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Li C, Li J. Dysregulation of systemic immunity in colorectal cancer and its clinical applications as biomarkers and therapeutics. Crit Rev Oncol Hematol 2024; 204:104543. [PMID: 39454739 DOI: 10.1016/j.critrevonc.2024.104543] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 10/13/2024] [Accepted: 10/21/2024] [Indexed: 10/28/2024] Open
Abstract
The immune system plays critical roles in the initiation and progression of colorectal cancer (CRC), and the majority of studies have focused on immune perturbations within the tumor microenvironment. In recent years, systemic immunity, which mainly occurs in the periphery, has attracted much attention. In CRC, both the tumor itself and treatments have extensive effects on systemic immunity, characterized by alterations in circulating cytokines and immune cells. In addition, intact systemic immunity is critical for the efficacy of therapies for CRC, especially immunotherapy. Therefore, various strategies aimed at alleviating the detrimental effects of traditional therapies or directly harnessing the components of systemic immunity for CRC treatment have been developed. However, whether these improvements can translate to survival benefits requires further study. This review aims to comprehensively outline the current knowledge of systemic immunity in CRC.
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Affiliation(s)
- Changqin Li
- Department of Clinical Laboratory, the Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan, China
| | - Jian Li
- Department of General Surgery, the Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan, China.
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2
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Seo JW, Park KB, Kim EY, Jun KH, Chin HM. Surgical outcomes and prognosis of intracorporeal versus extracorporeal esophagojejunostomy after laparoscopic total gastrectomy for gastric cancer: a propensity score-matching study. Sci Rep 2024; 14:17793. [PMID: 39090191 PMCID: PMC11294522 DOI: 10.1038/s41598-024-67681-8] [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: 08/24/2023] [Accepted: 07/15/2024] [Indexed: 08/04/2024] Open
Abstract
This study compared the surgical outcomes and long-term prognosis of intracorporeal and extracorporeal esophagojejunostomy after laparoscopic total gastrectomy (LTG) for gastric cancer patients. In total 228 clinical stage I gastric cancer patients undergoing LTG were enrolled from January 2012 and December 2022. Each case in the totally laparoscopic total gastrectomy (TLTG) group was 1:1 propensity score-matched to control cases in the laparoscopy-assisted total gastrectomy (LATG) group. In total, 95 and 93 LATG and TLTG patients were included after propensity score matching (PSM). Clinicopathological features, surgical outcomes, and survival variables were compared, and risk factors for postoperative complications were analyzed. Patient characteristics were well balanced between the LATG and TLTG groups after PSM. The TLTG group showed less blood loss, decreased frequency of analgesic use, and shorter duration of analgesic use. The TLTG group had significantly lower rates of intestinal obstruction and surgical site infection. Larger tumor size and advanced pTNM stage were independent risk factors for postoperative complications. There was no significant difference in overall survival (OS). Compared with LATG, TLTG was associated with better surgical outcomes and fewer postoperative surgical complications in gastric cancer patients although there was no significant difference in OS.
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Affiliation(s)
- Ji Won Seo
- Department of Surgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, 93, Jungbudaero, Paldal-Gu, Suwon, Gyeonggi-Do, Seoul, 16247, Republic of Korea
| | - Ki Bum Park
- Department of Surgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, 93, Jungbudaero, Paldal-Gu, Suwon, Gyeonggi-Do, Seoul, 16247, Republic of Korea
| | - Eun Young Kim
- Department of Surgery, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Kyong-Hwa Jun
- Department of Surgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, 93, Jungbudaero, Paldal-Gu, Suwon, Gyeonggi-Do, Seoul, 16247, Republic of Korea.
| | - Hyung Min Chin
- Department of Surgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, 93, Jungbudaero, Paldal-Gu, Suwon, Gyeonggi-Do, Seoul, 16247, Republic of Korea
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Chauhan S, Sharma S. Recent Approaches on Molecular Markers, Treatment and Novel Drug Delivery System Used for the Management of Colorectal Cancer: A Comprehensive Review. Curr Pharm Biotechnol 2024; 25:1969-1985. [PMID: 38275054 DOI: 10.2174/0113892010270975231208113157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 09/29/2023] [Accepted: 10/16/2023] [Indexed: 01/27/2024]
Abstract
Colorectal cancer affects 1 in 25 females and 1 in 24 males, making it the third most frequent cancer with over 6,08,030 deaths worldwide, despite advancements in detection and treatments, including surgery, chemotherapeutics, radiotherapy, and immune therapeutics. Novel potential agents have increased survival in acute and chronic disease conditions, with a higher risk of side effects and cost. However, metastatic disease has an insignificant long-term diagnosis, and significant challenges remain due to last-stage diagnosis and treatment failure. Early detection, survival, and treatment efficacy are all improved by biomarkers. The advancement of cancer biomarkers' molecular pathology and genomics during the last three decades has improved therapy. Clinically useful prognostic biomarkers assist clinical judgment, for example, by predicting the success of EGFR-inhibiting antibodies in the presence of KRAS gene mutations. Few biomarkers are currently used in clinical settings, so further research is still needed. Nanocarriers, with materials like Carbon nanotubes and gold nanoparticles, provide targeted CRC drug delivery and diagnostics. Light-responsive drugs with gold and silica nanoparticles effectively target and destroy CRC cells. We evaluate the potential use of the long non-coding RNA (non-coding RNA) oncogene plasmacytoma variant translocation 1 (PVT1) as a diagnostic, prognostic, and therapeutic biomarker, along with the latest nanotech breakthroughs in CRC diagnosis and treatment.
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Affiliation(s)
- Sonia Chauhan
- Noida Institute of Engineering and Technology (Pharmacy Institute), Greater Noida, U.P, 201306, India
| | - Sakshi Sharma
- Noida Institute of Engineering and Technology (Pharmacy Institute), Greater Noida, U.P, 201306, India
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Shakhpazyan N, Mikhaleva L, Bedzhanyan A, Sadykhov N, Midiber K, Orekhov A. Commentary: PFKFB3 overexpression in monocytes of patients with colon but not rectal cancer programs pro-tumor macrophages and is indicative for higher risk of tumor relapse. Front Immunol 2023; 14:1290459. [PMID: 38193086 PMCID: PMC10773737 DOI: 10.3389/fimmu.2023.1290459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 12/11/2023] [Indexed: 01/10/2024] Open
Affiliation(s)
- Nikolay Shakhpazyan
- Avtsyn Research Institute of Human Morphology, Petrovsky National Research Center of Surgery, Moscow, Russia
| | - Liudmila Mikhaleva
- Avtsyn Research Institute of Human Morphology, Petrovsky National Research Center of Surgery, Moscow, Russia
| | - Arcady Bedzhanyan
- Department of Abdominal Surgery and Oncology II (Coloproctology and Uro-Gynecology), Petrovsky National Research Center of Surgery, Moscow, Russia
| | - Nikolay Sadykhov
- Avtsyn Research Institute of Human Morphology, Petrovsky National Research Center of Surgery, Moscow, Russia
| | - Konstantin Midiber
- Avtsyn Research Institute of Human Morphology, Petrovsky National Research Center of Surgery, Moscow, Russia
- Institute of Medicine, Peoples’ Friendship University of Russia named after Patrice Lumumba, Moscow, Russia
| | - Alexander Orekhov
- Avtsyn Research Institute of Human Morphology, Petrovsky National Research Center of Surgery, Moscow, Russia
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Moscow, Russia
- Institute for Atherosclerosis Research, Moscow, Russia
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5
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Lian J, Liang Y, Zhang H, Lan M, Ye Z, Lin B, Qiu X, Zeng J. The role of polyamine metabolism in remodeling immune responses and blocking therapy within the tumor immune microenvironment. Front Immunol 2022; 13:912279. [PMID: 36119047 PMCID: PMC9479087 DOI: 10.3389/fimmu.2022.912279] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022] Open
Abstract
The study of metabolism provides important information for understanding the biological basis of cancer cells and the defects of cancer treatment. Disorders of polyamine metabolism is a common metabolic change in cancer. With the deepening of understanding of polyamine metabolism, including molecular functions and changes in cancer, polyamine metabolism as a new anti-cancer strategy has become the focus of attention. There are many kinds of polyamine biosynthesis inhibitors and transport inhibitors, but not many drugs have been put into clinical application. Recent evidence shows that polyamine metabolism plays essential roles in remodeling the tumor immune microenvironment (TIME), particularly treatment of DFMO, an inhibitor of ODC, alters the immune cell population in the tumor microenvironment. Tumor immunosuppression is a major problem in cancer treatment. More and more studies have shown that the immunosuppressive effect of polyamines can help cancer cells to evade immune surveillance and promote tumor development and progression. Therefore, targeting polyamine metabolic pathways is expected to become a new avenue for immunotherapy for cancer.
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Affiliation(s)
- Jiachun Lian
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Yanfang Liang
- Department of Pathology, Dongguan Hospital Affiliated to Jinan University, Binhaiwan Central Hospital of Dongguan, Dongguan, China
| | - Hailiang Zhang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Minsheng Lan
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
| | - Ziyu Ye
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Department of Pathology, Dongguan Hospital Affiliated to Jinan University, Binhaiwan Central Hospital of Dongguan, Dongguan, China
- Dongguan Metabolite Analysis Engineering Technology Center of Cells for Medical Use, Guangdong Xinghai Institute of Cell, Dongguan, China
| | - Bihua Lin
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Key Laboratory of Medical Bioactive Molecular Research for Department of Education of Guangdong Province, Collaborative Innovation Center for Antitumor Active Substance Research and Development, Zhanjiang, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Guangdong Medical University, Zhanjiang, China
| | - Xianxiu Qiu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Key Laboratory of Medical Bioactive Molecular Research for Department of Education of Guangdong Province, Collaborative Innovation Center for Antitumor Active Substance Research and Development, Zhanjiang, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Guangdong Medical University, Zhanjiang, China
| | - Jincheng Zeng
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Dongguan Metabolite Analysis Engineering Technology Center of Cells for Medical Use, Guangdong Xinghai Institute of Cell, Dongguan, China
- Key Laboratory of Medical Bioactive Molecular Research for Department of Education of Guangdong Province, Collaborative Innovation Center for Antitumor Active Substance Research and Development, Zhanjiang, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Guangdong Medical University, Zhanjiang, China
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Bhat AA, Nisar S, Singh M, Ashraf B, Masoodi T, Prasad CP, Sharma A, Maacha S, Karedath T, Hashem S, Yasin SB, Bagga P, Reddy R, Frennaux MP, Uddin S, Dhawan P, Haris M, Macha MA. Cytokine- and chemokine-induced inflammatory colorectal tumor microenvironment: Emerging avenue for targeted therapy. Cancer Commun (Lond) 2022; 42:689-715. [PMID: 35791509 PMCID: PMC9395317 DOI: 10.1002/cac2.12295] [Citation(s) in RCA: 100] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/28/2022] [Accepted: 04/24/2022] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer (CRC) is a predominant life-threatening cancer, with liver and peritoneal metastases as the primary causes of death. Intestinal inflammation, a known CRC risk factor, nurtures a local inflammatory environment enriched with tumor cells, endothelial cells, immune cells, cancer-associated fibroblasts, immunosuppressive cells, and secretory growth factors. The complex interactions of aberrantly expressed cytokines, chemokines, growth factors, and matrix-remodeling enzymes promote CRC pathogenesis and evoke systemic responses that affect disease outcomes. Mounting evidence suggests that these cytokines and chemokines play a role in the progression of CRC through immunosuppression and modulation of the tumor microenvironment, which is partly achieved by the recruitment of immunosuppressive cells. These cells impart features such as cancer stem cell-like properties, drug resistance, invasion, and formation of the premetastatic niche in distant organs, promoting metastasis and aggressive CRC growth. A deeper understanding of the cytokine- and chemokine-mediated signaling networks that link tumor progression and metastasis will provide insights into the mechanistic details of disease aggressiveness and facilitate the development of novel therapeutics for CRC. Here, we summarized the current knowledge of cytokine- and chemokine-mediated crosstalk in the inflammatory tumor microenvironment, which drives immunosuppression, resistance to therapeutics, and metastasis during CRC progression. We also outlined the potential of this crosstalk as a novel therapeutic target for CRC. The major cytokine/chemokine pathways involved in cancer immunotherapy are also discussed in this review.
