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      The Prognostic Value of Tumor-Infiltrating Neutrophils in Gastric Adenocarcinoma after Resection

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          Abstract

          Background

          Several pieces of evidence indicate that tumor-infiltrating neutrophils (TINs) are correlated to tumor progression. In the current study, we explore the relationship between TINs and clinicopathological features of gastric adenocarcinoma patients. Furthermore, we investigated the prognostic value of TINs.

          Patients and Methods

          The study was comprised of two groups, training group (115 patients) and test group (97 patients). Biomarkers (intratumoral CD15+ neutrophils) were assessed by immunohistochemistry. The relationship between clinicopathological features and patient outcome were evaluated using Cox regression and Kaplan-Meier analysis.

          Results

          Immunohistochemical detection showed that the tumor-infiltrating neutrophils (TINs) in the training group ranged from 0.00–115.70 cells/high-power microscopic field (HPF) and the median number was 21.60 cells/HPF. Based on the median number, the patients were divided into high and low TINs groups. Chi-square test analysis revealed that the density of CD15+ TINs was positively associated with lymph node metastasis (p = 0.024), distance metastasis (p = 0.004) and UICC (International Union Against Cancer) staging (p = 0.028). Kaplan-Meier analysis showed that patients with a lower density of TINs had a better prognosis than patients with a higher density of TINs (p = 0.002). Multivariate Cox's analysis showed that the density of CD15+ TINs was an independent prognostic factor for overall survival of gastric adenocarcinoma patients. Using another 97 patients as a test group and basing on the median number of TINs (21.60 cells/HPF) coming from the training group, Kaplan-Meier analysis also showed that patients with a lower density of TINs had a better prognosis than patients with a higher density of TINs (p = 0.032). The results verify that the number of CD15+ TINs can predict the survival of gastric adenocarcinoma surgical patients.

          Conclusions

          The presence of CD15+ TINs is an independent and unfavorable factor in the prognosis of gastric adenocarcinoma patients. Targeting CD15+ TINs may be a potential intervenient therapy in the future.

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          Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis.

          Hiroaki Nozawa, Christopher Chiu, Douglas Hanahan (2006)
          Matrix metalloprotease type 9 (MMP-9) has been functionally implicated in VEGF activation, the induction and maintenance of chronic angiogenesis, and early stage tumor growth in a number of mouse models of cancer. In this article, we have identified two inflammatory cell types that are major sources of MMP-9 in the angiogenic stages of pancreatic islet carcinogenesis that unfold in RIP1-Tag2 transgenic mice. MMP-9-expressing neutrophils were predominantly found inside angiogenic islet dysplasias and tumors, whereas MMP-9-expressing macrophages were localized along the periphery of such lesions. Transient depletion of neutrophils significantly suppressed VEGF:VEGF-receptor association, a signature of MMP-9 activity, and markedly reduced the frequency of initial angiogenic switching in dysplasias. Thus infiltrating neutrophils can play a crucial role in activating angiogenesis in a previously quiescent tissue vasculature during the early stages of carcinogenesis.
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            Breast cancer cells stimulate neutrophils to produce oncostatin M: potential implications for tumor progression.

