Serum levels of vascular endothelial growth factor are increased and correlate with malnutrition, immunosuppression involving MDSCs and systemic inflammation in patients with cancer of the digestive system

Nakamura,Izumi; Shibata,Masahiko; Gonda,Kenji; Yazawa,Takashi; Shimura,Tatsuo; Anazawa,Takayuki; Suzuki,Satoshi; Sakurai,Kenichi; Koyama,Yoshihisa; Ohto,Hitoshi; Tomita,Ryouichi; Gotoh,Mitsukazu; Takenoshita,Seiichi

doi:10.3892/ol.2013.1231

Serum levels of vascular endothelial growth factor are increased and correlate with malnutrition, immunosuppression involving MDSCs and systemic inflammation in patients with cancer of the digestive system

Authors:
- Izumi Nakamura
- Masahiko Shibata
- Kenji Gonda
- Takashi Yazawa
- Tatsuo Shimura
- Takayuki Anazawa
- Satoshi Suzuki
- Kenichi Sakurai
- Yoshihisa Koyama
- Hitoshi Ohto
- Ryouichi Tomita
- Mitsukazu Gotoh
- Seiichi Takenoshita
View Affiliations

Affiliations: Department of Organ Regulatory Surgery, Fukushima Medical University, Fukushima 960‑1295, Japan, Department of Tumor and Host Bioscience, Fukushima Medical University, Fukushima 960‑1295, Japan, Department of Regenerative Surgery, Fukushima Medical University, Fukushima 960‑1295, Japan, Department of Surgery, Nihon University School of Medicine, Itabashi, Tokyo 173‑8610, Japan, Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University, Fukushima 960‑1295, Japan, Department of Surgery, Nippon Dental University, Chiyoda, Tokyo 102‑8158, Japan
Published online on: March 6, 2013 https://doi.org/10.3892/ol.2013.1231
Pages: 1682-1686

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Vascular endothelial growth factor (VEGF) reportedly has an important role in the progression of malignant neoplasms and has been reported to induce myeloid‑derived suppressor cells (MDSCs) that appear in cancer and inflammation. In the present study, serum concentrations of VEGF were measured in patients with digestive system cancer and the correlations with nutritional damage, immune suppression and systemic inflammation were analyzed. A significant increase in VEGF serum levels was observed in patients with esophageal, gastric and colorectal cancers compared with healthy volunteers. Levels of VEGF were inversely correlated with the serum concentrations of albumin, prealbumin and retinol‑binding protein. The serum concentrations of VEGF were inversely correlated with the production of interleukin (IL)‑12 and correlated with MDSC counts. VEGF levels were also correlated with neutrophil and neutrophil/lymphocyte counts and inversely correlated with lymphocyte count. Serum VEGF levels were divided at a cutoff of 500 pg/ml, with levels of prealbumin and retinol‑binding protein significantly decreased in patients with higher VEGF levels. The stimulation index and IL‑12 production were significantly decreased in the group with higher VEGF levels and MDSC counts tended to be higher in this group. These results demonstrated that increased production of VEGF was correlated with systemic inflammation, nutritional impairment and the inhibition of cell‑mediated immunity involving MDSCs.

