, Guangzhou, China
| | - Wei Xu
- KingMed Diagnostics and KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, China
| | - Xinpeng Shi
- Department of Oncology, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China
| | - Haocai Chang
- MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, Joint Laboratory of Laser Oncology with Cancer Center of Sun Yat-sen University, College of Biophotonics, South China Normal University, No. 55 Zhongshan Road West, Guangzhou, China
| | - Bing Li
- Department of Oncology, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China
| | - Xiurong Yu
- Department of Oncology, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China
| | - Zhengzhi Zou
- MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, Joint Laboratory of Laser Oncology with Cancer Center of Sun Yat-sen University, College of Biophotonics, South China Normal University, No. 55 Zhongshan Road West, Guangzhou, China.
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Li X, Shi L, Wu J, Ji M, Zhao J, Qiang W, Ding W, Jiang J, Lu Q, Wu C. First-line treatment with hepatic arterial infusion plus capecitabine vs capecitabine alone for elderly patients with unresectable colorectal liver metastases. Cancer Biol Ther 2016; 17:14-9. [PMID: 26619222 DOI: 10.1080/15384047.2015.1108487] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
This study aimed to compare the efficacy and safety of HAI fluoropyrimidine (FUDR)/capecitabine or single capecitabine as first-line treatment for elderly patients with unresectable colorectal liver metastases (CLMs). Fifty-one elderly patients with liver-only CLMs were eligible for enrollment. Patients were divided into HAI FUDR /capecitabine group and single capecitabine group randomly. The primary endpoint was median survival time (MST), defined as the time from the date of catheter implantation to the date of death or the date of the last follow-up. The secondary endpoint was objective antitumor response and adverse events. The HAI pump was implanted before chemotherapy. All patients received a 3-week cycle of oral capecitabin. In Group A, the RR and DCR were both 95.8%. In Group B, the RR and DCR were 48.1% and 81.5%, respectively. There was significant difference between the RRs of the 2 groups (P < 0.001). But there was no significant difference between the DCRs of the 2 groups (P = 0.053). There was a statistical difference between the MSTs of the 2 groups (18.5 vs.13 months, P = 0.0312). HAI FUDR combined with oral capecitabine as the first-line treatment for elderly patients with CLMs has promising efficacy and safety.
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Affiliation(s)
- Xiaodong Li
- a Department of Oncology , The Third Affiliated Hospital of Soochow University Changzhou , China.,b Department of Biological Treatment , The Third Affiliated Hospital of Soochow University Changzhou , China.,c Jiangsu Engineering Research Center for Tumor Immunotherapy Changzhou , China
| | - Liangrong Shi
- a Department of Oncology , The Third Affiliated Hospital of Soochow University Changzhou , China.,c Jiangsu Engineering Research Center for Tumor Immunotherapy Changzhou , China
| | - Jun Wu
- a Department of Oncology , The Third Affiliated Hospital of Soochow University Changzhou , China
| | - Mei Ji
- a Department of Oncology , The Third Affiliated Hospital of Soochow University Changzhou , China
| | - Jiemin Zhao
- a Department of Oncology , The Third Affiliated Hospital of Soochow University Changzhou , China
| | - Weiguang Qiang
- a Department of Oncology , The Third Affiliated Hospital of Soochow University Changzhou , China
| | - Wenge Ding
- d Department of Orthopedics , The Third Affiliated Hospital of Soochow University Changzhou , China
| | - Jingting Jiang
- b Department of Biological Treatment , The Third Affiliated Hospital of Soochow University Changzhou , China.,c Jiangsu Engineering Research Center for Tumor Immunotherapy Changzhou , China
| | - Qicheng Lu
- e Department of Gastrointestinal Surgery , The Third Affiliated Hospital of Soochow University Changzhou , China
| | - Changping Wu
- a Department of Oncology , The Third Affiliated Hospital of Soochow University Changzhou , China.,b Department of Biological Treatment , The Third Affiliated Hospital of Soochow University Changzhou , China.,c Jiangsu Engineering Research Center for Tumor Immunotherapy Changzhou , China
