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Yi DH, Stetter N, Jakobsen K, Jonsson R, Appel S. 3-Day monocyte-derived dendritic cells stimulated with a combination of OK432, TLR7/8 ligand, and prostaglandin E 2 are a promising alternative for cancer immunotherapy. Cancer Immunol Immunother 2018; 67:1611-1620. [PMID: 30069688 PMCID: PMC11028251 DOI: 10.1007/s00262-018-2216-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 07/23/2018] [Indexed: 12/28/2022]
Abstract
Numerous trials using dendritic cell (DC)-based vaccinations for the treatment of cancer are being carried out. However, an improvement of the quality of DC used is highly warranted. We here generated human monocyte-derived dendritic cells using a 3 day protocol and stimulated the cells using a combination of OK432 (Picibanil), TLR7/8 ligand CL097, and reduced amounts of prostaglandin (PG)E2. We analyzed phenotype, migratory, and T-cell stimulatory capacity compared to a cytokine cocktail consisting of IL-1β, IL-6, TNF, and PGE2. The OK432 cocktail stimulated cells had a similar mature phenotype with upregulated co-stimulatory molecules, HLA-DR and CCR7 as the cytokine cocktail-matured cells and a similar cytokine profile except increased amounts of IL-12p70. Chemotaxis towards CCL19 was reduced compared to the cytokine cocktail, but increased compared to OK432 alone. The T-cell stimulatory capacity was similar to the cytokine cocktail stimulated cells. In conclusion, the OK432 cocktail has the advantage of inducing IL-12p70 production without impairing phenotype or T-cell stimulatory capacity of the cells and might, therefore, be an advantageous alternative to be used in DC-based immunotherapy.
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Affiliation(s)
- Dag Heiro Yi
- Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Jonas Lies vei 87, 5021, Bergen, Norway
| | - Nadine Stetter
- Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Jonas Lies vei 87, 5021, Bergen, Norway
| | - Kjerstin Jakobsen
- Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Jonas Lies vei 87, 5021, Bergen, Norway
| | - Roland Jonsson
- Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Jonas Lies vei 87, 5021, Bergen, Norway
- Department of Rheumatology, Haukeland University Hospital, Bergen, Norway
| | - Silke Appel
- Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Jonas Lies vei 87, 5021, Bergen, Norway.
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Ishii H, Chikamatsu K, Igarashi S, Takahashi H, Sakamoto K, Higuchi H, Tanaka S, Matsuoka T, Masuyama K. Establishment of Synergistic Chemoimmunotherapy for Head and Neck Cancer Using Peritumoral Immature Dendritic Cell Injections and Low-Dose Chemotherapies. Transl Oncol 2017; 11:132-139. [PMID: 29268186 PMCID: PMC5738236 DOI: 10.1016/j.tranon.2017.11.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 11/28/2017] [Indexed: 01/30/2023] Open
Abstract
The lack of available tumor antigens with strong immunogenicity, human leukocyte antigen restriction, and immunosuppression via regulatory T-cells (Tregs) and myeloid-derived suppressor cells are limitations for dendritic cell (DC)–based immunotherapy in patients with advanced head and neck cancer (HNC). We sought to overcome these limitations and induce effective antitumor immunity in the host. The effect of low-dose docetaxel (DTX) treatment on DC maturation was examined in an ex vivo study, and a phase I clinical trial of combination therapy with direct peritumoral immature DC (iDC) injection with OK-432 and low-dose cyclophosphamide (CTX) plus DTX was designed. Low-dose DTX did not negatively affect iDC viability and instead promoted maturation and IL-12 production. Five patients with metastatic or recurrent HNC were enrolled for the trial. All patients experienced grade 1 to 3 fevers. Intriguingly, elevated CD8+ effector T-cells and reduced Tregs were observed in four patients who completed two treatment cycles. All patients were judged to have progressive disease, but tumor regressions were observed in a subset of targeted metastatic lesions in two of five patients. Our results show that the combination of direct peritumoral iDC injection with OK-432 and low-dose CTX plus DTX is well tolerated and should give rise to changing the immune profile of T-cell subsets and improvement of immunosuppression in advanced HNC patients. Additionally, our ex vivo data on the effect of low-dose DTX treatment on DC maturation may contribute to developing new combination therapies with low-dose chemotherapy and immunotherapy.
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Affiliation(s)
- Hiroki Ishii
- Department of Otolaryngology, Head and Neck Surgery, University of Yamanashi.
| | - Kazuaki Chikamatsu
- Department of Otolaryngology, Head and Neck Surgery, University of Yamanashi; Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine
| | - Satoshi Igarashi
- Department of Otolaryngology, Head and Neck Surgery, University of Yamanashi
| | - Hideyuki Takahashi
- Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine
| | - Kaname Sakamoto
- Department of Otolaryngology, Head and Neck Surgery, University of Yamanashi
| | - Hiroji Higuchi
- Division of Transfusion Medicine and Cell Therapy, University of Yamanashi Hospital
| | - Shota Tanaka
- Department of Otolaryngology, Head and Neck Surgery, University of Yamanashi
| | - Tomokazu Matsuoka
- Department of Otolaryngology, Head and Neck Surgery, University of Yamanashi
| | - Keisuke Masuyama
- Department of Otolaryngology, Head and Neck Surgery, University of Yamanashi.