View Figures

View References

1	Goldman E: The growth of malignant disease in man and the lower animals with special reference to the vascular system. Proc R Soc Med. 1:1–13. 1907.
2	Folkman J: Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1:27–31. 1995. View Article : Google Scholar : PubMed/NCBI
3	Senger DR, Galli SJ, Dvorak AM, et al: Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 219:983–985. 1983. View Article : Google Scholar
4	Ferrara N: Vascular endothelial growth factor and the regulation of angiogenesis. Recent Prog Horm Res. 55:15–36. 2000.PubMed/NCBI
5	Terheyden P, Schrama D, Pedersen LØ, et al: Longitudinal analysis of MART-1/HLA-A2-reactive T cells over the course of melanoma progression. Scand J Immunol. 58:566–571. 2003. View Article : Google Scholar : PubMed/NCBI
6	Gabrilovich DI and Nagaraj S: Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 9:162–174. 2009. View Article : Google Scholar : PubMed/NCBI
7	Rosenberg SO and Sinha P: Myeloid-derived suppressor cells: Linking inflammation and cancer. J Immunol. 182:4499–4506. 2009. View Article : Google Scholar : PubMed/NCBI
8	Rubin H: Cancer cachexia: its correlations and causes. Proc Natl Acad Sci USA. 100:5384–5389. 2003. View Article : Google Scholar : PubMed/NCBI
9	Deans C and Wigmore SJ: Systemic inflammation, cachexia and prognosis in patients with cancer. Curr Opin Clin Nutr Metab Care. 8:265–269. 2005. View Article : Google Scholar : PubMed/NCBI
10	Kajdaniuk D, Marek B, Foltyn W and Kos-Kudła B: Vascular endothelial growth factor (VEGF) - part 2: in endocrinology and oncology. Endokrynol Pol. 62:456–464. 2011.PubMed/NCBI
11	Sanz R, Ovejero VJ, González JJ, et al: Mortality risk scales in esophagotomy for cancer: their usefulness in preoperative patient selection. Hepatogastroenterology. 53:869–873. 2006.PubMed/NCBI
12	Oñate-Ocaña LF, Aiello-Crocifoglio V, Gallardo-Rincón D, et al: Serum albumin as a significant prognostic factor for patients with gastric carcinoma. Ann Surg Oncol. 14:381–389. 2007.PubMed/NCBI
13	Chua W, Charles KA, Baracos VE and Clarke SJ: Neutrophil/lymphocyte ratio predicts chemotherapy outcomes in patients with advanced colorectal cancer. Br J Cancer. 104:1288–1295. 2011. View Article : Google Scholar : PubMed/NCBI
14	Cho H, Hur HW, Kim SW, et al: Pre-treatment neutrophil to lymphocyte ratio is elevated in epithelial ovarian cancer and predicts survival after treatment. Cancer Immunol Immunother. 58:15–23. 2009. View Article : Google Scholar : PubMed/NCBI
15	Nevala WK, Vachon CM, Leontovich AA, Scott CG, Thompson MA and Markovic SN: Melanoma Study Group of the Mayo Clinic Cancer Center: Evidence of systemic Th2-driven chronic inflammation in patients with metastatic melanoma. Clin Cancer Res. 15:1931–1939. 2009. View Article : Google Scholar : PubMed/NCBI
16	Coussens LM and Werb Z: Inflammation and cancer Nature. 420:860–868. 2002.
17	Shibata M, Shimura T, Gonda K, Suzuki S, Nakamura I, Ohki S and Takenoshita S: Myeloid-Derived Suppressor Cells (MDSC) is increased and correlated to immune suppression, nutritional impairment and inflammatory markers in patients with gastrointestinal cancer. In: 2012 ASCO Gastrointestinal Cancer Symposium (Abstract 675); 2012
18	Ohki S, Shibata M, Gonda K, et al: Circulating myeloid-derived suppressor cells are increased and correlate to immune suppression, inflammation and hypoalbuminemia in patients with cancer. Oncol Rep. 28:453–458. 2012.PubMed/NCBI
19	Gabrilovich DI, Chen DL, Girgis KR, et al: Production of vascular endothelial growth factor by human tumors inhibits the functional maduration of dendritic cells. Nat Med. 2:1096–1103. 1996. View Article : Google Scholar : PubMed/NCBI
20	Menetrier-Caux C, Montmain G, Dieu MC, et al: Inhibition of the differentiation of dendritic cells from CD34(+) progenitors by tumor cells: role of interleukin-6 and macrophage colony-stimulating factor. Blood. 92:4778–4791. 1998.
21	Gabrilovich D, Ishida T, Oyama T, et al: Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood. 92:4150–4166. 1998.