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van der Stok EP, Smid M, Sieuwerts AM, Vermeulen PB, Sleijfer S, Ayez N, Grünhagen DJ, Martens JWM, Verhoef C. mRNA expression profiles of colorectal liver metastases as a novel biomarker for early recurrence after partial hepatectomy. Mol Oncol 2016; 10:1542-1550. [PMID: 27692894 DOI: 10.1016/j.molonc.2016.09.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 08/31/2016] [Accepted: 09/12/2016] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Identification of specific risk groups for recurrence after surgery for isolated colorectal liver metastases (CRLM) remains challenging due to the heterogeneity of the disease. Classical clinicopathologic parameters have limited prognostic value. The aim of this study was to identify a gene expression signature measured in CRLM discriminating early from late recurrence after partial hepatectomy. METHODS CRLM from two patient groups were collected: I) with recurrent disease ≤12 months after surgery (N = 33), and II) without recurrences and disease free for ≥36 months (N = 30). The patients were clinically homogeneous; all had a low clinical risk score (0-2) and did not receive (neo-) adjuvant chemotherapy. Total RNA was hybridised to Illumina arrays, and processed for analysis. A leave-one-out cross validation (LOOCV) analysis was performed to identify a prognostic gene expression signature. RESULTS LOOCV yielded an 11-gene profile with prognostic value in relation to recurrent disease ≤12 months after partial hepatectomy. This signature had a sensitivity of 81.8%, with a specificity of 66.7% for predicting recurrences (≤12 months) versus no recurrences for at least 36 months after surgery (X2 P < 0.0001). CONCLUSION The current study yielded an 11-gene signature at mRNA level in CRLM discriminating early from late or no relapse after partial hepatectomy.
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Affiliation(s)
- E P van der Stok
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands.
| | - M Smid
- Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands
| | - A M Sieuwerts
- Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands
| | - P B Vermeulen
- Translational Cancer Research Group, Sint-Augustinus (GZA Hospitals) & CORE (Antwerp University), Oosterveldlaan 24, 2610 Wilrijk-Antwerp, Belgium
| | - S Sleijfer
- Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands
| | - N Ayez
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands
| | - D J Grünhagen
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands
| | - J W M Martens
- Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands
| | - C Verhoef
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands
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Wang H, Ma B, Gao P, Song Y, Xu Q, Hu Y, Zhang C, Wang Z. Efficacy and safety of anti-epidermal growth factor receptor therapy compared with anti-vascular endothelial growth factor therapy for metastatic colorectal cancer in first-line and second-line therapies: a meta-analysis. Onco Targets Ther 2016; 9:5405-16. [PMID: 27621654 PMCID: PMC5012842 DOI: 10.2147/ott.s111240] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Aim This study aimed to compare anti-epidermal growth factor receptor (anti-EGFR) therapy and anti-vascular endothelial growth factor therapy as first-line and second-line therapies in patients with KRAS exon 2 codon 12/13 wild-type (KRAS-WT) metastatic colorectal cancer (mCRC). Methods Major databases were systematically searched. The hazard ratio (HR), odds ratio (OR), and 95% confidence intervals (95% CIs) were used to estimate the effect measures. Review Manager software version 5.3 was used for statistical analysis. Results Seven trials including ten articles were eligible in the meta-analysis. The patients treated with anti-EGFR as first-line therapy showed a longer overall survival (OS) for KRAS-WT and all RAS wild-type (RAS-WT) mCRC (HR =0.81, 95% CI: 0.72–0.92, P<0.01, n=5; HR =0.78, 95% CI: 0.66–0.93, P<0.01, n=3, respectively). The objective response rate (ORR) was better with the anti-EGFR therapy for KRAS-WT and all RAS-WT mCRC (OR =1.32, 95% CI: 1.11–1.56, P<0.01, n=5; OR =1.55, 95% CI: 1.21–2.00, P<0.01, n=3, respectively). There was no difference in progression-free survival (PFS) for KRAS-WT mCRC and all RAS-WT mCRC between the two groups (HR =1.00; 95% CI: 0.92–1.09, P=0.99, n=4; HR =0.92, 95% CI: 0.71–1.19, P=0.52, n=3, respectively). In addition, two trials provided data on the second-line therapy; there was no significant difference in OS and PFS for the second-line therapy, but a significant improvement in ORR was found in the anti-EGFR group (OR =1.91, 95% CI: 1.16–3.16, P=0.01, n=2). No difference in the conversion therapy (OR =1.34; 95% CI: 0.91–1.99; P=0.14, n=4) was observed between the two therapies. Conclusion Our results indicate that anti-EGFR therapy is superior to anti-vascular endothelial growth factor therapy for OS and ORR as a first-line therapy for KRAS-WT mCRC. In the second-line therapy, there was no significant difference in the survival outcomes on the basis of OS and PFS between the two groups. However, ORR improved significantly in the anti-EGFR group.