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Li L, Wang W, Pan H, Ma G, Shi X, Xie H, Liu X, Ding Q, Zhou W, Wang S. Microwave ablation combined with OK-432 induces Th1-type response and specific antitumor immunity in a murine model of breast cancer. J Transl Med 2017; 15:23. [PMID: 28137271 PMCID: PMC5282633 DOI: 10.1186/s12967-017-1124-9] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 01/19/2017] [Indexed: 12/11/2022] Open
Abstract
Background Minimally invasive therapies, such as microwave ablation (MWA), are widely used for the treatment of solid tumors. Previous studies suggest that MWA is feasible for the treatment of small breast cancer, and thermal ablation may induce adaptive antitumor immunity. However, the induced immune responses are mostly weak, and the immunomodulation effects of MWA in breast cancer are unclear. Immunostimulant OK-432 can induce tumor-specific T-cell responses and may augment the immunity induced by MWA. Methods We treated 4T1 breast cancer bearing BALB/c mice with MWA, OK-432, MWA plus OK-432, or left without treatment. Survival time was evaluated with the Kaplan–Meyer method comparing survival curves by log-rank test. On day 25 after ablation, surviving mice received tumor rechallenge, and the rechallenged tumor volumes were calculated every 5 days. Immunohistochemistry and flow cytometry were used to evaluate the T-cell immune responses in ablated tissues and spleens. The tumor-specific immunity was assessed by enzyme-linked immunospot assays. Besides, the cytokine patterns were identified from enzyme-linked immunosorbent assay. Results Microwave ablation plus OK-432 resulted in longer survival than single treatment and protect most surviving mice from tumor rechallenge. Both local and systemic T-cell responses were induced by MWA and were further enhanced by subsequent administration of OK-432. Moreover, the combination of MWA and OK-432 induced stronger tumor-specific immune responses than MWA alone. In addition, OK-432 and MWA synergistically promoted the production of Th1-type but not Th2-type cytokines, and polarized T-cell responses to Th1-dominant state. Conclusions The T-cell immune responses were activated by MWA in breast cancer. Furthermore, the combination of MWA and OK-432 induced Th1-type response and elicited specific antitumor immunity.
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Affiliation(s)
- Li Li
- Department of Breast Surgery, the First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Wei Wang
- Department of Breast Surgery, the First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Hong Pan
- Department of Breast Surgery, the First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Ge Ma
- Department of Breast Surgery, the First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Xinyi Shi
- Department of Breast Surgery, the First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Hui Xie
- Department of Breast Surgery, the First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Xiaoan Liu
- Department of Breast Surgery, the First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Qiang Ding
- Department of Breast Surgery, the First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Wenbin Zhou
- Department of Breast Surgery, the First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.
| | - Shui Wang
- Department of Breast Surgery, the First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.
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Wang Y, Wang C, Xiao H, Niu C, Wu H, Jin H, Yao C, He H, Tian H, Han F, Li D, Han W, Xu J, Chen J, Cui J, Li W. Adjuvant treatment combining cellular immunotherapy with chemotherapy improves the clinical outcome of patients with stage II/III gastric cancer. Cancer Med 2016; 6:45-53. [PMID: 27790867 PMCID: PMC5269688 DOI: 10.1002/cam4.942] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Revised: 09/16/2016] [Accepted: 09/26/2016] [Indexed: 12/21/2022] Open
Abstract
Postsurgical relapse remains a common issue for resectable gastric cancer (GC). Here, we investigated the efficacy and safety of an adjuvant treatment combining chemotherapy with cellular immunotherapy (CIT) using autologous natural killer cells, γδT cells, and cytokine-induced killer cells in the treatment of stage II/III GC. A pilot prospective cohort study was conducted in 169 patients with stage II/III GC who had undergone gastrectomy with D2 lymph node dissection. Patients were assigned into two groups according to the patient choice of treatment, including chemotherapy alone (chemo) or chemotherapy combined with CIT (chemo/CIT). Disease-free survival (DFS), overall survival (OS), and adverse events were evaluated. Univariate and multivariate Cox models were used to analyze the impact of chemo/CIT on DFS and OS. Kaplan-Meier analysis with the log-rank test was used to compare the clinical outcome between two groups. Three-year DFS rate was 60.6% and 74.7% (P = 0.036) and 3-year OS rate was 64.9% and 83% (P = 0.051) for the chemo and chemo/CIT group, respectively. TNM stage and chemo/CIT were independent prognostic factors for both DFS (for TNM stage, P < 0.001, hazard ratio [HR]: 5.599, 95% confidence interval [CI]: 2.791-11.232; for chemo/CIT, P = 0.013, HR: 0.478, 95% CI: 0.266-0.858) and OS (for TNM stage, P < 0.001, HR: 6.559, 95% CI: 2.903-14.817; for chemo/CIT, P = 0.04, HR: 0.506, 95% CI: 0.264-0.970). In subgroup analysis, 3-year DFS and OS rates of patients with stage III GC in the chemo/CIT group were significantly higher than those in the chemo group (38.4% vs. 57.1%, P = 0.038; and 45.9% vs. 76%, P = 0.06, respectively), while there was no significant difference between the two groups in patients with stage II GC. Only 15.9% of patients (10/63) in the chemo/CIT group had mild and manageable fever (grades 1 and 2), while no other side effects were observed. The adjuvant treatment combining chemotherapy with cellular immunotherapy is well tolerated and significantly improves the clinical outcome of patients with stage II/III GC, when compared with chemotherapy alone, therefore warrants further attention in treatment for relapsed GC after tumor resection.