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Affiliation(s)
- Ajaz A. Bhat
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Sabah Nisar
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Mayank Singh
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Bazella Ashraf
- Department of BiotechnologySchool of Life SciencesCentral University of KashmirGanderbalJammu & Kashmir191201India
| | - Tariq Masoodi
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Chandra P. Prasad
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Atul Sharma
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Selma Maacha
- Division of Translational MedicineResearch BranchSidra MedicineDoha26999Qatar
| | | | - Sheema Hashem
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Syed Besina Yasin
- Department of PathologySher‐I‐Kashmir Institute of Medical SciencesSrinagarJammu & Kashmir190011India
| | - Puneet Bagga
- Department of Diagnostic ImagingSt. Jude Children's Research HospitalMemphisTN38105USA
| | - Ravinder Reddy
- Center for Advanced Metabolic Imaging in Precision MedicineDepartment of RadiologyPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPA19104USA
| | | | - Shahab Uddin
- Translational Research InstituteHamad Medical CorporationDoha3050Qatar
| | - Punita Dhawan
- Department of Biochemistry and Molecular BiologyUniversity of Nebraska Medical CenterOmahaNE68198USA
| | - Mohammad Haris
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
- Laboratory Animal Research CenterQatar UniversityDoha2713Qatar
| | - Muzafar A. Macha
- Watson‐Crick Centre for Molecular MedicineIslamic University of Science and TechnologyAwantiporaJammu & Kashmir192122India
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Chen M, Zhang J, Lin X, Zhu X, Xie T. A pyroptosis-related prognosis model to predict survival in colorectal cancer patients. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2022; 15:168-182. [PMID: 35535204 PMCID: PMC9077106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 03/15/2022] [Indexed: 06/14/2023]
Abstract
Pyroptosis is a recently-identified pathway of host cell death that is stimulated by a range of microbial infections. Emerging evidence indicates pyroptosis plays crucial roles in tumor growth, disease progression, and migration of different cancer cells. However, the clinical significance of pyroptosis in tumor behavior prognosis, as well as the underlying mechanism in different cancers remains elusive. Here, by evaluating the expression level of pyroptosis genes in colorectal cancer (CRC) patients from the TCGA cohort and GEO cohort (GSE39582), we identified pyroptosis-related DEGs and then built a 13-gene risk model by applying the LASSO Cox regression algorithm. Furthermore, functional analysis using GSEA and GSEV revealed that our prognostic model may function through regulating immune responses and tumor biogenesis pathways. Significant infiltration of activated immune cells (e.g. cytotoxic T cells) was observed in the low risk score group. The selected gene set was further validated in the GEO cohort. Time-dependent ROC curves confirmed that our risk score model is robust in predicting 1, 3 and 5-year overall survival in CRC patients. Overall, we have identified a pyroptosis-related gene signature that consists of 13 genes, which serves as a potent indicator of CRC prognosis. Thus, our model provides insights in how to make better clinical decision in the future.
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Affiliation(s)
- Meiyan Chen
- Department of Gastroenterology, Chenggong Hospital, Xiamen UniversityXiamen 361003, Fujian, China
| | - Jingyi Zhang
- Department of Gastroenterology, Chenggong Hospital, Xiamen UniversityXiamen 361003, Fujian, China
| | - Xiaoyan Lin
- Department of Dermatology, Chenggong Hospital, Xiamen UniversityXiamen 361003, Fujian, China
| | - Xiaosan Zhu
- Department of Gastroenterology, Chenggong Hospital, Xiamen UniversityXiamen 361003, Fujian, China
| | - Tao Xie
- Department of Obstetrics and Gynecology, Chenggong Hospital, Xiamen UniversityXiamen 361003, Fujian, China
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Hematological, immunological, and polyamines alterations in the concomitant occurrence of Fasciola gigantica and hepatic leiomyoma in cattle. Vet Parasitol 2021; 300:109617. [PMID: 34775152 DOI: 10.1016/j.vetpar.2021.109617] [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: 04/18/2021] [Revised: 11/02/2021] [Accepted: 11/03/2021] [Indexed: 11/20/2022]
Abstract
No previous studies have investigated the polyamines alterations during fascioliasis due to F. gigantica in ruminants. This study was therefore carried out to find out the possible relationship between the extent of liver destruction and leiomyoma and some hematological and immunological parameters and polyamines alterations in F. gigantica infection. Fifty cattle with liver fascioliasis and fifteen healthy cattle were selected for the study. For the histopathological study, liver tissue samples were stained with hematoxylin and eosin (H&E) and Masson's Trichrome methods. The leiomyoma suspected specimens were immunohistochemically stained for smooth muscle actin and desmin. Different hematological parameters were investigated in infected and non-infected animals. Furthermore, levels of putrescine, spermidine, and spermine were measured in homogenized liver samples. Serum IL-4 and TNF-α levels were also evaluated. By histological examination, the lesions were noted in all the infected specimens. These lesions were varied from leiomyoma, chronic catarrhal cholangitis, arteriosclerosis, telangiectasia, and fresh migratory tunnels filled with RBC and eosinophils. Comparison of hemogram results between infected and non-infected groups revealed a significant decrease in red blood cell counts (RBC), mean corpuscular hemoglobin concentration (MCHC), and platelet count (PLT) in infected animals. Also, a significant elevation in mean corpuscular volume (MCV) concentration was detected in infected animals. The putrescine and spermine levels of the infected animals were significantly higher than the non-infected animals. Although spermidine was increased in infected livers, its elevation was not significant. Based on the results, the level of IL-4 and TNF-α was not significantly changed in infected animals. In conclusion, the concurrent occurrence of leiomyoma and fascioliasis due to F. gigantica and polyamines elevation (putrescine and spermine) is reported for the first time. The role of polyamines in the concurrent occurrence of leiomyoma and fascioliasis is an area for future research.
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Czajka-Francuz P, Francuz T, Cisoń-Jurek S, Czajka A, Fajkis M, Szymczak B, Kozaczka M, Malinowski KP, Zasada W, Wojnar J, Chudek J. Serum cytokine profile as a potential prognostic tool in colorectal cancer patients - one center study. Rep Pract Oncol Radiother 2020; 25:867-875. [PMID: 32982592 PMCID: PMC7498852 DOI: 10.1016/j.rpor.2020.08.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 08/12/2020] [Indexed: 02/07/2023] Open
Abstract
AIM Comparison of 14 cytokines levels between a control group and prospectively enrolled CRC patients to confirm their significance in CRC development. We tested if a model based on 14 cytokines levels could predict prognosis in Caucasian CRC patients treated with 5-FU based chemotherapy. BACKGROUND Novel prognostic tools in colorectal cancer (CRC) are necessary to optimize treatment, reduce toxicity and chemotherapy (CHT) costs. MATERIALS AND METHODS We assessed prognostic significance of 14 cytokines: IL-1 beta, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL12p70, IL-13, IL-17A in 75 prospectively enrolled CRC patients before initiation of palliative or adjuvant CHT and in 22 control subjects. Readings were taken using the Bio-Plex 200 System. Response to treatment was assessed after 6 months from initiation of CHT. The treated group was divided depending on the response into a progressors (death, progression of disease) and non-progressors group (stable disease, partial response, complete response). RESULTS We found that increased concentration of IL-8 was a negative prognostic factor in the whole group and palliative subgroup, whereas increased level of IL-10, IL-7, and IL-12p70 was a negative predictor in the adjuvant group CHT. CONCLUSIONS We proposed a statistical model based on circulating cytokine levels, showing a good prognostic value in prediction of the response to CHT (AUC = 0.956). The model, including combined IL-2, IL-8, IL-10 and IL-13 levels, established in the whole treated group, should be validated in larger trials.
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Affiliation(s)
- Paulina Czajka-Francuz
- Department of Internal Medicine and Oncology, Silesian Medical University, ul. Reymonta 8, 40-027 Katowice, Poland
| | - Tomasz Francuz
- Department of Biochemistry, Silesian Medical University, ul. Medyków 18, 40-752 Katowice, Poland
| | - Sylwia Cisoń-Jurek
- Department of Internal Medicine and Oncology, Silesian Medical University, ul. Reymonta 8, 40-027 Katowice, Poland
| | - Aleksander Czajka
- Department of General and Vascular Surgery, Silesian Medical University, Ziołowa 45/47, 40-635 Katowice, Poland
| | - Marcin Fajkis
- Department of Internal Medicine and Oncology, Silesian Medical University, ul. Reymonta 8, 40-027 Katowice, Poland
| | - Bożena Szymczak
- Department of Internal Medicine and Oncology, Silesian Medical University, ul. Reymonta 8, 40-027 Katowice, Poland
| | - Maciej Kozaczka
- National Institute of Oncology, Public Research Institute in Gliwice, Department of Radiotherapy and Chemotherapy, 44-101 Gliwice, Wybrzeże Armii Krajowej 15, Poland
| | - Krzysztof Piotr Malinowski
- Institute of Public Health, Faculty of Health Sciences, Jagiellonian University Medical College, Kraków, Poland
| | - Wojciech Zasada
- 2nd Department of Cardiology, University Hospital in Krakow, Poland
| | - Jerzy Wojnar
- Department of Internal Medicine and Oncology, Silesian Medical University, ul. Reymonta 8, 40-027 Katowice, Poland
| | - Jerzy Chudek
- Department of Internal Medicine and Oncology, Silesian Medical University, ul. Reymonta 8, 40-027 Katowice, Poland
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Chok KC, Ng CH, Koh RY, Ng KY, Chye SM. The potential therapeutic actions of melatonin in colorectal cancer. Horm Mol Biol Clin Investig 2019; 39:hmbci-2019-0001. [DOI: 10.1515/hmbci-2019-0001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Accepted: 04/01/2019] [Indexed: 12/24/2022]
Abstract
Abstract
Colorectal cancer (CRC) is the third most common cancer and lethal disease worldwide. Melatonin, an indoleamine produced in pineal gland, shows anticancer effects on a variety of cancers, especially CRC. After clarifying the pathophysiology of CRC, the association of circadian rhythm with CRC, and the relationship between shift work and the incidence of CRC is reviewed. Next, we review the role of melatonin receptors in CRC and the relationship between inflammation and CRC. Also included is a discussion of the mechanism of gene regulation, control of cell proliferation, apoptosis, autophagy, antiangiogenesis and immunomodulation in CRC by melatonin. A review of the drug synergy of melatonin with other anticancer drugs suggests its usefulness in combination therapy. In summary, the information compiled may serve as comprehensive reference for the various mechanisms of action of melatonin against CRC, and as a guide for the design of future experimental research and for advancing melatonin as a therapeutic agent for CRC.
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Affiliation(s)
- Kian Chung Chok
- School of Health Sciences, International Medical University , Kuala Lumpur , Malaysia
| | - Chew Hee Ng
- School of Pharmacy, International Medical University , Kuala Lumpur , Malaysia
| | - Rhun Yian Koh
- School of Health Sciences, International Medical University , Kuala Lumpur , Malaysia
| | - Khuen Yen Ng
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia , Selangor , Malaysia
| | - Soi Moi Chye
- School of Health Sciences, International Medical University , Kuala Lumpur , Malaysia , Phone: +6032731 7220; Fax: +60386567229
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Behrenbruch C, Shembrey C, Paquet-Fifield S, Mølck C, Cho HJ, Michael M, Thomson BNJ, Heriot AG, Hollande F. Surgical stress response and promotion of metastasis in colorectal cancer: a complex and heterogeneous process. Clin Exp Metastasis 2018; 35:333-345. [PMID: 29335811 DOI: 10.1007/s10585-018-9873-2] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 01/06/2018] [Indexed: 12/12/2022]
Abstract
Surgery remains the curative treatment modality for colorectal cancer in all stages, including stage IV with resectable liver metastasis. There is emerging evidence that the stress response caused by surgery as well as other perioperative therapies such as anesthesia and analgesia may promote growth of pre-existing micro-metastasis or potentially initiate tumor dissemination. Therapeutically targeting the perioperative period may therefore reduce the effect that surgical treatments have in promoting metastases, for example by combining β-adrenergic receptor antagonists and cyclooxygenase-2 (COX-2) inhibitors in the perioperative setting. In this paper, we highlight some of the mechanisms that may underlie surgery-related metastatic development in colorectal cancer. These include direct tumor spillage at the time of surgery, suppression of the anti-tumor immune response, direct stimulatory effects on tumor cells, and activation of the coagulation system. We summarize in more detail results that support a role for catecholamines as major drivers of the pro-metastatic effect induced by the surgical stress response, predominantly through activation of β-adrenergic signaling. Additionally, we argue that an improved understanding of surgical stress-induced dissemination, and more specifically whether it impacts on the level and nature of heterogeneity within residual tumor cells, would contribute to the successful clinical targeting of this process. Finally, we provide a proof-of-concept demonstration that ex-vivo analyses of colorectal cancer patient-derived samples using RGB-labeling technology can provide important insights into the heterogeneous sensitivity of tumor cells to stress signals. This suggests that intra-tumor heterogeneity is likely to influence the efficacy of perioperative β-adrenergic receptor and COX-2 inhibition, and that ex-vivo characterization of heterogeneous stress response in tumor samples can synergize with other models to optimize perioperative treatments and further improve outcome in colorectal and other solid cancers.