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Affiliation(s)
- Hongchi Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, People's Republic of China
| | - Bin Ma
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, People's Republic of China
| | - Peng Gao
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, People's Republic of China
| | - Yongxi Song
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, People's Republic of China
| | - Qingzhou Xu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, People's Republic of China
| | - Yaoyuan Hu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, People's Republic of China
| | - Cong Zhang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, People's Republic of China
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, People's Republic of China
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De Greef K, Rolfo C, Russo A, Chapelle T, Bronte G, Passiglia F, Coelho A, Papadimitriou K, Peeters M. Multisciplinary management of patients with liver metastasis from colorectal cancer. World J Gastroenterol 2016; 22:7215-7225. [PMID: 27621569 PMCID: PMC4997640 DOI: 10.3748/wjg.v22.i32.7215] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Revised: 06/21/2016] [Accepted: 08/01/2016] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related death. Surgery, radiotherapy and chemotherapy have been till now the main therapeutic strategies for disease control and improvement of the overall survival. Twenty-five per cent (25%) of CRC patients have clinically detectable liver metastases at the initial diagnosis and approximately 50% develop liver metastases during their disease course. Twenty-thirty per cent (20%-30%) are CRC patients with metastases confined to the liver. Some years ago various studies showed a curative potential for liver metastases resection. For this reason some authors proposed the conversion of unresectable liver metastases to resectable to achieve cure. Since those results were published, a lot of regimens have been studied for resectability potential. Better results could be obtained by the combination of chemotherapy with targeted drugs, such as anti-VEGF and anti-EGFR monoclonal antibodies. However an accurate selection for patients to treat with these regimens and to operate for liver metastases is mandatory to reduce the risk of complications. A multidisciplinary team approach represents the best way for a proper patient management. The team needs to include surgeons, oncologists, diagnostic and interventional radiologists with expertise in hepatobiliary disease, molecular pathologists, and clinical nurse specialists. This review summarizes the most important findings on surgery and systemic treatment of CRC-related liver metastases.
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Metastatic Spread Emerging From Liver Metastases of Colorectal Cancer: Does the Seed Leave the Soil Again? Ann Surg 2016; 263:345-52. [PMID: 26501709 DOI: 10.1097/sla.0000000000001341] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To investigate whether liver metastases contribute to metastatic spread of colorectal cancer (CRC) by shedding intact tumor cells. BACKGROUND Metastases represent the primary cause of death in CRC. Understanding the metastatic activity of metastases and which patients are at high risk for tumor cell dissemination may, therefore, have significant influence on cancer care in the future. METHODS Circulating tumor cells (CTCs) were detected in the hepatic inflow (portal venous blood [PVB]) and outflow compartment (hepatic venous blood [HVB]) of a training (n = 55) and validation (n = 50) set using the CellSearch system. Isolated CTC from the HVB were subjected to gene expression analyses by quantitative polymerase chain reaction. RESULTS CTC detection rate (37.2% vs 19.6%; P = 0.04) and count (mean: 12.7, SEM: ± 5.9 vs 1.9; ± 1.2; P = 0.01) were significantly higher in HVB compared to PVB. The increased CTC detection rate (54% vs 11.4%; P < 0.001) and CTC count (14.7 ± 5.1 vs 1.1 ± 0.6; P < 0.001) in the HVB compared to the PVB compartment was confirmed in the validation cohort. Expression of epithelial markers and genes involved in cell-to-cell and cell-to-matrix adhesion was reduced in CTC compared to tumor cells in liver metastases. Metastasis size greater than 5 cm was associated with CTC shedding from established liver metastases in the training and validation cohorts. CONCLUSIONS Colorectal liver metastases shed intact tumor cells with an invasive phenotype. Metastasis size serves as a surrogate marker for metastatic activity of colorectal liver metastases.