            Marisa Queen, Randall E Ryan, Ryan Holzer … (2005)
            Tumor-associated and tumor-infiltrating neutrophils (TAN) and macrophages (TAM) can account for as much as 50% of the total tumor mass in invasive breast carcinomas. It is thought that tumors secrete factors that elicit a wound-repair response from TAMs and TANs and that this response inadvertently stimulates tumor progression. Oncostatin M is a pleiotropic cytokine belonging to the interleukin-6 family that is expressed by several cell types including activated human T lymphocytes, macrophages, and neutrophils. Whereas oncostatin M can inhibit the proliferation of breast cancer cells in vitro, recent studies suggest that oncostatin M may promote tumor progression by enhancing angiogenesis and metastasis. In addition, neutrophils can be stimulated to synthesize and rapidly release large quantities of oncostatin M. In this article, we show that human neutrophils secrete oncostatin M when cocultured with MDA-MB-231 and T47D human breast cancer cells. Neutrophils isolated from whole blood or breast cancer cells alone express little oncostatin M by immunocytochemistry and ELISA, but neutrophils express and release high levels of oncostatin M when they are cocultured with breast cancer cells. In addition, we show that granulocyte-macrophage colony-stimulating factor produced by breast cancer cells and cell-cell contact are both necessary for the release of oncostatin M from neutrophils. Importantly, neutrophil-derived oncostatin M induces vascular endothelial growth factor from breast cancer cells in coculture and increases breast cancer cell detachment and invasive capacity, suggesting that neutrophils and oncostatin M may promote tumor progression in vivo.
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              The Baseline Ratio of Neutrophils to Lymphocytes Is Associated with Patient Prognosis in Advanced Gastric Cancer

              Takeharu Yamanaka, Shigemi Matsumoto, Satoshi Teramukai … (2008)
              Objective: In cancer patients, the balance between neutrophil (N) and lymphocyte (L) cell counts fluctuates with advancing disease. The objective of our study was to determine the prognostic implications of the N/L ratio in the peripheral blood of gastric cancer patients. Methods: Study participants were identified from a prospective cohort of patients with advanced gastric cancer in Japan (n = 1,220). Results: The median baseline N/L was 2.58 (range, 0.63–12.7). Univariate analysis revealed that patients with an N/L ≧2.5 (n = 644) had a significantly poorer prognosis than those with an N/L –12 ). The median survival times for these two groups were 239 (95% confidence interval, CI, 217–251 days) and 363 days (95% CI, 334–406 days), respectively, while the 1-year survival rates were 30 (95% CI, 26–34%) and 50% (95% CI, 45–54%), respectively. A multivariate Cox model established a significant relationship between the N/L ratio and survival (adjusted hazard ratio = 1.52; 95% CI, 1.32–1.75; p = 0.077 × 10 –8 ). Conclusions: These results suggest that the N/L ratio is an independent prognostic factor in advanced gastric cancer. Measurement of this ratio may serve as a clinically accessible and useful biomarker for patient survival.
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2012
                Publication date (Electronic): 19 March 2012
                Volume: 7
                Issue: 3
                Electronic Location Identifier: e33655
                Affiliations
                [1 ]State Key Laboratory of Oncology in Southern China and Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
                [2 ]Department of Gastric and Pancreatic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
                [3 ]Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
                [4 ]First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, People's Republic of China
                Tufts University, United States of America
                Author notes

                Conceived and designed the experiments: KP XDL JCX. Performed the experiments: JJZ KP WW JGC. Analyzed the data: JJZ YHW LL JJL YBC DDW QZP. Contributed reagents/materials/analysis tools: WW. Wrote the paper: JJZ KP.

                Article
                Publisher ID: PONE-D-11-17116
                DOI: 10.1371/journal.pone.0033655
                PMC ID: 3307751
                PubMed ID: 22442706
                SO-VID: 24dd5577-a837-4652-94c4-03f0e931b305
                Copyright © Zhao et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 1 September 2011
                Date accepted : 17 February 2012
                Page count
                Pages: 6
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Anatomy and Physiology
                Subject: Immune Physiology
                Subject: Immunology
                Subject: Molecular Cell Biology
                Subject: Cellular Types
                Subject: Medicine
                Subject: Anatomy and Physiology
                Subject: Immune Physiology
                Subject: Clinical Immunology
                Subject: Diagnostic Medicine
                Subject: Pathology
                Subject: General Pathology
                Subject: Gastroenterology and Hepatology
                Subject: Oncology
                Subject: Basic Cancer Research
                Subject: Cancers and Neoplasms
                Subject: Gastrointestinal Tumors

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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