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Affiliation(s)
- Corina Behrenbruch
- Department of Pathology, University of Melbourne Centre for Cancer Research, The University of Melbourne, Victorian Comprehensive Cancer Centre, Level 10, 305 Grattan Street, Melbourne, VIC, 3000, Australia
- Division of Cancer Surgery, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre, 305 Grattan St, Melbourne, 3000, Australia
| | - Carolyn Shembrey
- Department of Pathology, University of Melbourne Centre for Cancer Research, The University of Melbourne, Victorian Comprehensive Cancer Centre, Level 10, 305 Grattan Street, Melbourne, VIC, 3000, Australia
| | - Sophie Paquet-Fifield
- Department of Pathology, University of Melbourne Centre for Cancer Research, The University of Melbourne, Victorian Comprehensive Cancer Centre, Level 10, 305 Grattan Street, Melbourne, VIC, 3000, Australia
| | - Christina Mølck
- Department of Pathology, University of Melbourne Centre for Cancer Research, The University of Melbourne, Victorian Comprehensive Cancer Centre, Level 10, 305 Grattan Street, Melbourne, VIC, 3000, Australia
| | - Hyun-Jung Cho
- Biological Optical Microscopy Platform, The University of Melbourne, Medical Building, Grattan Street, Parkville, 3010, Australia
| | - Michael Michael
- Division of Cancer Medicine, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre, 305 Grattan St, Melbourne, 3000, Australia
| | - Benjamin N J Thomson
- Division of Cancer Surgery, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre, 305 Grattan St, Melbourne, 3000, Australia
- Department of Surgery, Royal Melbourne Hospital, The University of Melbourne, 300 Grattan St, Parkville, 3000, Australia
| | - Alexander G Heriot
- Division of Cancer Surgery, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre, 305 Grattan St, Melbourne, 3000, Australia
| | - Frédéric Hollande
- Department of Pathology, University of Melbourne Centre for Cancer Research, The University of Melbourne, Victorian Comprehensive Cancer Centre, Level 10, 305 Grattan Street, Melbourne, VIC, 3000, Australia.
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12
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Crombe T, Bot J, Messager M, Roger V, Mariette C, Piessen G. Malignancy is a risk factor for postoperative infectious complications after elective colorectal resection. Int J Colorectal Dis 2016; 31:885-94. [PMID: 26838016 DOI: 10.1007/s00384-016-2521-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/25/2016] [Indexed: 02/04/2023]
Abstract
PURPOSE Patient and technical factors influencing the postoperative infectious complications (ICs) after elective colorectal resections are satisfactorily described. However, the underlying disease-related factors have not been extensively evaluated. This study aimed to measure the effect of malignancy on postoperative surgical site and extra surgical site infections after elective colorectal resection. METHODS This study is a bicentric retrospective matched pair study of prospectively gathered data. Between 2004 and 2013, 1104 consecutive patients underwent colorectal resection in two centers. Patients undergoing elective resection with supraperitoneal anastomosis for benign diseases (excluding inflammatory bowel disease) (group B, n = 305) were matched to randomly selected patients with malignancy (group M, n = 305). The matching variables were age, gender, American Society of Anesthesiologists (ASA) score, malnutrition, type of resection, and surgical approach. We compared the 30-day IC rates between patients with benign diseases (group B) and malignancy (group M). Multivariate logistic regression analysis was performed to identify the risk factors for ICs. RESULTS Group M had a higher overall rate of IC (25.6 vs 16.1 %, P = 0.004) as well as a higher risk of extra surgical site infections (P = 0.007) and anastomotic leakage (P = 0.039). The independent risk factors for ICs were malignancy (odds ratio (OR) = 2.02; P = 0.002), age ≥70 years (OR = 1.73, P = 0.018), tobacco history (OR = 1.87; P = 0.030), and obesity (OR = 1.68; P = 0.039). CONCLUSION Malignancy, age, tobacco history, and obesity increase the risk of ICs after colorectal resection. Improvement of the modifiable risk factors, increased compliance with an enhanced recovery after surgery (ERAS) program in the overall population, and optimization of immune function in patients with malignancy should be considered.
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Affiliation(s)
- Thibault Crombe
- Department of Digestive and Oncological Surgery, University Hospital Claude Huriez, Centre Hospitalier Régional Universitaire, Place de Verdun, 59037, Lille cedex, France.,University of Lille Nord de France, Lille, France
| | - Jérôme Bot
- Department of Digestive and Oncological Surgery, University Hospital Claude Huriez, Centre Hospitalier Régional Universitaire, Place de Verdun, 59037, Lille cedex, France.,University of Lille Nord de France, Lille, France
| | - Mathieu Messager
- Department of Digestive and Oncological Surgery, University Hospital Claude Huriez, Centre Hospitalier Régional Universitaire, Place de Verdun, 59037, Lille cedex, France.,University of Lille Nord de France, Lille, France
| | | | - Christophe Mariette
- Department of Digestive and Oncological Surgery, University Hospital Claude Huriez, Centre Hospitalier Régional Universitaire, Place de Verdun, 59037, Lille cedex, France.,University of Lille Nord de France, Lille, France.,Inserm UMR-S 1172, Jean Pierre Aubert Research Center, Team 5 "Mucins, epithelial differentiation and carcinogenesis, Lille, France
| | - Guillaume Piessen
- Department of Digestive and Oncological Surgery, University Hospital Claude Huriez, Centre Hospitalier Régional Universitaire, Place de Verdun, 59037, Lille cedex, France. .,University of Lille Nord de France, Lille, France. .,Inserm UMR-S 1172, Jean Pierre Aubert Research Center, Team 5 "Mucins, epithelial differentiation and carcinogenesis, Lille, France.
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Dalgleish AG. Vaccines versus immunotherapy: overview of approaches in deciding between options. Hum Vaccin Immunother 2015; 10:3369-74. [PMID: 25625932 DOI: 10.4161/21645515.2014.980707] [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] [Indexed: 12/28/2022] Open
Abstract
This review compares the optimal use of vaccines vs. other forms of immunotherapy, which includes cytokines, such as IL-2, monoclonal antibodies, such as the 'checkpoint inhibitors', against CTLA-4 and PD-1. The review includes both prophylactic and therapeutic vaccines using a variety of technologies. It is already established that vaccines can be enhanced by other immunotherapies, such as cytokines (IL-2) and there is scope for combining both of these with the 'checkpoint' antibodies. Moreover, both can be enhanced with other modalities, such as radiotherapy, ablative therapy and both high and low dose chemotherapies.
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Key Words
- BCG, Bacillus Colmette Guerin
- CpG, cytosine-phosphate-guanosine
- GM-CSF, Granulocyte-macrophage colony-stimulating factor
- HBV, Human hepatitis virus
- HPV, Human papilloma virus
- IL-2, Interleukin-2
- PFS, progression free survival
- PSA, Prostate-specific antigen
- TGFβ, Tumour growth factor beta
- TLR, Toll-like receptor
- antibodies
- checkpoint inhibitors
- cytokines
- immune modulators
- immunotherapy
- therapeutic vaccines
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Affiliation(s)
- Angus G Dalgleish
- a Institute of Infection and Immunity ; St George's University of London ; Tooting , London, UK
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Abstract
Interleukin-13 (IL-13) is an immunosuppressive cytokine produced by several immune cells and cancer cells. The aim of this retrospective study was to determine if serum IL-13 levels have an association with clinical outcome in patients with colorectal cancer. A total of 241 patients with colorectal cancer were enrolled in the present study. Preoperative serum IL-13 concentrations were measured by enzyme-linked immunosorbent assay. We analyzed the association of serum IL-13 levels with clinicopathological variables. Patients with lymph node metastasis, lymphatic invasion, vascular invasion, distant metastases or advanced stage of disease had significantly lower serum IL-13 levels. Low serum IL-13 was significantly associated with both poor recurrence-free and overall survival. Multivariate analysis showed that low IL-13 levels were an independent predictive marker for poor prognosis. In conclusion, our data suggest that low serum IL-13 levels may be a useful predictive marker for poor prognosis in colorectal cancer.
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15
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Varela-Calviño R, Cordero OJ. Stem and immune cells in colorectal primary tumour: Number and function of subsets may diagnose metastasis. World J Immunol 2015; 5:68-77. [DOI: 10.5411/wji.v5.i2.68] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Revised: 03/27/2015] [Accepted: 07/17/2015] [Indexed: 02/05/2023] Open
Abstract
An important percentage of colorectal cancer (CRC) patients will develop metastasis, mainly in the liver, even after a successful curative resection. This leads to a very high mortality rate if metastasis is not detected early on. Disseminated cancer cells develop from metastatic stem cells (MetSCs). Recent knowledge has accumulated about these cells particularly in CRC, so they may now be tracked from the removed primary tumour. This approach could be especially important in prognosis of metastasis because it is becoming clear that metastasis does not particularly rely on testable driver mutations. Among the many traits supporting an epigenetic amplification of cell survival and self-renewal mechanisms of MetSCs, the role of many immune cell populations present in tumour tissues is becoming clear. The amount of tumour-infiltrating lymphocytes (T, B and natural killer cells), dendritic cells and some regulatory populations have already shown prognostic value or to be correlated with disease-free survival time, mainly in immunohistochemistry studies of unique cell populations. Parallel analyses of these immune cell populations together with MetSCs in the primary tumour of patients, with later follow-up data of the patients, will define the usefulness of specific combinations of both immune and MetSCs cell populations. It is expected that these combinations, together to different biomarkers in the form of an immune score, may predict future tumour recurrences, metastases and/or mortality in CRC. It will also support the future design of improved immunotherapeutic approaches against metastasis.
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Abstract
Immunotherapy has usually been considered as an alternative to more traditional modalities. Moreover, it has previously been felt that chemotherapy is inherently immunosuppressive and not suitable for combining with immunotherapy. In this review, the concept of combining different modalities that result in cell death, such as radiotherapy and chemotherapy, with immunotherapy is explored. Tumors actively cause immune suppression which can be reversed by their removal but when this is not possible, enhancing the immune response with nonspecific immune stimulation can enhance the response to other modalities, such as radiotherapy and chemotherapy. Additionally, several chemotherapy agents at low doses selectively inhibit regulatory and suppressor cells.