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Rosenthal MH, Kim KW, Fuchs CS, Meyerhardt JA, Ramaiya NH. CT predictors of overall survival at initial diagnosis in patients with stage IV colorectal cancer. ACTA ACUST UNITED AC 2016; 40:1170-6. [PMID: 25326260 DOI: 10.1007/s00261-014-0272-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE We investigated whether the initial CT distribution of metastatic disease is predictive of overall survival in patients with stage IV colorectal cancer. MATERIALS AND METHODS A retrospective study of 65 patients (37 males, 28 females, mean age 56, range 28-88 years) with stage IV colorectal cancer was derived from an institutional database. Inclusion criteria required KRAS mutation testing and pretreatment CT examinations to be available (65 abdomen/pelvis, 63 chest). Disease burden was jointly characterized by two radiologists in consensus. Median follow-up was 39 months (range 8-115 months). Survival was assessed using Cox proportional hazards models. RESULTS Univariate analysis showed that stratified site(s) of measurable disease and counts of measurable lesions ≥1 cm in the liver, peritoneum, and retroperitoneum were statistically significant risk factors for overall mortality [univariate HR 8.2 (CI 2.7-25.4) for isolated peritoneal disease, HR 1.11 per 5 lesions (CI 1.05-1.17) for liver lesions, HR 1.15 per lesion (CI 1.05-1.26) for peritoneal lesions, and HR 1.11 (CI 1.03-1.19) for retroperitoneal lymph nodes ≥1 cm in short axis]. The stratified site(s) of disease and counts of measurable liver lesions remained significant in the multivariate model (p < 0.0001 for isolated peritoneal disease and count of liver lesions). Thoracic metastases were not statistically significant predictors of overall mortality in this cohort. CONCLUSION This study identified site(s) of measurable metastasis and counts of measurable liver lesions as independent predictors of overall survival. These findings may have value for future prognostic assessments once validated in a larger, independent, and potentially prospective cohort.
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Affiliation(s)
- Michael H Rosenthal
- Department of Imaging, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, 02115, MA, USA,
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Zhang H, Zhong H, Li L, Ji W, Zhang X. Overexpressed transcription factor FOXM1 contributes to the progression of colorectal cancer. Mol Med Rep 2016; 13:2696-700. [PMID: 26861549 DOI: 10.3892/mmr.2016.4875] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2015] [Accepted: 11/30/2015] [Indexed: 11/06/2022] Open
Abstract
Forkhead box M1 (FOXM1) is a characteristic proliferation‑associated transcription factor, which is overexpressed in various types of human cancer. The aim of the present study was to determine the expression of FOXM1 in a large collection of colorectal cancer (CRC) samples. Between March 2012 and January 2014, 96 patients with histologically diagnosed CRC were recruited into the current study. Using immunohistochemistry, reverse transcription‑quantitative polymerase chain reaction and western blotting, mRNA and protein expression levels of FOXM1 in CRC tissue samples were determined. The function of FOXM1 in the CRC cells was evaluated by small interfering RNA‑mediated depletion of FOXM1, followed by analyses of cell proliferation and invasion. High levels of staining for FOXM1 were observed in significantly more CRC tissue samples: 85.42% (82/96) of CRC tissue samples compared with 18.75% (18/96) of adjacent normal mucosa tissue samples. Silencing FOXM1 inhibited the proliferation of LoVo cells, which express a relatively high level of FOXM1, and the invasion and migration of LoVo cells were also markedly suppressed. The data from the present study suggested that the pathogenesis of human CRC may be mediated by FOXM1, and that FOXM1 inhibition may provide a promising therapeutic strategy for CRC.