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Affiliation(s)
- Yizhuo Wang
- Cancer Center, the First Hospital of Jilin University, Changchun, China
| | - Chang Wang
- Cancer Center, the First Hospital of Jilin University, Changchun, China
| | - Huijie Xiao
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Chao Niu
- Cancer Center, the First Hospital of Jilin University, Changchun, China
| | - Haitao Wu
- Cancer Center, the First Hospital of Jilin University, Changchun, China
| | - Haofan Jin
- Cancer Center, the First Hospital of Jilin University, Changchun, China
| | - Cheng Yao
- Cancer Center, the First Hospital of Jilin University, Changchun, China
| | - Hua He
- Cancer Center, the First Hospital of Jilin University, Changchun, China
| | - Huimin Tian
- Cancer Center, the First Hospital of Jilin University, Changchun, China
| | - Fujun Han
- Cancer Center, the First Hospital of Jilin University, Changchun, China
| | - Dan Li
- Cancer Center, the First Hospital of Jilin University, Changchun, China
| | - Wei Han
- Cancer Center, the First Hospital of Jilin University, Changchun, China
| | - Jianting Xu
- Cancer Center, the First Hospital of Jilin University, Changchun, China
| | - Jingtao Chen
- Cancer Center, the First Hospital of Jilin University, Changchun, China.,Institute of Translational Medicine, the First Hospital of Jilin University, Changchun, 130031, China
| | - Jiuwei Cui
- Cancer Center, the First Hospital of Jilin University, Changchun, China
| | - Wei Li
- Cancer Center, the First Hospital of Jilin University, Changchun, China
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Oba MS, Teramukai S, Ohashi Y, Ogawa K, Maehara Y, Sakamoto J. The efficacy of adjuvant immunochemotherapy with OK-432 after curative resection of gastric cancer: an individual patient data meta-analysis of randomized controlled trials. Gastric Cancer 2016; 19:616-624. [PMID: 25804300 DOI: 10.1007/s10120-015-0489-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Accepted: 03/13/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND OK-432 has been used as a cancer treatment for 40 years, and the immunostimulatory effects of OK-432 therapy have been intensely investigated in Japan. Recently, it has received attention as a possible booster for cancer vaccine treatments. Our previous meta-analysis based on summary measures revealed a significant improvement in the survival of patients with curatively resected gastric cancer. However, it is impossible to exclude the possibility of bias due to several prognostic factors. METHODS We collected individual data for patients with stage III or stage IV gastric cancer after curative resection from 14 trials that were identified in a previous meta-analysis. Immunochemotherapy with OK-432 was compared with treatment with standard chemotherapy on an intention-to-treat basis. The primary end point was overall survival. Stratified survival analyses were performed with the trial as the stratification factor. Subgroup analyses were also performed according to the potential prognostic factors, which included pathological factors, splenectomy, and delayed-type hypersensitivity. RESULTS There were 796 and 726 patients in the OK-432 and control groups, respectively. The median overall survival was 42.6 months for the OK-432 group and 32.3 months for the control group. The overall hazard ratio was 0.88 (95 % confidence interval 0.77-1.00, p = 0.050). No factor showed a statistically significant interaction in the subgroup analyses. CONCLUSIONS The results suggest that immunochemotherapy treatment with OK-432 could have a borderline significant effect for patients with stage III or stage IV gastric cancer after curative resection.
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Affiliation(s)
- Mari S Oba
- Department of Biostatistics and Epidemiology, Yokohama City University, Yokohama, Japan. .,, 4-57 Urafune-cho, Minami-ku, Yokohama, 232-0024, Japan.
| | - Satoshi Teramukai
- Department of Biostatistics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yasuo Ohashi
- Department of Integrated Science and Engineering for Sustainable Society, Chuo University, Tokyo, Japan
| | - Kenji Ogawa
- Department of Surgery, Tokyo Women's Medical University Medical Center East, Tokyo, Japan
| | - Yoshihiko Maehara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Raufi AG, Klempner SJ. Immunotherapy for advanced gastric and esophageal cancer: preclinical rationale and ongoing clinical investigations. J Gastrointest Oncol 2015; 6:561-9. [PMID: 26487950 DOI: 10.3978/j.issn.2078-6891.2015.037] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Gastric and esophageal cancers represent a major global cancer burden and novel approaches are needed. Despite recent improvements in outcomes with trastuzumab and ramucirumab the prognosis for advanced disease remains poor, with a median overall survival of 1 year. Comprehensive genomic characterization has defined molecular subgroups and potentially actionable genomic alterations, but the majority of patients do not yet benefit from molecularly directed therapies. Breakthroughs in immune checkpoint blockade have provided new therapeutic avenues in melanoma, and continue to expand into other tumor types, with ongoing investigations in gastrointestinal (GI) malignancies. The frequency of programmed death ligand 1 (PD-L1) overexpression, a putative response biomarker, approaches forty percent in gastric cancers. Translational studies and molecular classification suggest gastric and esophageal cancers are candidate malignancies for immune checkpoint inhibition trials and early clinical data is promising. Here we review the mechanisms, preclinical, and early clinical data supporting the role for immune checkpoint blockade in gastric and esophageal cancer.