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17
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Varela-Calviño R, Cordero OJ. Immunology and Immunotherapy of Colorectal Cancer. CANCER IMMUNOLOGY 2015:217-236. [DOI: 10.1007/978-3-662-46410-6_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Rahma OE, Myint ZW, Estfan B. Dendritic Cell Cancer Vaccines for Treatment of Colon Cancer. CURRENT COLORECTAL CANCER REPORTS 2014. [DOI: 10.1007/s11888-014-0243-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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Ganapathi SK, Beggs AD, Hodgson SV, Kumar D. Expression and DNA methylation of TNF, IFNG and FOXP3 in colorectal cancer and their prognostic significance. Br J Cancer 2014; 111:1581-9. [PMID: 25225903 PMCID: PMC4200101 DOI: 10.1038/bjc.2014.477] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Revised: 08/03/2014] [Accepted: 08/05/2014] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) progression is associated with suppression of host cell-mediated immunity and local immune escape mechanisms. Our aim was to assess the immune function in terms of expression of TNF, IFNG and FOXP3 in CRC. METHODS Sixty patients with CRC and 15 matched controls were recruited. TaqMan quantitative PCR and methylation-specific PCR was performed for expression and DNA methylation analysis of TNF, IFNG and FOXP3. Survival analysis was performed over a median follow-up of 48 months. RESULTS TNF was suppressed in tumour and IFNG was suppressed in peripheral blood mononuclear cells (PBMCs) of patients with CRC. Tumours showed enhanced expression of FOXP3 and was significantly higher when tumour size was >38 mm (median tumour size; P=0.006, Mann-Whitney U-test). Peripheral blood mononuclear cell IFNG was suppressed in recurrent CRC (P=0.01). Methylated TNFpromoter (P=0.003) and TNFexon1 (P=0.001) were associated with significant suppression of TNF in tumours. Methylated FOXP3cpg was associated with significant suppression of FOXP3 in both PBMC (P=0.018) and tumours (P=0.010). Reduced PBMC FOXP3 expression was associated with significantly worse overall survival (HR=8.319, P=0.019). CONCLUSIONS We have detected changes in the expression of immunomodulatory genes that could act as biomarkers for prognosis and future immunotherapeutic strategies.
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Affiliation(s)
- S K Ganapathi
- Department of Colorectal Surgery, St. George's Hospital, London, UK
| | - A D Beggs
- Department of Cancer Genetics, St. George's University of London, London, UK
| | - S V Hodgson
- Department of Cancer Genetics, St. George's University of London, London, UK
| | - D Kumar
- Department of Colorectal Surgery, St. George's Hospital, London, UK
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Stanilov N, Dobreva Z, Stanilova S. Higher TNF-Alpha Production Detected in Colorectal Cancer Patients Monocytes. BIOTECHNOL BIOTEC EQ 2014. [DOI: 10.5504/50yrtimb.2011.0020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
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Pengjun Z, Xinyu W, Feng G, Xinxin D, Yulan L, Juan L, Xingwang J, Zhennan D, Yaping T. Multiplexed cytokine profiling of serum for detection of colorectal cancer. Future Oncol 2014; 9:1017-27. [PMID: 23837764 DOI: 10.2217/fon.13.71] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM To evaluate the concentrations of eight cytokines in order to identify potential biomarkers for assisting in the detection of colorectal cancer. MATERIALS & METHODS The concentrations of IFN-γ, IL-10, IL-6, IL-8, TNF-α, MMP-2, MMP-7 and MMP-9 were detected in the sera of 69 healthy controls, 93 colorectal adenoma patients and 149 colorectal cancer (CRC) patients. RESULTS Multivariate logistic regression analyses, which included CEA, CA199, IL-8, TNF-α and MMP-7, were used to evaluate the diagnostic value for differentiating between colorectal adenoma and CRC. The area under the curve was 0.945 (95% CI: 0.909-0.981). The sensitivity and specificity were 85.86 and 96.78%, respectively. Compared with the conventional biomarkers CEA and CA199, multivariate logistic regression showed significant improvement. CONCLUSION Our data demonstrated that testing using a panel of three serum cytokines, CEA and CA199 may have strong potential to assist in the detection of CRC.
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Affiliation(s)
- Zhang Pengjun
- Department of Clinical Biochemistry, State Key Laboratory of Kidney Disease, Chinese PLA General Hospital, Fuxin Road #28, Beijing, China
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Cananzi FCM, Mudan S, Dunne M, Belonwu N, Dalgleish AG. Long-term survival and outcome of patients originally given Mycobacterium vaccae for metastatic malignant melanoma. Hum Vaccin Immunother 2013; 9:2427-33. [PMID: 23863507 DOI: 10.4161/hv.25618] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND The long-term prognosis of patients with stage IV AJCC melanoma is extremely poor. We have previously published short-term clinical outcome and immunological responses to a heat killed Mycobacterium vaccae-based vaccine. RESULTS In this study we report on a better than expected long-term survival (3-y DSS 29·6%, 5-y, and 7-y DSS both 23·9%) relative to historical controls in the patients who received the vaccine in these trials, published in 1999 and 2003. Although the complete or partial response was only 10%, it was the remarkable response to other interventions upon relapse, such as surgery and radiotherapy followed by stable disease that was previously unexpected. METHODS We reviewed the outcome of 72 patients who were treated with M. vaccae for metastatic melanoma between January 1996 and July 2004. CONCLUSION Given this remarkable outcome in stage IV metastatic melanoma and its lack of toxicity we propose that this would make a promising candidate for randomized trials for stage III fully resected melanoma.
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23
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Suzuki N, Takimoto Y, Suzuki R, Arai T, Uebaba K, Nakai M, Strong JM, Tokuda H. Efficacy of Oral Administration of Lentinula eododes Mycelia Extract for Breast Cancer Patients Undergoing Postoperative Hormone Therapy. Asian Pac J Cancer Prev 2013; 14:3469-72. [DOI: 10.7314/apjcp.2013.14.6.3469] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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24
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Advanced tumor stage is an independent risk factor of postoperative infectious complications after colorectal surgery: arguments from a case-matched series. Dis Colon Rectum 2013; 56:568-76. [PMID: 23575395 DOI: 10.1097/dcr.0b013e318282e790] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Patient and technical factors influencing postoperative infectious complications after elective colorectal resections for cancer are well described. Tumor related factors, however, have not been extensively evaluated. OBJECTIVE This study aimed to measure the effect of tumor stage on postoperative surgical site and extra surgical site infections after elective colorectal cancer resection. DESIGN This was a retrospective matched-cohort analysis of prospectively gathered data. SETTINGS The study was conducted in a tertiary referral center and a private hospital specializing in colorectal surgery. PATIENTS Between 2004 and 2011, 740 consecutive patients underwent elective resection for colorectal cancer in 2 centers. Patients undergoing resection for advanced tumors (group A, ≥ stage IIB, n = 177) were matched to randomly selected patients with localized disease (group L, <stage IIB, n = 354). Matching variables were age, sex, American Society of Anesthesiologists score, malnutrition, and surgical approach. MAIN OUTCOME MEASURES We compared 30-day infectious complications rates between patients with advanced (group A) and localized (group L) tumors. Multivariable logistic regression analysis was performed to identify risk factors for infectious complications. RESULTS Group A had a higher overall rate of IC (44.6 vs 25.4 %, p < 0.001), with a higher risk of infectious complications at both the resection site (p < 0.001) and distant to the resection site (p = 0.015). Independent risk factors for infectious complications were advanced tumors (OR = 2.70; p < 0.001), obesity (OR = 1.89; p = 0.018), malnutrition (OR = 2.22; p = 0.008), and open rather than laparoscopic procedure (OR = 5.11; p < 0.001). LIMITATIONS This study is limited by its retrospective methodology. CONCLUSION Advanced tumors increase the risk of infectious complications after colorectal resection, with other risk factors including malnutrition, obesity, and resection by laparotomy. Optimization of modifiable risk factors through nutritional repletion and the choice of a minimally invasive operation should be considered.
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Reynolds JT, Watkins JM, Dufan TA, Kubsad SS. Irradiation of donor mononuclear cells for treatment of chemorefractory metastatic solid cancers: a community-based immune transplant pilot study. Cancer Res Treat 2012; 44:133-41. [PMID: 22802752 PMCID: PMC3394863 DOI: 10.4143/crt.2012.44.2.133] [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] [Received: 03/08/2012] [Accepted: 06/12/2012] [Indexed: 11/28/2022] Open
Abstract
Purpose Chemotherapy has demonstrated ability to generate tumor antigens secondary to induction of apoptosis, against which human leukocyte antigen-compatible, irradiated, related donor mononuclear cells may be administered with immune stimulation to activate antigen presenting and cytotoxic T cells, while minimizing risk of graft-versus-host disease (GVHD). The present study endeavours to describe feasibility and efficacy of this treatment, specifically in the community setting. Materials and Methods Eligible patients had rapidly progressive, chemorefractory metastatic solid tumors. Treatment consisted of intravenous etoposide and cyclosporine for three days followed by granulocyte-macrophage colony-stimulating factor for 5 days. The following week, 5×107 haploidentical or more closely matched irradiated donor mononuclear cells were given weekly for 10 weeks along with interleukin-2. Results Three patients were enrolled, and the regimen was well-tolerated, with no GVHD observed. All patients had clinical response, despite advanced and heavily pretreated disease. Conclusion The above-outlined protocol demonstrates favorable tolerability and efficacy, and appears to be feasible in the community setting. While the optimal chemotherapy, immunostimulation, and irradiation regimens may be further optimized, future investigation appears warranted, and may include community oncology programs.
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Affiliation(s)
- John T Reynolds
- MedCenter One Health Systems, Department of Hematology & Oncology, Bismarck, ND, USA
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26
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Abstract
Many immunotherapeutic agents in phase II cancer studies have given optimistic results, which were not confirmed in larger randomized studies. Here we explore the evidence that, contrary to previous opinion, many chemotherapeutic agents and other classes of drugs may enhance the response to therapeutic vaccines by reducing inflammation and/or by inhibiting regulatory T lymphocytes or myeloid-derived suppressor cells. In addition, some of these agents, such as the immunomodulatory drugs, may produce marked costimulatory activities as in the case of lenalidomide, which also has marked anti-inflammatory properties. With the first approval for a vaccine-based therapy for prostate cancer, we propose that many more vaccines will be able to achieve approval, especially when combined with the optimal chemotherapy and/or immunomodulatory drug schedule.
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Affiliation(s)
- Wai M Liu
- Department of Oncology, Division of Clinical Sciences, St George's, University of London, London, UK
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Cui G, Shi Y, Cui J, Tang F, Florholmen J. Immune microenvironmental shift along human colorectal adenoma-carcinoma sequence: is it relevant to tumor development, biomarkers and biotherapeutic targets? Scand J Gastroenterol 2012; 47:367-77. [PMID: 22229663 DOI: 10.3109/00365521.2011.648950] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Human colorectal carcinoma (CRC) is one of the leading cancers. Every year, the WHO estimates a total of 945,000 new CRC cases, with 492,000 deaths worldwide. Most CRCs arise from the main premalignant lesion, colorectal adenomas, and the progression of colorectal adenoma to CRCs may take a long-term time course. The development of human CRCs is not only determined by the adenomatous cells, but also by the interaction between adenomatous cells and host immune environment. In response to tumor initiation or invasion, many inflammatory cells and components will be inevitably activated and form an inflammatory microenvironment surrounding the CRC tumors. Accumulative evidence has revealed that inflammatory response plays a key role in the development of human CRCs by implicating in many aspects including in determining the microenvironmental immune function shift from immunosurveillance to immunosuppression and significantly influences the progression of precancerous lesions to cancers. In this review, the functional changes of immune microenvironment from precancerous stage (adenoma) to cancer stage are summarized, and their potential as predictive biomarkers and biotherapeutic significance in preventing the development of CRCs are discussed.
