Significance of CD47 expression in gastric cancer

Integrin-associated protein (CD47) is ubiquitously expressed on the surface of cells and functions as an identifier of self. In blood cancer, tumor cells expressing CD47 evade phagocytosis by macrophages, leading to a poor patient prognosis. However, the status of CD47 expression in solid tumors, particularly in gastric cancer, is not well understood. The purpose of the present study was to examine the level of CD47 in the primary tumor, peripheral blood (PB) and bone marrow (BM) of patients with gastric cancer, and to determine its effect. Reverse transcription-quantitative polymerase chain reaction analysis was performed to determine the level of CD47 mRNA expression in primary tumor, PB and BM samples collected from 168 patients with gastric cancer. Cell sorting was performed to investigate CD47 protein expression in PB and BM fractions, and to identify the source of CD47 expression. In primary tumors, the expression of CD47 was not associated with any clinicopathological factors or prognosis. By contrast, in PB, the low CD47 expression group demonstrated a significantly increased tumor size, and frequency of lymphatic invasion and lymph node metastasis, compared with the high CD47 expression group. In addition, the clinical tumor stage of the low CD47 expression group was significantly increased compared with that of the high CD47 expression group. Conversely, in PB, the high CD47 expression group had a significantly higher frequency of lymphatic invasion and lymph node metastasis compared with the low CD47 expression group. The lymphocyte fraction exhibited the highest CD47 expression compared with the other fractions in PB and BM samples. Low expression of CD47 was associated with the advancement of gastric cancer, in contrast to other cancers, and it may be associated with a decrease in lymphocytes during later stages. These results indicate that CD47 expression in the PB and BM may serve as a marker to analyze the immunological function of patients with gastric cancer; however, the significance of CD47 in gastric cancer requires further study.

[1]  T. Sano.  Gastric cancer: Asia and the world , 2017, Gastric Cancer.

[2]  F. Ciardiello,et al.  Prognostic implications of baseline neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) in metastatic gastric cancer (GC) patients , 2016 .

[3]  Japanese Gastric Cancer Association.  Japanese gastric cancer treatment guidelines 2014 (ver. 4) , 2016, Gastric Cancer.

[4]  yang-xin fu,et al.  CD47 Blockade Triggers T cell-mediated Destruction of Immunogenic Tumors , 2015, Nature Medicine.

[5]  Kazumichi Yoshida,et al.  CD47 is an adverse prognostic factor and a therapeutic target in gastric cancer , 2015, Cancer medicine.

[6]  Hiroshi Nishimoto,et al.  An updated report on the trends in cancer incidence and mortality in Japan, 1958-2013. , 2015, Japanese journal of clinical oncology.

[7]  Lijin Feng,et al.  Prognostic Significance of Neutrophil Lymphocyte Ratio in Patients with Gastric Cancer: A Meta-Analysis , 2014, PloS one.

[8]  S. Shin,et al.  Pre-treatment neutrophil to lymphocyte ratio as a prognostic marker to predict chemotherapeutic response and survival outcomes in metastatic advanced gastric cancer , 2014, Gastric Cancer.

[9]  Ş. Balta,et al.  Neutrophil-to-Lymphocyte Ratio in Prognosis of Gastric Cancer , 2013, Journal of gastric cancer.

[10]  N. Rogers,et al.  Therapeutic opportunities for targeting the ubiquitous cell surface receptor CD47 , 2013, Expert opinion on therapeutic targets.

[11]  A. Jemal,et al.  Cancer statistics, 2013 , 2013, CA: a cancer journal for clinicians.

[12]  T. Osaki,et al.  Increased apoptosis and elevated Fas expression in circulating natural killer cells in gastric cancer patients , 2013, Gastric Cancer.

[13]  J. Lee,et al.  Prognostic significance of neutrophil lymphocyte ratio and platelet lymphocyte ratio in advanced gastric cancer patients treated with FOLFOX chemotherapy , 2013, BMC Cancer.

[14]  W. Hoffmann.  Stem cells, self-renewal and cancer of the gastric epithelium. , 2012, Current medicinal chemistry.

[15]  I. Weissman,et al.  The CD47-SIRPα pathway in cancer immune evasion and potential therapeutic implications. , 2012, Current opinion in immunology.

[16]  Ash A. Alizadeh,et al.  Therapeutic antibody targeting of CD47 eliminates human acute lymphoblastic leukemia. , 2011, Cancer research.

[17]  Tomotaka Sobue,et al.  Population-based survival of cancer patients diagnosed between 1993 and 1999 in Japan: a chronological and international comparative study. , 2011, Japanese journal of clinical oncology.

[18]  H. Shimada,et al.  High preoperative neutrophil-lymphocyte ratio predicts poor survival in patients with gastric cancer , 2010, Gastric Cancer.

[19]  K. Mimori,et al.  Correlated Expression of CD47 and SIRPA in Bone Marrow and in Peripheral Blood Predicts Recurrence in Breast Cancer Patients , 2010, Clinical Cancer Research.

[20]  Howard Y. Chang,et al.  Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells , 2009, Proceedings of the National Academy of Sciences.

[21]  I. Weissman,et al.  CD47 Is Upregulated on Circulating Hematopoietic Stem Cells and Leukemia Cells to Avoid Phagocytosis , 2009, Cell.

[22]  Ash A. Alizadeh,et al.  CD47 Is an Adverse Prognostic Factor and Therapeutic Antibody Target on Human Acute Myeloid Leukemia Stem Cells , 2009, Cell.

[23]  W. Hoffmann.  Regeneration of the gastric mucosa and its glands from stem cells. , 2008, Current medicinal chemistry.

[24]  Shigemi Matsumoto,et al.  The Baseline Ratio of Neutrophils to Lymphocytes Is Associated with Patient Prognosis in Advanced Gastric Cancer , 2008, Oncology.

[25]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[26]  C. Lagenaur,et al.  Role of CD47 as a marker of self on red blood cells. , 2000, Science.

[27]  M. Hirashima,et al.  The ratio of neutrophils to lymphocytes and the phenotypes of neutrophils in patients with early gastric cancer , 1998, Journal of Cancer Research and Clinical Oncology.

[28]  K. Mimori,et al.  The expression of tumor-rejection antigen "MAGE" genes in human gastric carcinoma. , 1995, Gastroenterology.

[29]  E. Brown,et al.  In vivo expression of alternatively spliced forms of integrin-associated protein (CD47). , 1995, Journal of cell science.

[30]  M. Tanner,et al.  Isolation and characterization of CD47 glycoprotein: a multispanning membrane protein which is the same as integrin-associated protein (IAP) and the ovarian tumour marker OA3. , 1994, The Biochemical journal.

[31]  P. Chomczyński,et al.  A reagent for the single-step simultaneous isolation of RNA, DNA and proteins from cell and tissue samples. , 1993, BioTechniques.

[32]  E. Lee.  Dynamic histology of the antral epithelium in the mouse stomach: III. Ultrastructure and renewal of pit cells. , 1985, The American journal of anatomy.

[33]  C. P. Leblond,et al.  Dynamic histology of the antral epithelium in the mouse stomach: II. Ultrastructure and renewal of isthmal cells. , 1985, The American journal of anatomy.