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Affiliation(s)
- Alexander G Raufi
- 1 Department of Medicine, Orange, CA, USA ; 2 Division of Hematology-Oncology, University of California Irvine, Orange, CA 92868, USA
| | - Samuel J Klempner
- 1 Department of Medicine, Orange, CA, USA ; 2 Division of Hematology-Oncology, University of California Irvine, Orange, CA 92868, USA
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Liu JS, He SC, Zhang ZL, Chen R, Fan L, Qiu GL, Chang S, Li L, Che XM. Anticancer effects of β-elemene in gastric cancer cells and its potential underlying proteins: a proteomic study. Oncol Rep 2014; 32:2635-47. [PMID: 25333415 DOI: 10.3892/or.2014.3490] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Accepted: 08/26/2014] [Indexed: 01/19/2023] Open
Abstract
Gastric cancer is a common malignancy with a poor prognosis. β-elemene is a broad-spectrum anticancer drug extracted from the traditional Chinese medicinal herb Curcuma wenyujin. In the present study, we investigated the anticancer effects of β-elemene in gastric cancer cells and the potential proteins involved. Human SGC7901 and MKN45 gastric cancer cells were treated with different concentrations of β-elemene. Cell viability, clonogenic survival and apoptotic cell death were assessed. β-elemene inhibited viability and decreased clonogenic survival of gastric cancer cells in a dose-dependent manner. Apoptosis induction contributed to the anticancer effects. We then employed a proteomic method, isobaric tags for relative and absolute quantitation (iTRAQ), to detect the proteins altered by β-elemene. In total, 147 upregulated proteins and 86 downregulated proteins were identified in response to β-elemene treatment in SGC7901 gastric cancer cells. Among them, expression of p21-activated protein kinase‑interacting protein 1 (PAK1IP1), Bcl-2-associated transcription factor 1 (BTF) and topoisomerase 2-α (TOPIIα) were validated by western blot analyses and the trends were consistent with iTRAQ results. Top pathways involved in β-elemene treatment in SGC7901 gastric cancer cells included ribosome signaling, peroxisome proliferator-activated receptors (PPARs) signaling pathway, regulation of actin cytoskeleton, phagosome, biosynthesis and metabolism of some amino acids. Collectively, our results suggest a promising therapeutic role of β-elemene in gastric cancer. The differentially expressed proteins provide further insight into the potential mechanisms involved in gastric cancer treatment using β-elemene.
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Affiliation(s)
- Jun-Song Liu
- Department of General Surgery, The First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Shi-Cai He
- Department of General Surgery, The First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Zheng-Liang Zhang
- Department of General Surgery, The First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Rui Chen
- Department of General Surgery, The First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Lin Fan
- Department of General Surgery, The First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Guang-Lin Qiu
- Department of General Surgery, The First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Shuai Chang
- Department of General Surgery, The First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Liang Li
- Department of General Surgery, The First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Xiang-Ming Che
- Department of General Surgery, The First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
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Ina K, Kataoka T, Ando T. The use of lentinan for treating gastric cancer. Anticancer Agents Med Chem 2014; 13:681-8. [PMID: 23092289 PMCID: PMC3664515 DOI: 10.2174/1871520611313050002] [Citation(s) in RCA: 136] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2012] [Revised: 08/23/2012] [Accepted: 10/17/2012] [Indexed: 12/11/2022]
Abstract
Natural compounds containing fungal β-glucans have been used to improve general health for thousands of years in China and Japan. Lentinan, the backbone of β-(1, 3)-glucan with β-(1, 6) branches, is one of the active ingredients purified from Shiitake mushrooms and has been approved as a biological response modifier for the treatment of gastric cancer in Japan. Despite recent advances in chemotherapeutic agents, unresectable or recurrent gastric cancer remains an incurable disease, with survival rates being far from satisfactory. Recent clinical studies have shown that chemo-immunotherapy using lentinan prolongs the survival of patients with advanced gastric cancer, as compared to chemotherapy alone. In addition, trastuzumab, an antibody against HER2/neu growth factor receptor, has been used for the treatment of gastric cancer in combination with cytotoxic chemotherapeutic agents. Lentinan may exert a synergistic action with anti-cancer monoclonal antibodies to activate complement systems through the mechanism of antibody-dependent cellular cytotoxicity and complement dependent cytotoxicity. Because a better understanding of its biological activities should enable us to use lentinan more efficiently in the treatment of gastric cancer, immunological effects provided by β-glucans, a possible mode of action of lentinan, and its clinical application including future potential uses are discussed in the present review.
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Affiliation(s)
- Kenji Ina
- Department of Medical Oncology, Nagoya Memorial Hospital, Nagoya 468-8520, Japan.