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Affiliation(s)
- Guanglin Cui
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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Seyedi S, Andalib A, Rezaei A, Hosseini SM, Mohebbi SR, Zali MR, Vafai M, Behboo R, Tabatabaei SA, Shahabi S. The Effects of Isoproterenol and Propranolol on Cytokine Profile Secretion by Cultured Tumor-infiltrating Lymphocytes Derived from Colorectal Cancer Patients. CELL JOURNAL 2012; 13:281-9. [PMID: 23507624 PMCID: PMC3584474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2011] [Accepted: 09/13/2011] [Indexed: 10/26/2022]
Abstract
OBJECTIVE Anti-tumor immunity and cytokine profiles have important roles in the development of cancer. Norepinephrine (NE) release due to sympathetic activation leads to a Th2 deviation via the beta-2 adrenergic receptor Beta-2 adrenergic receptor (β-2AR) and could increase cancer progression. This study intends to determine the effects of isoproterenol (ISO; beta-agonist) and propranolol (PRO; beta-antagonist) on the production of IFN-γ, IL-4, and IL-17. Cytokine levels have been examined in tumor-infiltrating lymphocytes (TILs) and peripheral blood mononuclear cells (PBMCs) of patients with colorectal cancer (CRC). The β-2AR expression on lymphocyte subsets was also assessed. MATERIALS AND METHODS In this experimental study, TILs were isolated from fresh CRC tissue and patient PBMCs were obtained just prior to surgery. The cells were cultured in medium for 72 hours. Concomitantly, cells were stimulated with 10 µg/ml phytohemagglutinin (PHA) alone or in the presence of either 1 µmol/L of PRO or 1 µmol/L ISO. The concentration of cytokines in the supernatants was measured by ELISA. Three-color flow cytometry was used to determine the expression of β-2AR on the lymphocyte subsets. Statistical analyses were performed via paired or independent t-test. RESULTS Levels of IFN-γ, IL-4 and IL-17 were elevated after PHA-stimulation of PBMCs and TILs. However, the elevation of IFN-γ and IL-17 production by TILs in response to PHA was significantly lower than PBMCs. In the presence of ISO, the IFN-γ/IL-4 ratio reduced in all groups, but this reduction was very low in TILs. Interestingly, the effects of PRO on cytokine production were, at least partially, comparable to those of ISO. Depressed levels of β-2AR expression were demonstrated on CD4+IFN-γ+ and CD4+IL-17+ lymphocytes in patients' PBMCs and TILs. CONCLUSION This study has demonstrated the effects of ISO and PRO on cytokine production by TILs and determined β-2AR expression on these cells. ISO failed to induce a shift toward the expected Th2 cytokine profile in CRC patients' TILs, which might be due to the downregulation of β-2AR expression on TILs. Additionally, in this study, PRO induced a shift to a Th2 profile in PBMCs.
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Affiliation(s)
- Shahram Seyedi
- 1. Department of Immunology, Isfahan Medical School, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Alireza Andalib
- 1. Department of Immunology, Isfahan Medical School, Isfahan University of Medical Sciences, Isfahan, Iran,* Corresponding Address:
Department of ImmunologyIsfahan Medical SchoolIsfahan University of Medical SciencesIsfahanIran
| | - Abbas Rezaei
- 1. Department of Immunology, Isfahan Medical School, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Seyed Mohsen Hosseini
- 2. Department of Epidemiology and Biostatistics, School of Health, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Seyed Reza Mohebbi
- 3. Research Center for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- 3. Research Center for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohamad Vafai
- 4. Iranian Scientific Society of Osteoma Care, Tehran, Iran
| | - Roubik Behboo
- 4. Iranian Scientific Society of Osteoma Care, Tehran, Iran
| | - Seyed Abbas Tabatabaei
- 5. Department of Thoracic Surgery, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shahram Shahabi
- 6. Department of Microbiology, Immunology and Genetics, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
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Bessler H, Salman H, Bergman M, Djaldetti M. Caffeine alters cytokine secretion by PBMC induced by colon cancer cells. Cancer Invest 2011; 30:87-91. [PMID: 22149008 DOI: 10.3109/07357907.2011.636113] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Studies have shown that caffeine might be capable to prevent colon cancer development. This activity is linked in part to its anti-inflammatory properties mediated through modulation of immune responses. It was the aim of the study to evaluate the role of caffeine in the immune balance between peripheral blood mononuclear cells (PBMC) and those of HT-29 and RKO human colon cancer lines. METHODS Cytokine production was evaluated following incubation of the two types of cancer cells without and with three concentrations of caffeine. RESULTS A concentration-dependent inhibition of TNFα and IFNγ secretion by PBMC was observed only after their stimulation by cancer cells. Reduction of the anti-inflammatory IL-1ra and IL-10 production was observed using higher caffeine concentrations only. CONCLUSION We presume that by changing the equilibrium between pro- and anti-inflammatory cytokines in favor of anti-inflammation, caffeine may reduce the inflammatory process with a consequent suppression of colorectal cancer progress.
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Affiliation(s)
- Hanna Bessler
- Laboratory for Immunology and Hematology Research, Rabin Medical Center-Hasharon Hospital, Keren Kayemet St., Petah-Tiqva, Israel
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Soda K. The mechanisms by which polyamines accelerate tumor spread. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2011; 30:95. [PMID: 21988863 PMCID: PMC3206444 DOI: 10.1186/1756-9966-30-95] [Citation(s) in RCA: 199] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/15/2011] [Accepted: 10/11/2011] [Indexed: 11/23/2022]
Abstract
Increased polyamine concentrations in the blood and urine of cancer patients reflect the enhanced levels of polyamine synthesis in cancer tissues arising from increased activity of enzymes responsible for polyamine synthesis. In addition to their de novo polyamine synthesis, cells can take up polyamines from extracellular sources, such as cancer tissues, food, and intestinal microbiota. Because polyamines are indispensable for cell growth, increased polyamine availability enhances cell growth. However, the malignant potential of cancer is determined by its capability to invade to surrounding tissues and metastasize to distant organs. The mechanisms by which increased polyamine levels enhance the malignant potential of cancer cells and decrease anti-tumor immunity are reviewed. Cancer cells with a greater capability to synthesize polyamines are associated with increased production of proteinases, such as serine proteinase, matrix metalloproteinases, cathepsins, and plasminogen activator, which can degrade surrounding tissues. Although cancer tissues produce vascular growth factors, their deregulated growth induces hypoxia, which in turn enhances polyamine uptake by cancer cells to further augment cell migration and suppress CD44 expression. Increased polyamine uptake by immune cells also results in reduced cytokine production needed for anti-tumor activities and decreases expression of adhesion molecules involved in anti-tumor immunity, such as CD11a and CD56. Immune cells in an environment with increased polyamine levels lose anti-tumor immune functions, such as lymphokine activated killer activities. Recent investigations revealed that increased polyamine availability enhances the capability of cancer cells to invade and metastasize to new tissues while diminishing immune cells' anti-tumor immune functions.
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Affiliation(s)
- Kuniyasu Soda
- Department of Surgery and Cardiovascular Research Institute, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma, Omiya, Saitama-city, Saitama 330-0834, Japan.
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Moselli NM, Baricocchi E, Ribero D, Sottile A, Suita L, Debernardi F. Intraoperative epidural analgesia prevents the early proinflammatory response to surgical trauma. Results from a prospective randomized clinical trial of intraoperative epidural versus general analgesia. Ann Surg Oncol 2011; 18:2722-2731. [PMID: 21479690 DOI: 10.1245/s10434-011-1700-9] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2010] [Indexed: 01/04/2025]
Abstract
BACKGROUND The intraoperative epidural analgesia (EA) has the potential to reduce stress response to surgical trauma which induces a transient immunoactivation that has a negative impact on the outcome. This study investigates the effect of intraoperative EA versus intravenous analgesia (IA) on the immune function. METHODS A total of 35 consecutive patients candidated to undergo major surgery for colon cancer were randomly assigned to intraoperative EA (n = 18) or IA (n = 17). Blood samples for TNF-α, IFN-γ, IL-1, IL-2, IL-4, IL-6, IL-10, IL-12, and GM-CSF were obtained before surgery (T(pre)), 3 h (T(3h)), and 24 h (T(24h)) after skin incision. Data on postoperative complications were prospectively collected and analyzed. RESULTS In the EA group, IL-4 increased from T(pre) to T(3h) and from T(3h) to T(24h), IL-10 increased from T(pre) to T(3h) and persisted unmodified thereafter. At all time-points, IL-4 and IL-10 serum levels were significantly higher than those in the IA group. Conversely, in the IA group, IL-4 and IL-10 serum levels did not change while all other cytokines levels were significantly higher compared with the EA group. In particular, IL-6 progressively reached a 7-fold increase of its basal value at T(24h). Complications were significantly more common in IA patients (13 of 17) compared with EA patients (7 of 18) (P = .024). CONCLUSIONS Our results indicate that in cancer patients undergoing major elective colon surgery, the EA attenuates the surgery-induced proinflammatory response and the typical postoperative transient immunosuppression and seems associated with a reduced rate of postoperative complications compared with IA.
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Affiliation(s)
- Nora Maria Moselli
- Department of Anesthesiology, Intensive Care and Pain Therapy, IRCC-Institute for Cancer Research and Treatment, Candiolo, Italy
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Liu WM, Fowler DW, Gravett AM, Smith P, Dalgleish AG. Supernatants from lymphocytes stimulated with Bacillus Calmette-Guerin can modify the antigenicity of tumours and stimulate allogeneic T-cell responses. Br J Cancer 2011; 105:687-93. [PMID: 21829193 PMCID: PMC3188926 DOI: 10.1038/bjc.2011.306] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2011] [Revised: 07/12/2011] [Accepted: 07/15/2011] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Reduced expression of class 1 human leucocyte antigens (HLA1) is often a mechanism by which tumours evade surveillance by the host immune system. This is often associated with an immune function that is unable to mount appropriate responses against disease, which can result in a state that favours carcinogenesis. METHODS In the current study, we have explored the effects of Bacillus Calmette-Guerin (BCG) on the cytokine output of leucocytes, which is a key determinant in generating antitumour action, and have also assessed the effect of these cytokine cocktails on HLA1 expression in solid tumour cell lines. RESULTS BCG potently activated a broad range of leucocytes, and also enhanced the production of cytokines that were Th(1)-predominant. Supernatants from BCG-treated leucocytes significantly increased the expression of HLA1 on the surface of cancer cell lines, which correlated with increased cytolytic T-cell activity. We also showed that the increased HLA1 expression was associated with activation of intracellular signalling pathways, which was triggered by the increases in the Th(1)-cytokines interferon-γ and tumour necrosis factor-α, as counteracting their effects negated the enhancement. CONCLUSION These studies reaffirm the role of BCG as a putative immunotherapy through their cytokine-modifying effects on leucocytes and their capacity to enhance tumour visibility.
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Affiliation(s)
- W M Liu
- Department of Oncology, Division of Clinical Sciences, St George's, University of London, 2nd floor, Jenner Wing, London SW17 0RE, UK.
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Abstract
Vitamin E is the most important chain-breaking, lipid-soluble antioxidant present in body tissues of all cells and is considered the first line of defense against lipid peroxidation and it is important for normal function of the immune cells. However, vitamin E deficiency is rare in well-nourished healthy subjects and is not a problem, even among people living on relatively poor diets, both T- and B-cell functions are impaired by vitamin E deficiency. While immune cells are particularly enriched in vitamin E because of their high polyunsaturated fatty acid content, this point puts them at especially high risk for oxidative damage. Besides its immunomodulatory effects, vitamin E also plays an important role in carcinogenesis with its antioxidant properties against cancer, and ischemic heart disease with limiting the progression of atherosclerosis. Supplementation of vitamin E significantly enhances both cell mediated and humoral immune functions in humans, especially in the elderly and animals.
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Affiliation(s)
- Didem Pekmezci
- Department of Internal Medicine, Faculty of Veterinary Medicine, University of Ondokuz Mayıs, Kurupelit, Samsun, Turkey
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Combined treatment with bevacizumab and standard chemotherapy restores abnormal immune parameters in advanced colorectal cancer patients. Invest New Drugs 2010; 30:395-402. [PMID: 20820907 DOI: 10.1007/s10637-010-9533-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2010] [Accepted: 08/29/2010] [Indexed: 10/19/2022]
Abstract
BACKGROUND Bevacizumab, a monoclonal antibody (mAb) targeting vascular endothelial growth factor (VEGF), has produced promising results when combined with chemotherapy in the treatment of advanced colorectal cancer (CRC). The aim of the present study was to define the immunological profile of metastatic CRC patients at baseline and following chemotherapy with either irinotecan/5-fluorouracil/leucovorin (IFL) alone or IFL in combination with.bevacizumab (B-IFL). METHODS Peripheral blood mononuclear cells (PBMCs) obtained from healthy donors (HD) (n = 20) and patients (n = 40) were tested for T-cell proliferation in the autologous mixed lymphocyte reaction (auto-MLR), and cytokine production following stimulation with anti-CD3 mAb. RESULTS PBMCs obtained from CRC patients prior to treatment exhibited lower auto-MLR responses and low production of IL-2, IFN-γ, IL-12 and IL-18 cytokines, whereas IL-4 and IL-10 cytokines were increased as compared to HD (p < 0.001, for all parameters) following in vitro stimulation with anti-CD3 mAb. During treatment, and in particular in week 12 of evaluation, IL-2 (p < 0.001 for both IFL and B-IFL groups), IFN-γ (p < 0.001 for IFL and p = 0.001 for B-IFL), IL-12 (p < 0.001 for both IFL and B-IFL) and IL-18 (p < 0.001 for both IFL and B-IFL) production, as well as auto-MLR responses increased (p < 0.001 for both IFL and B-IFL), whereas IL-4 (p < 0.001 for IFL and p = 0.001 for B-IFL) and IL-10 [p < 0.001 for IFL and p = 0.067 (non-significant) for B-IFL] production decreased over baseline in the two treatment groups, yet their respective values never reached those of HD. Moreover, IL-2, IFN-γ production, and auto-MLR were higher in the B-IFL over the IFL treatment group (p < 0.001, p < 0.04, p < 0.001, respectively). CONCLUSION Our study demonstrates that the abnormal immune parameters observed in metastatic CRC patients at presentation can substantially improve during treatment with either IFL or B-IFL. The immune parameters examined can provide a sensitive and valuable tool for monitoring immune function in CRC patients, and could be applied as surrogate markers predicting treatment-related outcome.