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Affiliation(s)
- Hongmei Zhang
- Department of Gastroenterology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261031, P.R. China
| | - Hua Zhong
- Department of Gastroenterology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261031, P.R. China
| | - Lei Li
- Department of Gastroenterology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261031, P.R. China
| | - Wansheng Ji
- Department of Gastroenterology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261031, P.R. China
| | - Xiaoqian Zhang
- Department of Gastroenterology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261031, P.R. China
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El Messaoudi S, Mouliere F, Du Manoir S, Bascoul-Mollevi C, Gillet B, Nouaille M, Fiess C, Crapez E, Bibeau F, Theillet C, Mazard T, Pezet D, Mathonnet M, Ychou M, Thierry AR. Circulating DNA as a Strong Multimarker Prognostic Tool for Metastatic Colorectal Cancer Patient Management Care. Clin Cancer Res 2016; 22:3067-77. [DOI: 10.1158/1078-0432.ccr-15-0297] [Citation(s) in RCA: 114] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Accepted: 01/03/2016] [Indexed: 02/07/2023]
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Jiao L, Li DD, Yang CL, Peng RQ, Guo YQ, Zhang XS, Zhu XF. Reactive oxygen species mediate oxaliplatin-induced epithelial-mesenchymal transition and invasive potential in colon cancer. Tumour Biol 2016; 37:8413-23. [PMID: 26733168 DOI: 10.1007/s13277-015-4736-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2015] [Accepted: 12/22/2015] [Indexed: 01/06/2023] Open
Abstract
Therapeutic benefits offered by common chemotherapy drugs, such as oxaliplatin, are limited due to the development of resistance, which contributes to treatment failure and metastasis. The epithelial-mesenchymal transition (EMT) is a key event contributing to the development of resistance to chemotherapeutics. Although the relationship between oxaliplatin and chemotherapy resistance has been described for decades, the molecular mechanisms have remained elusive. The aim of the present study was to investigate the underlying mechanisms of oxaliplatin-mediated metastasis. Here, we identify reactive oxygen species (ROS) as mediators that promote the oxaliplatin-induced EMT. Following oxaliplatin treatment, the messenger RNA (mRNA) levels of most peroxiredoxin family genes, except for peroxiredoxin 1 (prdx1) gene, were constant or even decreased, resulting in ROS abundance. And the antioxidant guardian Nrf2 was unconspicuously raised both transcriptionally and translationally with oxaliplatin treatment as compared to those induced by topotecan treatment, which has been proved with no induced metastasis. In addition, the study evaluated high levels of ROS leading to EMT via activation of the known oncogenes Akt and Snail. Using the Akt inhibitor LY294002 or knocking down Snail expression via RNA interference (RNAi) reversed the effects of oxaliplatin on the EMT and metastasis. Our studies establish a role for the ROS-Akt-Snail axis as a mechanism by which chemotherapeutics induce EMT and cancer metastasis.
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Affiliation(s)
- Lin Jiao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Dan-Dan Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, 651 Dongfeng Road East, Guangzhou, 510060, China.,Department of Biotherapy, Cancer Center, Sun Yat-sen University, Guangzhou, 510060, China
| | - Chen-Lu Yang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, 651 Dongfeng Road East, Guangzhou, 510060, China.,Department of Gynecologic Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, 510060, China
| | - Rui-Qing Peng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, 651 Dongfeng Road East, Guangzhou, 510060, China.,Department of Biotherapy, Cancer Center, Sun Yat-sen University, Guangzhou, 510060, China
| | - Yi-Qun Guo
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, 651 Dongfeng Road East, Guangzhou, 510060, China.,Department of Biotherapy, Cancer Center, Sun Yat-sen University, Guangzhou, 510060, China
| | - Xiao-Shi Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, 651 Dongfeng Road East, Guangzhou, 510060, China. .,Department of Biotherapy, Cancer Center, Sun Yat-sen University, Guangzhou, 510060, China.
| | - Xiao-Feng Zhu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, 651 Dongfeng Road East, Guangzhou, 510060, China.