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Romano F, Uggeri F, Nespoli L, Gianotti L, Garancini M, Maternini M, Nespoli A, Uggeri F. Gastric Cancer Immunotherapy: An Overview. ACTA ACUST UNITED AC 2013. [DOI: 10.4236/jct.2013.45116] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Shi L, Zhou Q, Wu J, Ji M, Li G, Jiang J, Wu C. Efficacy of adjuvant immunotherapy with cytokine-induced killer cells in patients with locally advanced gastric cancer. Cancer Immunol Immunother 2012; 61:2251-9. [PMID: 22674056 PMCID: PMC3506195 DOI: 10.1007/s00262-012-1289-2] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2012] [Accepted: 05/18/2012] [Indexed: 12/15/2022]
Abstract
Purpose To determine the long-term efficacy of adjuvant immunotherapy with autologous cytokine-induced killer (CIK) cells for locally advanced gastric cancer patients. Experimental design One hundred and fifty-one patients with stage III/IV gastric cancer who had undergone gastrectomy were enrolled, assigned to two groups (immunotherapy group versus no immunotherapy group/or control group), and followed. Results The 5-year overall survival (OS) and 5-year disease-free survival (DFS) rates for immunotherapy versus control group were 32.4 versus 23.4 % (P = 0.071) and 28.3 versus 10.4 % (P = 0.044), respectively. For patients with intestinal-type tumors, the 5-year OS and DFS rates were significantly higher for immunotherapy (OS, 46.8 vs. 31.4 % and P = 0.045; DFS, 42.4 vs. 15.7 % and P = 0.023). In the immunotherapy group, the mean CD3+ level, CD4+ level, and CD4+/CD8+ ratio increased from 50.8, 26.5, and 0.9 %, respectively, at baseline to 62.6, 35.0, and 1.4 %, respectively, 1 week after the first CIK-cell treatment, returned to baseline after 2 months, and maintained a higher level (60.7 ± 8.2 %, 34.2 ± 7.1 %, and 1.3 ± 0.3 %, respectively) 2 months after 3 cycles of immunotherapy. Conclusions Adjuvant immunotherapy with CIK cells prolongs DFS in patients with locally advanced gastric cancer and significantly improves OS in patients with intestinal-type tumors. Intestinal-type tumors could be selected as an important indication for CIK-cell therapy. This treatment may help improve T-lymphocyte subset distribution and improve the host’s immune functions, but multiple cycles are necessary for long-term therapeutic efficacy.
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Affiliation(s)
- Liangrong Shi
- Department of Tumor Biological Treatment, The Third Affiliated Hospital, Soochow University, 185 Juqian Street, Changzhou, 213003, Jiangsu Province, China
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Hovden AO, Karlsen M, Jonsson R, Appel S. The bacterial preparation OK432 induces IL-12p70 secretion in human dendritic cells in a TLR3 dependent manner. PLoS One 2012; 7:e31217. [PMID: 22363584 PMCID: PMC3283639 DOI: 10.1371/journal.pone.0031217] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2011] [Accepted: 01/04/2012] [Indexed: 01/12/2023] Open
Abstract
Dendritic cells (DC) used in therapeutic cancer immunotherapy have to be able to stimulate T cells resulting in an immune response that can efficiently target the cancer cells. One of the critical hurdles has been the lack of IL-12p70 production when maturating the DC, which is rectified by using the bacterial preparation OK432 (trade name Picibanil) to mature the cells. In order to identify the mechanism behind OK432 stimulation of DC, we investigated the contribution of different TLR to examine their involvement in IL-12p70 production. By combining different inhibitors of TLR signaling, we demonstrate here that TLR3 is responsible for the IL-12p70 production of DC induced by OK432. Moreover, our data suggest that the ligand triggering IL-12p70 secretion upon TLR3 stimulation is sensitive to proteinase and partly also RNAse treatment. The fact that a bacterial compound like OK432 can activate the TLR3 pathway in human DC is a novel finding. OK432 demonstrates a critical ability to induce IL-12p70 production, which is of great relevance in DC based cancer immunotherapy.
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Affiliation(s)
- Arnt-Ove Hovden
- Broegelmann Research Laboratory, The Gade Institute, University of Bergen, Bergen, Norway
| | - Marie Karlsen
- Broegelmann Research Laboratory, The Gade Institute, University of Bergen, Bergen, Norway
| | - Roland Jonsson
- Broegelmann Research Laboratory, The Gade Institute, University of Bergen, Bergen, Norway
| | - Silke Appel
- Broegelmann Research Laboratory, The Gade Institute, University of Bergen, Bergen, Norway
- * E-mail:
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Ina K, Furuta R, Kataoka T, Kayukawa S, Yoshida T, Miwa T, Yamamura Y, Takeuchi Y. Lentinan prolonged survival in patients with gastric cancer receiving S-1-based chemotherapy. World J Clin Oncol 2011; 2:339-43. [PMID: 21994907 PMCID: PMC3191325 DOI: 10.5306/wjco.v2.i10.339] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2011] [Revised: 08/01/2011] [Accepted: 08/08/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine whether administration of lentinan, purified β-1, 3-glucan, can prolong survival in advanced gastric cancer patients receiving S-1-based chemotherapy.
METHODS: Since 2004, 78 patients with metastatic or recurrent gastric cancer have received S-1-based chemotherapy as first-line treatment. Survival, side effects, and the ratio of granulocytes/lymphocytes (G/L ratio) were compared between 2 groups of patients who received chemo-immunotherapy using lentinan and chemotherapy alone.
RESULTS: Median overall survival was significantly longer in the former group than in the latter group [689 d (95% CI: 431-2339 d) vs 565 d (95% CI: 323-662 d), P = 0.0406]. In addition, the G/L ratio in patients who received lentinan was maintained around or below 2, which was significantly lower than that in patients who received chemotherapy alone (P < 0.001).
CONCLUSION: Chemo-immunotherapy with lentinan offers a significant advantage over S-1-based chemotherapy alone in terms of survival in patients with advanced gastric cancer.