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Evans CFM, Galustian C, Bodman-Smith M, Dalgleish AG, Kumar D. The effect of colorectal cancer upon host peripheral immune cell function. Colorectal Dis 2010; 12:561-9. [PMID: 19250260 DOI: 10.1111/j.1463-1318.2009.01819.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Colorectal cancer is immunogenic. However, it is also associated with suppression of host immunity. Identifying the mechanisms involved in immune suppression is necessary to develop future immunotherapeutic strategies. The aim of this study was to assess immune cell function in colorectal cancer patients. METHOD A total of 80 colorectal cancer patients (41 male) prior to treatment and 38 matched controls (21 male) were recruited. Venous blood samples were taken. White blood cell composition was determined using monoclonal antibodies. Levels of cytokines IFN-gamma, TNF-alpha, IL-2, IL-10, IL-4 and IL-6 were measured from the supernatants of activated peripheral blood mononuclear cells (PBMC) following thawing and re-suspension. Peripheral blood mononuclear proliferation was measured using 3H-Thymidine. RESULTS Stage I-III cancer patients had elevated percentages of CD8 T cell (P = 0.004) whilst stage IV patients had low total lymphocyte percentages (P = 0.016). Monocyte and NKT cell percentage decreased with advanced tumour stages (P = 0.013 and P = 0.038). Patients had lower PBMC proliferation and production of the TH1 cytokines (IFN-gamma and TNF-alpha) (P < 0.001) than that of the controls. IL-6 and IL-4 production were not significantly different. IFN-gamma and TNF-alpha concentrations reduced with tumour vascular invasion (P = 0.011 and P = 0.019). CONCLUSION Colorectal cancer induces an immunological response, shifting the cytokine balance. The most profound changes are seen once disease has spread systemically.
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Affiliation(s)
- C F M Evans
- St Georges University of London, Cranmer Terrace, London, UK
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Toiyama Y, Miki C, Inoue Y, Minobe S, Urano H, Kusunoki M. Loss of tissue expression of interleukin-10 promotes the disease progression of colorectal carcinoma. Surg Today 2009; 40:46-53. [PMID: 20037839 DOI: 10.1007/s00595-009-4016-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2009] [Accepted: 04/14/2009] [Indexed: 12/17/2022]
Abstract
PURPOSE Interleukin-10 (IL-10) is a unique cytokine that is thought to be a potent immunostimulatory and immunosuppressive factor. The aim of this study was to investigate IL-10 expression in colorectal cancer, and clarify its relationship to the clinicopathological findings and prognosis. METHODS Tissue samples were collected from 92 patients with colorectal cancer and adjacent normal mucosa. The expression of IL-10 in colorectal cancer tissues was evaluated by immunohistochemistry. Tissue levels of IL-10 were measured by enzyme-linked immunosorbent assay. RESULTS The mean concentration of IL-10 did not significantly differ between the cancer tissue and adjacent normal mucosa. The IL-10 concentration in cancer tissue with positive staining immunohistochemically was significantly higher than that without IL-10 staining. The IL-10 level in cancer tissue decreased in accordance with advanced-stage serosal invasion and lymph node involvement, and thus predicted poor survival in patients undergoing surgery with curative intent. A Cox multivariate analysis demonstrated that a decreased IL-10 level in cancer tissue was an independent risk factor for poor survival. CONCLUSION The tumor IL-10 level in colorectal cancer was inversely correlated with serosal invasion and lymph node metastasis, which thus reflected tumor progression. Evaluating the tumor expression of IL-10 may therefore provide valuable information for predicting the long-term survival in patients undergoing surgery with curative intent.
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Affiliation(s)
- Yuji Toiyama
- Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
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Tahara H, Sato M, Thurin M, Wang E, Butterfield LH, Disis ML, Fox BA, Lee PP, Khleif SN, Wigginton JM, Ambs S, Akutsu Y, Chaussabel D, Doki Y, Eremin O, Fridman WH, Hirohashi Y, Imai K, Jacobson J, Jinushi M, Kanamoto A, Kashani-Sabet M, Kato K, Kawakami Y, Kirkwood JM, Kleen TO, Lehmann PV, Liotta L, Lotze MT, Maio M, Malyguine A, Masucci G, Matsubara H, Mayrand-Chung S, Nakamura K, Nishikawa H, Palucka AK, Petricoin EF, Pos Z, Ribas A, Rivoltini L, Sato N, Shiku H, Slingluff CL, Streicher H, Stroncek DF, Takeuchi H, Toyota M, Wada H, Wu X, Wulfkuhle J, Yaguchi T, Zeskind B, Zhao Y, Zocca MB, Marincola FM. Emerging concepts in biomarker discovery; the US-Japan Workshop on Immunological Molecular Markers in Oncology. J Transl Med 2009; 7:45. [PMID: 19534815 PMCID: PMC2724494 DOI: 10.1186/1479-5876-7-45] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2009] [Accepted: 06/17/2009] [Indexed: 02/08/2023] Open
Abstract
Supported by the Office of International Affairs, National Cancer Institute (NCI), the "US-Japan Workshop on Immunological Biomarkers in Oncology" was held in March 2009. The workshop was related to a task force launched by the International Society for the Biological Therapy of Cancer (iSBTc) and the United States Food and Drug Administration (FDA) to identify strategies for biomarker discovery and validation in the field of biotherapy. The effort will culminate on October 28th 2009 in the "iSBTc-FDA-NCI Workshop on Prognostic and Predictive Immunologic Biomarkers in Cancer", which will be held in Washington DC in association with the Annual Meeting. The purposes of the US-Japan workshop were a) to discuss novel approaches to enhance the discovery of predictive and/or prognostic markers in cancer immunotherapy; b) to define the state of the science in biomarker discovery and validation. The participation of Japanese and US scientists provided the opportunity to identify shared or discordant themes across the distinct immune genetic background and the diverse prevalence of disease between the two Nations. Converging concepts were identified: enhanced knowledge of interferon-related pathways was found to be central to the understanding of immune-mediated tissue-specific destruction (TSD) of which tumor rejection is a representative facet. Although the expression of interferon-stimulated genes (ISGs) likely mediates the inflammatory process leading to tumor rejection, it is insufficient by itself and the associated mechanisms need to be identified. It is likely that adaptive immune responses play a broader role in tumor rejection than those strictly related to their antigen-specificity; likely, their primary role is to trigger an acute and tissue-specific inflammatory response at the tumor site that leads to rejection upon recruitment of additional innate and adaptive immune mechanisms. Other candidate systemic and/or tissue-specific biomarkers were recognized that might be added to the list of known entities applicable in immunotherapy trials. The need for a systematic approach to biomarker discovery that takes advantage of powerful high-throughput technologies was recognized; it was clear from the current state of the science that immunotherapy is still in a discovery phase and only a few of the current biomarkers warrant extensive validation. It was, finally, clear that, while current technologies have almost limitless potential, inadequate study design, limited standardization and cross-validation among laboratories and suboptimal comparability of data remain major road blocks. The institution of an interactive consortium for high throughput molecular monitoring of clinical trials with voluntary participation might provide cost-effective solutions.
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Affiliation(s)
- Hideaki Tahara
- Department of Surgery and Bioengineering, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Marimo Sato
- Department of Surgery and Bioengineering, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Magdalena Thurin
- Cancer Diagnosis Program, National Cancer Institute (NCI), National Institutes of Health (NIH), Rockville, Maryland, 20852, USA
| | - Ena Wang
- Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Center for Human Immunology (CHI), NIH, Bethesda, Maryland, 20892, USA
| | - Lisa H Butterfield
- Departments of Medicine, Surgery and Immunology, Division of Hematology Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, 15213, USA
| | - Mary L Disis
- Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle, Washington, 98195, USA
| | - Bernard A Fox
- Earle A Chiles Research Institute, Robert W Franz Research Center, Providence Portland Medical Center, and Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon, 97213, USA
| | - Peter P Lee
- Department of Medicine, Division of Hematology, Stanford University, Stanford, California, 94305, USA
| | - Samir N Khleif
- Cancer Vaccine Section, NCI, NIH, Bethesda, Maryland, 20892, USA
| | - Jon M Wigginton
- Discovery Medicine-Oncology, Bristol-Myers Squibb Inc., Princeton, New Jersey, USA
| | - Stefan Ambs
- Laboratory of Human Carcinogenesis, Center of Cancer Research, NCI, NIH, Bethesda, Maryland, 20892, USA
| | - Yasunori Akutsu
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Damien Chaussabel
- Baylor Institute for Immunology Research and Baylor Research Institute, Dallas, Texas, 75204, USA
| | - Yuichiro Doki
- Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Oleg Eremin
- Section of Surgery, Biomedical Research Unit, Nottingham Digestive Disease Centre, University of Nottingham, NG7 2UH, UK
| | - Wolf Hervé Fridman
- Centre de la Reserche des Cordeliers, INSERM, Paris Descarte University, 75270 Paris, France
| | | | - Kohzoh Imai
- Sapporo Medical University, School of Medicine, Sapporo, Japan
| | - James Jacobson
- Cancer Diagnosis Program, National Cancer Institute (NCI), National Institutes of Health (NIH), Rockville, Maryland, 20852, USA
| | - Masahisa Jinushi
- Department of Surgery and Bioengineering, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Akira Kanamoto
- Department of Surgery and Bioengineering, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | | | - Kazunori Kato
- Department of Molecular Medicine, Sapporo Medical University, School of Medicine, Sapporo, Japan
| | - Yutaka Kawakami
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan
| | - John M Kirkwood
- Departments of Medicine, Surgery and Immunology, Division of Hematology Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, 15213, USA
| | - Thomas O Kleen
- Cellular Technology Ltd, Shaker Heights, Ohio, 44122, USA
| | - Paul V Lehmann
- Cellular Technology Ltd, Shaker Heights, Ohio, 44122, USA
| | - Lance Liotta
- Department of Molecular Pathology and Microbiology, Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia, 10900, USA
| | - Michael T Lotze
- Illman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213, USA
| | - Michele Maio
- Medical Oncology and Immunotherapy, Department. of Oncology, University, Hospital of Siena, Istituto Toscano Tumori, Siena, Italy
- Cancer Bioimmunotherapy Unit, Department of Medical Oncology, Centro di Riferimento Oncologico, IRCCS, Aviano, 53100, Italy
| | - Anatoli Malyguine
- Laboratory of Cell Mediated Immunity, SAIC-Frederick, Inc. NCI-Frederick, Frederick, Maryland, 21702, USA
| | - Giuseppe Masucci
- Department of Oncology-Pathology, Karolinska Institute, Stockholm, 171 76, Sweden
| | - Hisahiro Matsubara
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Shawmarie Mayrand-Chung
- The Biomarkers Consortium (BC), Public-Private Partnership Program, Office of the Director, NIH, Bethesda, Maryland, 20892, USA
| | - Kiminori Nakamura
- Department of Molecular Medicine, Sapporo Medical University, School of Medicine, Sapporo, Japan
| | - Hiroyoshi Nishikawa