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Circulating cell-free microRNAs as biomarkers for colorectal cancer. Surg Today 2016; 46:13-24. [PMID: 25712224 DOI: 10.1007/s00595-015-1138-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 02/11/2015] [Indexed: 02/07/2023]
Abstract
MicroRNAs (miRNAs) are a class of small, endogenous, non-coding, single-stranded RNAs that act as post-transcriptional regulators. Their discovery has provided new avenues for the diagnosis and treatment of cancer. The expression of both oncogenic and tumor suppressor miRNAs can be aberrantly either up- or down-regulated in cancer cells. These miRNAs target mRNAs of genes that either promote or inhibit tumor growth, and are one of several epigenetic factors that control the initiation and progression of colorectal cancer (CRC) and other cancers. Investigations of miRNAs as CRC biomarkers have employed the expression profiling of traditional tissue samples and, more recently, non-invasive samples, such as feces and body fluids, have been analyzed. MiRNAs may also be able to predict responses to chemo- and radiotherapy, and may be manipulated to modify CRC characteristics. We herein discuss the use of circulating miRNAs as possible non-invasive biomarkers of early CRC onset, relapse, or response to treatment. We also discuss the obstacles that currently limit the routine use of epigenetic biomarkers in clinical settings.
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Nakayama N, Yamashita K, Tanaka T, Kawamata H, Ooki A, Sato T, Nakamura T, Watanabe M. Genomic gain of the PRL-3 gene may represent poor prognosis of primary colorectal cancer, and associate with liver metastasis. Clin Exp Metastasis 2015; 33:3-13. [PMID: 26563151 DOI: 10.1007/s10585-015-9749-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Accepted: 09/18/2015] [Indexed: 12/30/2022]
Abstract
PRL-3 genomic copy number is increased in colorectal cancer (CRC), and PRL-3 expression is closely associated with lymph node and liver metastasis of CRC. However, the clinical significance of PRL-3 genomic gain for CRC remains obscure. Here, PRL-3 genomic status in 109 primary CRC tumors and in 44 CRC tumors that had metastasized to the liver, was quantified using real time PCR. Association of PRL-3 genomic status with clinicopathological factors and prognosis was assessed in detail. PRL-3 genomic gain was identified in 31 primary CRC (27.4 %) and was more frequently seen in stage III than in stage II (p = 0.025). Among the clinicopathological factors assessed, PRL-3 genomic gain was significantly associated with poorly differentiated histology (p = 0.0039). Moreover, CRC patients with PRL-3 genomic gain exhibited poorer prognosis than those with no gain in stage II-IV CRC (p = 0.017). PRL-3 genomic gain was identified in 18 (41 %) of the liver metastasis tumors, and this frequency of gain was significantly increased as compared to that of the corresponding primary CRCs (11 %) (p = 0.001). Our findings suggested that PRL-3 genomic gain may represent an aggressive phenotype of primary CRC, and may associate with liver metastasis.
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Affiliation(s)
- N Nakayama
- Department of Surgery, Kitasato University School of Medicine, Asamizodai 2-1-1, Minami-ku, Sagamihara, Kanagawa, 252-0380, Japan
| | - K Yamashita
- Department of Surgery, Kitasato University School of Medicine, Asamizodai 2-1-1, Minami-ku, Sagamihara, Kanagawa, 252-0380, Japan.