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Affiliation(s)
- Kenji Ina
- Kenji Ina, Ryuichi Furuta, Department of Medical Oncology, Nagoya Memorial Hospital, Nagoya 468-8520, Japan
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Hovden AO, Karlsen M, Jonsson R, Aarstad HJ, Appel S. Maturation of monocyte derived dendritic cells with OK432 boosts IL-12p70 secretion and conveys strong T-cell responses. BMC Immunol 2011; 12:2. [PMID: 21208424 PMCID: PMC3023782 DOI: 10.1186/1471-2172-12-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2010] [Accepted: 01/05/2011] [Indexed: 12/21/2022] Open
Abstract
Background Design of tumour specific immunotherapies using the patients' own dendritic cells (DC) is a fast advancing scientific field. The functional qualities of the DC generated in vitro are critical, and today's gold standard for maturation is a cytokine cocktail consisting of IL-1β, IL-6, TNF-α and PGE2 generating cells lacking IL-12p70 production. OK432 is an immunotherapeutic agent derived from killed Streptococcus pyogenes that has been used clinically to treat malignant and benign neoplasms for decades. Methods In this study, we analysed the effects of OK432 on DC maturation, DC migration, cytokine and chemokine secretion as well as T-cell stimulatory capacity, and compared it to the cytokine cocktail alone and combinations of OK432 with the cytokine cocktail. Results OK432 induced a marked up-regulation of CD40 on the cell surface as well as a strong inflammatory response from the DC with significantly more secretion of 19 different cytokines and chemokines compared to the cytokine cocktail. Interestingly, secretion of IL-15 and IL-12p70 was detected at high concentrations after maturation of DC with OK432. However, the OK432 treated DC did not migrate as well as DC treated with cytokine cocktail in a transwell migration assay. During allogeneic T-cell stimulation OK432 treated DC induced proliferation of over 50 percent of CD4 and 30 percent of CD8 T-cells for more than two cell divisions, whereas cytokine cocktail treated DC induced proliferation of 12 and 11 percent of CD4 and CD8 T-cells, respectively. Conclusions The clinically approved compound OK432 has interesting properties that warrants its use in DC immunotherapy and should be considered as a potential immunomodulating agent in cancer immunotherapy.
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Biondi A, Persiani R, Cananzi F, Zoccali M, Vigorita V, Tufo A, D’Ugo D. R0 resection in the treatment of gastric cancer: Room for improvement. World J Gastroenterol 2010; 16:3358-70. [PMID: 20632437 PMCID: PMC2904881 DOI: 10.3748/wjg.v16.i27.3358] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [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
Gastric carcinoma is one of the most frequent malignancies in the world and its clinical behavior especially depends on the metastatic potential of the tumor. In particular, lymphatic metastasis is one of the main predictors of tumor recurrence and survival, and current pathological staging systems reflect the concept that lymphatic spread is the most relevant prognostic factor in patients undergoing curative resection. This is compounded by the observation that two-thirds of gastric cancer in the Western world presents at an advanced stage, with lymph node metastasis at diagnosis. All current therapeutic efforts in gastric cancer are directed toward individualization of therapeutic protocols, tailoring the extent of resection and the administration of preoperative and postoperative treatment. The goals of all these strategies are to improve prognosis towards the achievement of a curative resection (R0 resection) with minimal morbidity and mortality, and better postoperative quality of life.
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Oba K, Teramukai S, Kobayashi M, Matsui T, Kodera Y, Sakamoto J. Efficacy of adjuvant immunochemotherapy with polysaccharide K for patients with curative resections of gastric cancer. Cancer Immunol Immunother 2007; 56:905-11. [PMID: 17106715 PMCID: PMC11030720 DOI: 10.1007/s00262-006-0248-1] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2006] [Accepted: 10/24/2006] [Indexed: 11/29/2022]
Abstract
Non-specific immunopotentiators, such as polysaccharide K (PSK), also known as OK-432, induce anti-tumor effects via immunological responses. The efficacy of combination immunochemotherapy using these immunopotentiators has been examined by multiple previous studies. The survival benefits of immunochemotherapy for patients with curative resections of gastric cancers are not widely accepted. To clarify this issue, we performed a meta-analysis to evaluate the effect of immunochemotherapy on survival in patients with curative resections of gastric cancer. For this study, we compared the results of chemotherapy and immunotherapy using the biological response modifier PSK as an immunopotentiator. The meta-analysis included 8,009 patients from eight randomized controlled trials after central randomization. The overall hazard ratio for eligible patients was 0.88 (95% confidence interval, 0.79-0.98; P = 0.018) with no significant heterogeneity [chi (2)(8) for heterogeneity = 11.7; P = 0.16]. The results of this meta-analysis suggest that adjuvant immunochemotherapy with PSK improves the survival of patients after curative gastric cancer resection.