- Department of Cancer Vaccine, Department of Immuno-gene Therapy, Mie University Graduate School of Medicine, Mie, Japan
| | - A Karolina Palucka
- Baylor Institute for Immunology Research and Baylor Research Institute, Dallas, Texas, 75204, USA
| | - Emanuel F Petricoin
- Department of Molecular Pathology and Microbiology, Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia, 10900, USA
| | - Zoltan Pos
- Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Center for Human Immunology (CHI), NIH, Bethesda, Maryland, 20892, USA
| | - Antoni Ribas
- Department of Medicine, Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, 90095, USA
| | - Licia Rivoltini
- Unit of Immunotherapy of Human Tumors, IRCCS Foundation, Istituto Nazionale Tumori, Milan, 20100, Italy
| | - Noriyuki Sato
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiroshi Shiku
- Department of Cancer Vaccine, Department of Immuno-gene Therapy, Mie University Graduate School of Medicine, Mie, Japan
| | - Craig L Slingluff
- Department of Surgery, Division of Surgical Oncology, University of Virginia School of Medicine, Charlottesville, Virginia, 22908, USA
| | - Howard Streicher
- Cancer Therapy Evaluation Program, DCTD, NCI, NIH, Rockville, Maryland, 20892, USA
| | - David F Stroncek
- Cell Therapy Section (CTS), Department of Transfusion Medicine, Clinical Center, NIH, Bethesda, Maryland, 20892, USA
| | - Hiroya Takeuchi
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Minoru Toyota
- Department of Biochemistry, Sapporo Medical University, School of Medicine, Sapporo, Japan
| | - Hisashi Wada
- Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Xifeng Wu
- Department of Epidemiology, University of Texas, MD Anderson Cancer Center, Houston, Texas, 77030, USA
| | - Julia Wulfkuhle
- Department of Molecular Pathology and Microbiology, Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia, 10900, USA
| | - Tomonori Yaguchi
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan
| | | | - Yingdong Zhao
- Biometric Research Branch, NCI, NIH, Bethesda, Maryland, 20892, USA
| | | | - Francesco M Marincola
- Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Center for Human Immunology (CHI), NIH, Bethesda, Maryland, 20892, USA
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Kawamoto J, Kimura F, Yoshitomi H, Shimizu H, Yoshidome H, Ohtsuka M, Kato A, Nozawa S, Furukawa K, Mitsuhashi N, Takeuchi D, Miyazaki M. Preoperative GATA3 mRNA Expression in Peripheral Blood Mononuclear Cells is Up-Regulated in Patients With Postoperative Infection Following Hepatobiliary Pancreatic Surgery. J Surg Res 2009; 152:118-27. [DOI: 10.1016/j.jss.2008.01.027] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2007] [Revised: 01/10/2008] [Accepted: 01/21/2008] [Indexed: 12/16/2022]
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Ando T, Mimura K, Johansson CC, Hanson MG, Mougiakakos D, Larsson C, Martins da Palma T, Sakurai D, Norell H, Li M, Nishimura MI, Kiessling R. Transduction with the antioxidant enzyme catalase protects human T cells against oxidative stress. THE JOURNAL OF IMMUNOLOGY 2009; 181:8382-90. [PMID: 19050255 DOI: 10.4049/jimmunol.181.12.8382] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Patients with diseases characterized by chronic inflammation, caused by infection or cancer, have T cells and NK cells with impaired function. The underlying molecular mechanisms are diverse, but one of the major mediators in this immune suppression is oxidative stress caused by activated monocytes, granulocytes, or myeloid-derived suppressor cells. Reactive oxygen species can seriously hamper the efficacy of active immunotherapy and adoptive transfer of T and NK cells into patients. In this study, we have evaluated whether enhanced expression of the antioxidant enzyme catalase in human T cells can protect them against reactive oxygen species. Human CD4(+) and CD8(+) T cells retrovirally transduced with the catalase gene had increased intracellular expression and activity of catalase. Catalase transduction made CD4(+) T cells less sensitive to H(2)O(2)-induced loss-of-function, measured by their cytokine production and ability to expand in vitro following anti-CD3 stimulation. It also enhanced the resistance to oxidative stress-induced cell death after coculture with activated granulocytes, exposure to the oxidized lipid 4-hydroxynonenal, or H(2)O(2). Expression of catalase by CMV-specific CD8(+) T cells saved cells from cell death and improved their capacity to recognize CMV peptide-loaded target cells when exposed to H(2)O(2). These findings indicate that catalase-transduced T cells potentially are more efficacious for the immunotherapy of patients with advanced cancer or chronic viral infections.
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Affiliation(s)
- Takashi Ando
- Department of Oncology and Pathology, Immune and Gene Therapy Laboratory, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden
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Marits P, Karlsson M, Thörn M, Winqvist O. Sentinel Node-Based Immunotherapy of Colon Cancer. COLORECTAL CANCER 2009. [DOI: 10.1007/978-1-4020-9545-0_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Enhanced CD3+/CD4+ T cell activities and modulation of Th1/Th2 lineage development in irradiated rats due to treatment with the male zooid of antheraea pernyi extracts. Chin J Cancer Res 2008. [DOI: 10.1007/s11670-008-0255-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
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Zhao WH, Li L, Zhang B, Zhang WD, Zong M, Tang JD, Zhang HY, Li S. Enhancement of CD4 + T cell activities and modulation of Th1/Th2 lineage development in radiated tumor-bearing rats treated with male zooid of Antheraea pernyi extracts. World J Gastroenterol 2008; 14:2094-9. [PMID: 18395913 PMCID: PMC2701533 DOI: 10.3748/wjg.14.2094] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate whether supplementation of male zooid of Antheraea pernyi extracts (MZAPE) could enhance immune function of radiated tumor-bearing rats.
METHODS: Eighty male Wistar rats were randomly divided into a control group, a simple radiation group, a MZAPE group, and a radiation plus MZAPE group. With the tumor model established by implanting Walker-256 ascites tumor cells, tumor weight and tumor control rate were calculated. The rats in the simple radiation and radiation plus MZAPE groups were underwent to radiation at 10 Gy within 2 d. In the MZAPE and radiation plus MZAPE groups, the MZAPE was gavaged at a dose of 16.53 mg/kg once a day for 7 d. T cell subsets in peripheral blood were determined by flow cytometry and the expression of IL-2, IFN-γ, IL-4 and IL-10 in sera were determined by ELISA on the 8th d.
RESULTS: The tumor weight of simple radiation group, MZAPE group and radiation plus MZAPE group was lower than that of control group (P < 0.01) and tumor control rates were 63.08% ± 6.43%, 69.86% ± 7.12% and 35.30% ± 7.67%, respectively. CD4+ T and CD8+ T cells in the peripheral blood of the simple radiation group were fewer than in control group. In the MZAPE and radiation plus MZAPE groups, the number of CD4+ T cells was higher while CD8+ T cells was lower than in the control and simple radiation groups. Expression of IL-2 and INF-γ in the radiation group was lower than in control group, and significantly enhanced during MZAPE therapy (P < 0.05). Expression of IL-4 and IL-10 in the radiation group had no significant changes compared with the control group, and decreased significantly after MZAPE treatment (P < 0.01).
CONCLUSION: MZAPE administration may help improve the immune function of the radiated tumor-bearing rats and reverse the radiation-induced immune inhibition by promoting the proliferation of T helper cells and inducing the transdifferentiation from Th2 to Th1.
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Cui G, Goll R, Olsen T, Steigen SE, Husebekk A, Vonen B, Florholmen J. Reduced expression of microenvironmental Th1 cytokines accompanies adenomas-carcinomas sequence of colorectum. Cancer Immunol Immunother 2007; 56:985-95. [PMID: 17160410 PMCID: PMC11030272 DOI: 10.1007/s00262-006-0259-y] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2006] [Accepted: 11/06/2006] [Indexed: 11/29/2022]
Abstract
Cytokines have been suggested to be key factors in modulating immune response against tumorigenesis in the microenvironment. Therefore, characterization of cytokine expression along the colorectal adenoma-carcinoma sequence may add important information for understanding the immune-related mechanisms of the development of colorectal carcinoma (CRC). In this study, biopsies from 32 patients with colorectal adenoma (CRA), 20 patients with CRC and 18 healthy controls were examined. Cytokine gene expressions of interleukin-4 (IL-4), IL-10, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma and its upstream inducers (IL-12A and IL-18) were measured at messenger RNA (mRNA) level with quantitative real-time PCR (Q-PCR). Cytokine expressing cells were characterized using immunohistochemistry (IHC). A distinct different cytokine profile between adenoma and CRC was observed: the Th1 cytokines (IFN-gamma, TNF-alpha, IL-12A and IL-18) were increased in local tissues of CRA and decreased in CRC. Consistent with the quantitative cytokine data, IHC examinations revealed slightly increased densities of Th1 cytokine-expressing cells in CRA and a remarkably decreased density of the Th1 cells in CRC. In CRA, the cytokine-expressing cells were highly polarized to the subepithelial stroma while the cells were evenly distributed through the stroma in CRC. In conclusion, distinct changes in the Th1 cytokine profile appear along the colorectal adenoma-carcinoma sequence. This may reflect a change in the host immune regulatory function in the adenoma-carcinoma sequence.
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Affiliation(s)
- Guanglin Cui
- Laboratory of Gastroenterology, Institute of Clinical Medicine, Faculty of Medicine, University of Tromsø, 9037 Tromsø, Norway.
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Kano Y, Soda K, Nakamura T, Saitoh M, Kawakami M, Konishi F. Increased blood spermine levels decrease the cytotoxic activity of lymphokine-activated killer cells: a novel mechanism of cancer evasion. Cancer Immunol Immunother 2007; 56:771-81. [PMID: 16972077 PMCID: PMC11029869 DOI: 10.1007/s00262-006-0229-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2006] [Accepted: 08/16/2006] [Indexed: 11/28/2022]
Abstract
Increased blood polyamine levels, often observed in cancer patients, have negative impacts on patient prognosis and are associated with tumor progression. The purpose of our study was to examine the effects of polyamines on cellular immune function. Peripheral blood mononuclear cells (PBMCs) from healthy volunteers were cultured with the human natural polyamines spermine, spermidine, or putrescine, and the effects on immune cell function were examined. The correlation between post-operative changes in blood polyamine levels and lymphokine-activated killer (LAK) activity was also examined in cancer patients. Spermine decreased the adhesion of non-stimulated PBMCs to tissue culture plastic in a dose- and a time-dependent manner without affecting cell viability or activity. This decrease in adhesion capacity was accompanied by a decrease in the number of CD11a bright-positive and CD56 bright-positive cells. Upon stimulation with interleukin 2 to activate LAK cytotoxicity, PBMCs cultured overnight with 100 or 500 microM spermine showed decreased cytotoxic activity against Daudi cells (91.5 +/- 1.7 and 84.9 +/- 3.0%, respectively (n = 6) compared to PBMC cultured without polyamines). In a group of 25 cancer patients, changes in blood spermine levels after surgery were negatively correlated with changes in LAK cytotoxicity after surgery (r = -0.510, P = 0.008: n = 25). Increased blood spermine levels may be an important factor in the suppression of anti-tumor immune cell function.