| | - T Tanaka
- Department of Surgery, Kitasato University School of Medicine, Asamizodai 2-1-1, Minami-ku, Sagamihara, Kanagawa, 252-0380, Japan
| | - H Kawamata
- Department of Surgery, Kitasato University School of Medicine, Asamizodai 2-1-1, Minami-ku, Sagamihara, Kanagawa, 252-0380, Japan
| | - A Ooki
- Department of Surgery, Kitasato University School of Medicine, Asamizodai 2-1-1, Minami-ku, Sagamihara, Kanagawa, 252-0380, Japan
| | - T Sato
- Department of Surgery, Kitasato University School of Medicine, Asamizodai 2-1-1, Minami-ku, Sagamihara, Kanagawa, 252-0380, Japan
| | - T Nakamura
- Department of Surgery, Kitasato University School of Medicine, Asamizodai 2-1-1, Minami-ku, Sagamihara, Kanagawa, 252-0380, Japan
| | - M Watanabe
- Department of Surgery, Kitasato University School of Medicine, Asamizodai 2-1-1, Minami-ku, Sagamihara, Kanagawa, 252-0380, Japan
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Okugawa Y, Grady WM, Goel A. Epigenetic Alterations in Colorectal Cancer: Emerging Biomarkers. Gastroenterology 2015; 149:1204-1225.e12. [PMID: 26216839 PMCID: PMC4589488 DOI: 10.1053/j.gastro.2015.07.011] [Citation(s) in RCA: 556] [Impact Index Per Article: 55.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Revised: 07/13/2015] [Accepted: 07/20/2015] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. One of the fundamental processes driving the initiation and progression of CRC is the accumulation of a variety of genetic and epigenetic changes in colonic epithelial cells. Over the past decade, major advances have been made in our understanding of cancer epigenetics, particularly regarding aberrant DNA methylation, microRNA (miRNA) and noncoding RNA deregulation, and alterations in histone modification states. Assessment of the colon cancer "epigenome" has revealed that virtually all CRCs have aberrantly methylated genes and altered miRNA expression. The average CRC methylome has hundreds to thousands of abnormally methylated genes and dozens of altered miRNAs. As with gene mutations in the cancer genome, a subset of these epigenetic alterations, called driver events, are presumed to have a functional role in CRC. In addition, the advances in our understanding of epigenetic alterations in CRC have led to these alterations being developed as clinical biomarkers for diagnostic, prognostic, and therapeutic applications. Progress in this field suggests that these epigenetic alterations will be commonly used in the near future to direct the prevention and treatment of CRC.
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Affiliation(s)
- Yoshinaga Okugawa
- Gastrointestinal Cancer Research Laboratory, Division of Gastroenterology, Department of Internal Medicine, Charles A. Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, Dallas, Texas
| | - William M Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Gastroenterology, University of Washington School of Medicine, Seattle, Washington.
| | - Ajay Goel
- Gastrointestinal Cancer Research Laboratory, Division of Gastroenterology, Department of Internal Medicine, Charles A. Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, Dallas, Texas.
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Liu G, Zhu J, Yu M, Cai C, Zhou Y, Yu M, Fu Z, Gong Y, Yang B, Li Y, Zhou Q, Lin Q, Ye H, Ye L, Zhao X, Li Z, Chen R, Han F, Tang C, Zeng B. Glutamate dehydrogenase is a novel prognostic marker and predicts metastases in colorectal cancer patients. J Transl Med 2015; 13:144. [PMID: 25947346 PMCID: PMC4490642 DOI: 10.1186/s12967-015-0500-6] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 04/21/2015] [Indexed: 12/15/2022] Open
Abstract
Background Glutamate dehydrogenase (GDH) is a key enzyme that catalyzes the final reaction of the glutamine metabolic pathway, and has been reported implicated in tumor growth and metastasis. However, it’s clinical significance and role in colorectal cancer (CRC) pathogenesis is largely unknown. Methods The expression of GDH was determined by qPCR, western blot and immunohistochemistry in CRC cells and samples. The correlation of GDH expression with clinicopathologic features and prognosis was analyzed. The functional role of GDH in CRC cell proliferation, motility and metastasis was evaluated. Results We found that GDH was up-regulated both in colorectal cancer and metastatic lesions (n = 104). Patients with high GDH expression had poorer overall survival (HR 2.32; 95% CI 1.26-4.26; P = 0.007) and poorer disease-free survival rates (HR 2.48; 95% CI 1.25-4.92; P = 0.009) than those with low GDH expression. Furthermore, we showed that GDH expression was an independent prognostic factor for CRC. In addition, over-expression of GDH promoted cell proliferation, migration and invasion in vitro, whereas loss function of GDH did the opposite. Finally, we demonstrated that the promotion of CRC progression by GDH correlated with activation of STAT3 mediated epithelial-mesenchymal transition (EMT) induction. Conclusions These results indicate that GDH plays a critical role in CRC progression, and may provide a novel metabolism therapeutic target for CRC treatment. Electronic supplementary material The online version of this article (doi:10.1186/s12967-015-0500-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Gaojie Liu
- Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China. .,Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China.