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Affiliation(s)
- Koji Oba
- Department of Epidemiological and Clinical Research Information Management, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
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16
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Cesana GC, Romano F, Piacentini G, Scotti M, Brenna A, Bovo G, Vaghi M, Aletti G, Caprotti R, Kaufman H, Uggeri F. Low-dose interleukin-2 administered pre-operatively to patients with gastric cancer activates peripheral and peritumoral lymphocytes but does not affect prognosis. Ann Surg Oncol 2007; 14:1295-304. [PMID: 17225981 DOI: 10.1245/s10434-006-9239-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2006] [Revised: 09/06/2006] [Accepted: 09/07/2006] [Indexed: 02/01/2023]
Abstract
BACKGROUND There is evidence that cancer is immunogenic under certain situations. IL-2 is described to stimulate an effective antitumor immune response in vitro and in vivo. The ability of cancer patients to undergo surgical resection is still the most important prognostic factor for many solid tumors, including gastric adenocarcinoma. The host immune system may be further compromised by surgical procedures leading to a generalized state of immunodepression in the post-operative period. The aim of this randomized case-control study is to evaluate the effects of pre-operative low-dose IL-2 treatment on patients with gastric adenocarcinoma who undergo surgery. METHODS Sixty-eight patients with gastric adenocarcinoma were enrolled in the study and randomized in two groups: 36 patients were pre-treated with IL-2 and 32 underwent surgery without any treatment. Total peripheral WBC, neutrophils, CD3(+) T, CD4(+) T, CD8(+) T and NK cells were obtained before and after surgery, at different times. Peritumoral infiltration was analyzed on all surgical specimens. Overall survival and relapse-free survival were studied with a median follow-up of 51 months. RESULTS Low-dose IL-2 treatment resulted in an increase peritumoral lymphocytic and eosinophilic infiltrations and in a minor decrease in CD3(+) T and CD4(+) T cells after surgery (P < 0.05). A stepwise multivariate analysis revealed that overall survival and relapse-free survival were affected only by stage of tumor and age of patients. CONCLUSIONS According to our data low-doses of IL-2 administered pre-operatively to patients with gastric cancer activate peripheral and peri-tumoral lymphocytes but did not affect prognosis.
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Affiliation(s)
- Giovanni Carlo Cesana
- Department of General Surgery, University of Milano-Bicocca, S. Gerardo Hospital, via Donizzetti 106, Monza, 20052 Milan, Italy.
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17
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Sakamoto J, Morita S, Oba K, Matsui T, Kobayashi M, Nakazato H, Ohashi Y. Efficacy of adjuvant immunochemotherapy with polysaccharide K for patients with curatively resected colorectal cancer: a meta-analysis of centrally randomized controlled clinical trials. Cancer Immunol Immunother 2006; 55:404-11. [PMID: 16133112 PMCID: PMC11030578 DOI: 10.1007/s00262-005-0054-1] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2005] [Accepted: 06/21/2005] [Indexed: 12/19/2022]
Abstract
The benefits of immunochemotherapy employing the biological response modifier polysaccharide K (PSK) for patients with curatively resected colorectal cancer was reassessed by means of a meta-analysis of data with center randomization from 1,094 patients enrolled in three clinical trials. In all three trials, patients were followed up for at least 5 years after surgery and enrollment of the last patient and outcomes for standard chemotherapy were compared with those for chemotherapy plus PSK. The endpoints were overall survival and disease-free survival; and intent-to-treat analysis was performed without patient exclusion. Data were analyzed using the weighted average of the individual log hazard ratios. The overall survival risk ratio for all eligible patients was 0.71 (95% confidence interval (CI) : 0.55-0.90; P=0.006), and the disease-free survival risk ratio was 0.72 (95% CI: 0.58-0.90; P=0.003). The results of this meta-analysis suggest that adjuvant immunochemotherapy with PSK can improve both survival and disease-free survival of patients with curatively resected colorectal cancer.
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Affiliation(s)
- Junichi Sakamoto
- Department of Epidemiological& Clinical Research Information Management, Kyoto University Graduate School of Medicine, Yoshidakonoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan.
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Sastre J, Garcia-Saenz JA, Diaz-Rubio E. Chemotherapy for gastric cancer. World J Gastroenterol 2006; 12:204-13. [PMID: 16482619 PMCID: PMC4066028 DOI: 10.3748/wjg.v12.i2.204] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2005] [Revised: 06/28/2005] [Accepted: 07/08/2005] [Indexed: 02/06/2023] Open
Abstract
Metastatic gastric cancer remains a non-curative disease. Palliative chemotherapy has been demonstrated to prolong survival without quality of life compromise. Many single-agents and combinations have been confirmed to be active in the treatment of metastatic disease. Objective response rates ranged from 10-30% for single-agent therapy and 30-60% for polychemotherapy. Results of phase II and III studies are reviewed in this paper as well as the potential efficacy of new drugs. For patients with localized disease, the role of adjuvant and neoadjuvant chemotherapy and radiation therapy is discussed. Most studies on adjuvant chemotherapy failed to demonstrate a survival advantage, and therefore, it is not considered as standard treatment in most centres. Adjuvant immunochemotherapy has been developed fundamentally in Korea and Japan. A meta-analysis of phase III trials with OK-432 suggested that immunochemotherapy may improve survival of patients with curatively resected gastric cancer. Based on the results of US Intergroup 0116 study, postoperative chemoradiation has been accepted as standard care in patients with resected gastric cancer in North America. However, the results are somewhat confounded by the fact that patients underwent less than a recommended D1 lymph node dissection and the pattern of recurrence suggested a positive effect derived from local radiotherapy without any effect on micrometastatic disease. Neoadjuvant chemotherapy or chemoradiation therapy remains experimental, but several phase II studies are showing promising results. Phase III trials are needed.