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Affiliation(s)
- Yoshihiko Kano
- Department of Surgery, Omiya Medical Center, Jichi Medical University, 1-847 Amanuma, Omiya, Saitama City, Saitama 330-0834 Japan
| | - Kuniyasu Soda
- Department of Surgery, Omiya Medical Center, Jichi Medical University, 1-847 Amanuma, Omiya, Saitama City, Saitama 330-0834 Japan
| | - Takeshi Nakamura
- Department of Surgery, Omiya Medical Center, Jichi Medical University, 1-847 Amanuma, Omiya, Saitama City, Saitama 330-0834 Japan
| | - Masaaki Saitoh
- Department of Surgery, Omiya Medical Center, Jichi Medical University, 1-847 Amanuma, Omiya, Saitama City, Saitama 330-0834 Japan
| | - Masanobu Kawakami
- First Department of Integrated Medicine, Omiya Medical Center, Jichi Medical University, 1-847 Amanuma, Omiya, Saitama City, Saitama 330-0834 Japan
| | - Fumio Konishi
- Department of Surgery, Omiya Medical Center, Jichi Medical University, 1-847 Amanuma, Omiya, Saitama City, Saitama 330-0834 Japan
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Matsuda A, Furukawa K, Suzuki H, Kan H, Tsuruta H, Matsumoto S, Shinji S, Tajiri T. Does impaired TH1/TH2 balance cause postoperative infectious complications in colorectal cancer surgery? J Surg Res 2007; 139:15-21. [PMID: 17292403 DOI: 10.1016/j.jss.2006.10.029] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2006] [Revised: 10/09/2006] [Accepted: 10/18/2006] [Indexed: 10/23/2022]
Abstract
BACKGROUND Recent studies have shown that the Th1/Th2 balance shifts toward Th2 dominance in cancer-bearing state or under surgical stress. This study was designed to investigate whether perioperative impaired Th1/Th2 balance is associated with the occurrence of postoperative infection following colorectal cancer surgery. METHODS From 53 patients with colorectal cancer, peripheral blood samples were collected, before surgery, and on the 3rd, 7th, and 14th postoperative days. The proportions of CD4(+) T-helper cells producing intracellular cytokines including interferon-gamma (Th1 cells) and interleukin-4 (Th2 cells) were measured by flow cytometry. The patients were divided into two groups according to the presence (infected group) and absence (noninfected group) of postoperative infection. RESULTS The infected group showed serum hypoalbuminemia and higher frequency of blood transfusion compared with the noninfected group. No significant difference in the proportion of Th1 cells was observed between the two groups. In contrast, the infected group showed significantly higher proportions of Th2 cells than the noninfected group (1.9 +/- 0.9% for noninfected group and 2.8 +/- 1.3% for infected group; P<0.05). Regarding Th1/Th2 ratio, the infected group showed a lower ratio than the noninfected group (14.7 +/- 8.8 for noninfected group and 9.0 +/- 3.2 for infected group; P<0.05). Throughout the postoperative period, the Th1/Th2 ratio in the infected group was significantly lower than that in the noninfected group. CONCLUSIONS This study demonstrated that perioperative Th2 dominance in addition to hypoalbuminemia and blood transfusion is associated with the occurrence of infection following colorectal cancer surgery. These results provide further information that may direct future treatments based on the Th1/Th2 concept focusing on decreasing the risk of postoperative infection.
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Affiliation(s)
- Akihisa Matsuda
- Surgery for Organ Function and Biological Regulation (Department of Surgery 1), Graduate School of Medicine, Nippon Medical School, Bunkyo-ku, Tokyo, Japan.
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Bhattacharyya S, Mandal D, Saha B, Sen GS, Das T, Sa G. Curcumin prevents tumor-induced T cell apoptosis through Stat-5a-mediated Bcl-2 induction. J Biol Chem 2007; 282:15954-64. [PMID: 17392282 DOI: 10.1074/jbc.m608189200] [Citation(s) in RCA: 81] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Patients with advanced cancer exhibit multifaceted defects in their immune capacity, which are likely to contribute to an increased susceptibility to infections and disease progression. We demonstrated earlier that curcumin inhibits tumor growth and prevents immune cell death in tumor-bearing hosts. Here we report that tumor-induced immunodepletion involves apoptosis of thymic CD4+/CD8+ single/double positive cells as well as loss of circulating CD4+/CD8+ T cells. Administration of curcumin to tumor-bearing animals resulted in restoration of progenitor, effecter, and circulating T cells. In fact, tumor burden decreased the expression level of the pro-proliferative protein Bcl-2 while increasing the pro-apoptotic protein Bax in T cells. Curcumin down-regulated the Bax level while augmenting Bcl-2 expression in these cells, thereby protecting the immunocytes from tumor-induced apoptosis. A search for the upstream mechanism revealed down-regulation of the common cytokine receptor gamma chain (gammac) expression in T cells by tumor-secreted prostaglandin E2. As a result, Jak-3 and Stat-5a phosphorylation and to a lesser extent Stat-5b phosphorylation were also decreased in T cells. These entire phenomena could be reverted back by curcumin, indicating that this phytochemical restored the cytokine-dependent Jak-3/Stat-5a signaling pathway in T cells of tumor bearers. Overexpressed Stat-5a/constitutively active Stat-5a1*6 but not Stat-5b could efficiently elevate Bcl-2 levels and protect T cells from tumor-induced death, whereas C-terminal truncated Stat-5a713 overexpression failed to do so, indicating the importance of Stat-5a signaling in T cell survival. Thus, these results raise the possibility of inclusion of curcumin in successful therapeutic regimens against cancer.
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Affiliation(s)
- Sankar Bhattacharyya
- Bose Institute, P-1/12 Calcutta Improvement Trust Scheme VII M, Kolkata 700 054, India
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Abstract
BACKGROUND Advances in immunology and molecular biology have shown that colorectal cancer is potentially immunogenic and that host immune responses influence survival. However, immune surveillance and activation is frequently ineffective in preventing and/or controlling tumour growth. AIM To discuss potential ways in which colorectal cancer induces immune suppression, its effect upon prognosis and avenues for therapeutic development. METHOD A literature review was undertaken for evidence of colorectal cancer-induced immune suppression using PubMed and Medline searches. Further studies were identified from the reference lists of identified papers. RESULTS Immune suppression occurs at a molecular and cellular level and can result in a shift from cellular to humoral immunity. Several mechanisms for immune suppression have been described affecting innate and adaptive immunity with suppression linked to poorer clinical outcome. CONCLUSIONS Colorectal cancer causes direct inhibition of the host's immune response with a detrimental effect upon prognosis. Immunotherapy offers a therapeutic strategy to counteract these effects with promising results seen particularly in precancerous conditions and early tumours. This review strongly suggests that immunotherapy should be incorporated into adjuvant therapeutic trials for stage 2 tumours and be considered as adjuvant treatment in conjunction with standard chemotherapy regimes for advanced disease.
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Affiliation(s)
- C Evans
- Institution Colorectal Surgery Unit & Division of Oncology, St George's Hospital, Blackshaw Road, London, UK
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48
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Okita A, Tsukuda K, Murakami M, Ota T, Doihara H, Suda M, Nakano T, Matsuoka K, Suzuki E, Naito M, Andou A, Shimizu N. Thymidine phosphorylase and dihydropyrimidine dehydrogenase expression levels in tumor and normal tissue specimens of T3 human colorectal carcinoma. Surg Today 2006; 36:348-53. [PMID: 16554992 DOI: 10.1007/s00595-005-3145-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2005] [Accepted: 07/12/2005] [Indexed: 10/24/2022]
Abstract
PURPOSE Thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) are important enzymes related to the metabolism of 5-fluorouracil and its derivatives. We evaluated the association between the clinicopathological factors and these enzymes in patients with T3 colorectal carcinoma. METHODS The TP and DPD expression levels in 15 patients with T3 colorectal carcinomas were measured in tumor and adjacent normal tissue specimens by enzyme-linked immunosorbent assay. Correlations between each enzyme and clinicopathological factors were also statistically evaluated. RESULTS The TP levels in tumor and normal tissue specimens were 77.9 +/- 33.6 and 24.7 +/- 10.3, respectively (P < 0.001). The DPD levels in tumor and normal tissue specimens were 44.1 +/- 18.2 and 53.1 +/- 24.1, respectively (P = 0.46). The TP/DPD ratios in tumor and normal tissue specimens were 1.84 +/- 0.52 and 0.53 +/- 0.26, respectively (P < 0.001). The tumor/normal ratios of TP level in patients with and without liver metastasis were 1.79 +/- 0.91 and 4.67 +/- 2.51, respectively (P = 0.024). CONCLUSION The measurement of the enzyme expression levels of TP and DPD is considered to be useful for better understanding the conditions of tumor progression. The mechanisms of regulation of these enzymes thus require further evaluation.
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Affiliation(s)
- Atsushi Okita
- Department of Surgery, National Hospital Organization, Shikoku Cancer Center, Matsuyama, Japan
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Dalgleish AG, Whelan MA. Cancer vaccines as a therapeutic modality: The long trek. Cancer Immunol Immunother 2006; 55:1025-32. [PMID: 16506069 PMCID: PMC11030604 DOI: 10.1007/s00262-006-0128-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2005] [Accepted: 12/29/2005] [Indexed: 10/25/2022]
Abstract
The development of cancer vaccines has been one of the several false dawns in which initial promising Phase I and Phase II clinical data have not been followed up with conclusive Phase III trials. In this review, we describe some of the successes and failures, and review the most likely reasons for Phase III failure, such as protocol changes, which are common between Phase II and III, and poorly defined patient groups. Nevertheless, significant survival results have been reported with autologous vaccines for colorectal, renal and, more recently, prostate cancer. In addition, it is becoming evident that immunotherapy is potentially synergistic with other treatment modalities, such as chemotherapy, which can reduce T-regulatory activity that inhibits the immune response to cancer vaccines. This potential for synergy should allow cancer vaccines to become part of the standard treatment regimen for many common tumours.
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Affiliation(s)
- A G Dalgleish
- Department of Oncology, St. George's Hospital Medical School, Cranmer Terrace, SW17 0RE, London, UK.
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50
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Evans C, Morrison I, Heriot AG, Bartlett JB, Finlayson C, Dalgleish AG, Kumar D. The correlation between colorectal cancer rates of proliferation and apoptosis and systemic cytokine levels; plus their influence upon survival. Br J Cancer 2006; 94:1412-9. [PMID: 16641913 PMCID: PMC2361288 DOI: 10.1038/sj.bjc.6603104] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer development is associated with a shift in host immunity with suppression of the cell-mediated immune system (CMI) and a predominance of humoral immunity (HI). Tumour progression is also associated with increased rates of cell proliferation and apoptosis. The aim of this study was to investigate whether these factors correlate and have an influence upon prognosis. Long-term follow-up was performed on 40 patients with colorectal cancer who had levels of tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma and interleukin (IL)-10 measured from stimulated blood cultures before surgery. Their archived tumour specimens were analysed to determine a Ki-67-derived proliferation index (PI) and a M30-derived apoptosis index (AI). Tumour necrosis factor-alpha levels negatively correlated to tumour proliferation (rho=-0.697, P=0.01). Interleukin-10 levels had a positive correlation with tumour proliferation (rho=0.452, P=0.05) and apoptosis (rho=0.587, P=0.01). Patient survival correlates to tumour pathological stage (P=0.0038) and vascular invasion (P=0.0014). An AI< or =0.6% and TNF-alpha levels > or =8148 pg ml(-1) correlate to improved survival (P=0.032, P=0.021). Tumour proliferation and apoptosis correlate to progressive suppression of the CMI-associated cytokine TNF-alpha and to and higher levels of IL-10. Survival is dependent upon the histological stage of the tumour, vascular invasion, rates of apoptosis and proliferation and systemic immunity which are all interconnected.
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Affiliation(s)
- C Evans
- Colorectal Surgery Unit & Division of Oncology, St James Wing (Level III), St George's Hospital, Blackshaw Road, London SW17 0QT, UK
| | - I Morrison
- Colorectal Surgery Unit & Division of Oncology, St James Wing (Level III), St George's Hospital, Blackshaw Road, London SW17 0QT, UK
| | - A G Heriot
- Colorectal Surgery Unit & Division of Oncology, St James Wing (Level III), St George's Hospital, Blackshaw Road, London SW17 0QT, UK
| | - J B Bartlett
- Colorectal Surgery Unit & Division of Oncology, St James Wing (Level III), St George's Hospital, Blackshaw Road, London SW17 0QT, UK
| | - C Finlayson
- Colorectal Surgery Unit & Division of Oncology, St James Wing (Level III), St George's Hospital, Blackshaw Road, London SW17 0QT, UK
| | - A G Dalgleish
- Colorectal Surgery Unit & Division of Oncology, St James Wing (Level III), St George's Hospital, Blackshaw Road, London SW17 0QT, UK
| | - D Kumar
- Colorectal Surgery Unit & Division of Oncology, St James Wing (Level III), St George's Hospital, Blackshaw Road, London SW17 0QT, UK
- Colorectal Surgery Unit & Division of Oncology, St James Wing (Level III), St George's Hospital, Blackshaw Road, London SW17 0QT, UK. E-mail:
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