| | - Jie Zhu
- Department of Emergency Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China.
| | - Menglei Yu
- Department of Emergency Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China.
| | - Canfeng Cai
- Department of Gastrointestinal Surgery, Qingyuan People's Hospital, The sixth affiliated hospital of Guangzhou Medical University, Guangdong, 511518, China.
| | - Yu Zhou
- Department of Pancreaticobiliary Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China. .,Department of Pancreaticobiliary Surgery, Guangdong Academy of Medical Sciences and Guangdong General Hospital, Guangzhou, 510120, China.
| | - Min Yu
- Department of Pancreaticobiliary Surgery, Guangdong Academy of Medical Sciences and Guangdong General Hospital, Guangzhou, 510120, China.
| | - Zhiqiang Fu
- Department of Pancreaticobiliary Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China.
| | - Yuanfeng Gong
- Department of Hepatobiliary Surgery, Cancer Center of Guangzhou Medical University, Guangzhou, 510120, China.
| | - Bin Yang
- Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China.
| | - Yingru Li
- Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China.
| | - Quanbo Zhou
- Department of Pancreaticobiliary Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China.
| | - Qin Lin
- Department of Pancreaticobiliary Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China.
| | - Huilin Ye
- Department of Pancreaticobiliary Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China.
| | - Liangtao Ye
- Department of Pancreaticobiliary Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China.
| | - Xiaohui Zhao
- Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
| | - Zhihua Li
- Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
| | - Rufu Chen
- Department of Pancreaticobiliary Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China.
| | - Fanghai Han
- Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China.
| | - Chaoming Tang
- Department of Gastrointestinal Surgery, Qingyuan People's Hospital, The sixth affiliated hospital of Guangzhou Medical University, Guangdong, 511518, China.
| | - Bing Zeng
- Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China. .,Department of Gastrointestinal Surgery, Qingyuan People's Hospital, The sixth affiliated hospital of Guangzhou Medical University, Guangdong, 511518, China. .,Department of Pancreaticobiliary Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China.
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Liu W, Zhang Z, Zhang Y, Chen X, Guo S, Lei Y, Xu Y, Ji C, Bi Z, Wang K. HMGB1-mediated autophagy modulates sensitivity of colorectal cancer cells to oxaliplatin via MEK/ERK signaling pathway. Cancer Biol Ther 2015; 16:511-7. [PMID: 25778491 DOI: 10.1080/15384047.2015.1017691] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
In the present study, we examined the mechanisms of oxaliplatin-induced drug resistance in human colorectal cancer cell lines HT29 and HCT116. Our results demonstrate a significant autophagy expression in CRC cells after an oxaliplatin treatment. Administration of oxaliplatin to human CRC cells significantly enhanced the expression of HMGB1, which regulated the autophagy response and negatively regulate the cell apoptosis. Moreover, a decreased oxaliplatin -induced autophagy response and an increased apoptosis level were detected in stable CRC cells harboring HMGB1 shRNA. Then we noted that HMGB1 significantly induced extracellular signal-regulated kinase (ERK)/Extracellular signal-regulated kinase kinase (MEK) phosphorylation. Taken together, these data suggest that HMGB1-mediated autophagy modulates sensitivity of colorectal cancer cells to oxaliplatin via MEK/ERK signaling pathway.
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Affiliation(s)
- Weijun Liu
- a Department of Anorectal Surgery; The First People's Hospital of Yunnan Province; Kunhua Hospital Affiliated to Kunming University of Science and Technology ; Kunming , Yunnan , China
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