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Affiliation(s)
- Javier Sastre
- Servicio de Oncologia Medica, HCU San Carlos, c/Martin Lagos s/n 28040 Madrid, Spain.
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Hundahl SA. Evidence-based recommendations for local-regional control of gastric cancer. Cancer Invest 2005; 23:352-62. [PMID: 16100947 DOI: 10.1081/cnv-58885] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Affiliation(s)
- Scott A Hundahl
- VA Northern California Health Care System, Surgical Services, University of California, Davis, Mather, California 95655-1200, USA.
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Silberman H. Perioperative adjunctive treatment in the management of operable gastric cancer. J Surg Oncol 2005; 90:174-86; discussion 186-7. [PMID: 15895444 DOI: 10.1002/jso.20226] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Outcome in the management of clinically resectable gastric carcinoma has been disappointing, at least in Western populations, despite increasingly radical surgery and extensive experience with adjunctive perioperative treatment with innumerable single and combined modality regimens. The United States Intergroup Study, a prospective, randomized, controlled trial of adjuvant chemoradiation, demonstrated significant improvement in disease-free and overall survival. Consequently, this regimen of postoperative fluoruracil plus leucovorin and locoregional radiation has been incorporated into current clinical practice. In hopes of further improving cure rates, many other regimens are under investigation, including the efficacy of neoadjuvant therapy alone, combined neoadjuvant and adjuvant therapy, and adjuvant therapy alone. In these clinical trials, therapeutic agents are prescribed alone or in multimodal regimens and include systemic chemotherapy, intraperitoneal (IP) chemotherapy with or without hyperthermia, intraoperative radiotherapy (IORT), and postoperative external beam irradiation. Several molecular markers have been identified, which seem to predict that a given tumor may be effective or resistant to a drug, raising the possibility of customized chemotherapy regimens. Preclinical studies suggest potential efficacy of angiogenesis inhibitors, monoclonal antibodies, and antisense agents.
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Affiliation(s)
- Howard Silberman
- Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
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Sato Y, Kondo M, Kohashi S, Takahashi N, Takahashi S, Sinohara T, Ono KI, Matsuda M, Ryoma Y, Shiroto H, Kondo Y, Uchino JI, Saito K, Todo S. A randomized controlled study of immunochemotherapy with OK-432 after curative surgery for gastric cancer. J Immunother 2005; 27:394-7. [PMID: 15314548 DOI: 10.1097/00002371-200409000-00008] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The effect of adjuvant immunochemotherapy including OK-432 (Picibanil) on survival was assessed in patients who underwent curative resection of gastric cancer. Patients enrolled in this randomized controlled study were randomly assigned to group A or group B. Group A patients received 800 mg/d 5'-DFUR (Furtulon) for 2 years from 2 weeks after the operation. Group B patients received OK-432 plus 5'-DFUR by the same regimen as in group A. This study enrolled 288 patients, and 1 patient with malignant lymphoma was excluded. Among the remaining 287 patients, 143 and 144 were allocated to group A and group B, respectively, and their data were included in statistical analysis. The 5-year survival rates for groups A and B were 62.9% and 63.8%, respectively, showing no significant difference (P = 0.7996).
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Affiliation(s)
- Yuji Sato
- First Department of Surgery, School of Medicine, Hokkaido University, Sapporo, Japan.
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N/A. N/A. Shijie Huaren Xiaohua Zazhi 2004; 12:1221-1222. [DOI: 10.11569/wcjd.v12.i5.1221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Chang F, Steelman LS, Lee JT, Shelton JG, Navolanic PM, Blalock WL, Franklin RA, McCubrey JA. Signal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokine receptors to transcription factors: potential targeting for therapeutic intervention. Leukemia 2003; 17:1263-93. [PMID: 12835716 DOI: 10.1038/sj.leu.2402945] [Citation(s) in RCA: 533] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
The Ras/Raf/Mitogen-activated protein kinase/ERK kinase (MEK)/extracellular-signal-regulated kinase (ERK) cascade couples signals from cell surface receptors to transcription factors, which regulate gene expression. Depending upon the stimulus and cell type, this pathway can transmit signals, which result in the prevention or induction of apoptosis or cell cycle progression. Thus, it is an appropriate pathway to target for therapeutic intervention. This pathway becomes more complex daily, as there are multiple members of the kinase and transcription factor families, which can be activated or inactivated by protein phosphorylation. The diversity of signals transduced by this pathway is increased, as different family members heterodimerize to transmit different signals. Furthermore, additional signal transduction pathways interact with the Raf/MEK/ERK pathway to regulate positively or negatively its activity, or to alter the phosphorylation status of downstream targets. Abnormal activation of this pathway occurs in leukemia because of mutations at Ras as well as genes in other pathways (eg PI3K, PTEN, Akt), which serve to regulate its activity. Dysregulation of this pathway can result in autocrine transformation of hematopoietic cells since cytokine genes such as interleukin-3 and granulocyte/macrophage colony-stimulating factor contain the transacting binding sites for the transcription factors regulated by this pathway. Inhibitors of Ras, Raf, MEK and some downstream targets have been developed and many are currently in clinical trials. This review will summarize our current understanding of the Ras/Raf/MEK/ERK signal transduction pathway and the downstream transcription factors. The prospects of targeting this pathway for therapeutic intervention in leukemia and other cancers will be evaluated.
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Affiliation(s)
- F Chang
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
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