New molecular staging with G-factors (VEGF-C and Reg IV) by supplementing TNM classification in colorectal cancers

Sawada,Tetsuji; Yashiro,Masakazu; Sentani,Kazuhiro; Oue,Naohide; Yasui,Wataru; Miyazaki,Kohji; Kai,Keita; Fujita,Hideto; Nakamura,Keishi; Maeda,Kiyoshi; Kakeji,Yoshihiro; Natsugoe,Shoji; Shirabe,Ken; Nomura,Sachiyo; Shimada,Yutaka; Tomita,Naohiro; Hirakawa,Kosei; Maehara,Yoshihiko

doi:10.3892/or.2013.2787

December 2013 Volume 30 Issue 6

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

December 2013 Volume 30 Issue 6

Full Size Image

Article Open Access

New molecular staging with G-factors (VEGF-C and Reg IV) by supplementing TNM classification in colorectal cancers

Authors:
- Tetsuji Sawada
- Masakazu Yashiro
- Kazuhiro Sentani
- Naohide Oue
- Wataru Yasui
- Kohji Miyazaki
- Keita Kai
- Hideto Fujita
- Keishi Nakamura
- Kiyoshi Maeda
- Yoshihiro Kakeji
- Shoji Natsugoe
- Ken Shirabe
- Sachiyo Nomura
- Yutaka Shimada
- Naohiro Tomita
- Kosei Hirakawa
- Yoshihiko Maehara
View Affiliations / Copyright

Affiliations: Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan, Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan, Department of Surgery, Saga University Faculty of Medicine, Saga, Japan, Department of Pathology and Microbiology, Saga University Faculty of Medicine, Saga, Japan, Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan, Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe, Japan, Department of Surgical Oncology and Digestive Surgery, Kagoshima University School of Medicine, Kagoshima, Japan, Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan, Department of Gastrointestinal Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan, Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama, Japan, Division of Lower GI, Department of Surgery, Hyogo College of Medicine, Hyogo, Japan

Copyright: © Sawada et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].
Pages: 2609-2616
|
Published online on: October 3, 2013

https://doi.org/10.3892/or.2013.2787
Expand metrics +

Abstract

Staging classification of colorectal cancers is performed by the UICC/TNM classification system, which is the global gold standard. However, we often experience in clinical practice that there are considerable differences in prognoses between patients who have the same classification particularly in stage II and III cancers. The aim of this study was to propose a new TNM-G classification to predict prognosis and recurrence by supplementing the conventional TNM classification. A total of 220 cases of colorectal cancer, including 77 at stage II and 143 at stage III, were registered from four independent facilities. Immunohistochemical staining for 7 molecules, such as p53, vascular endothelial growth factor (VEGF)-A, VEGF-C, regenerating islet-derived family, member 4 (Reg IV), olfactomedin 4, Claudin-18 and matrix metalloproteinase-7 (MMP‑7), was performed to investigate the correlation between clinicopathological factors and expression of each molecule. Based on the results, no significant correlation was observed between the immunostaining expression of these 7 factors and recurrence in total colorectal cancer. Recurrence in stage II (77 cases) was significantly higher in cases positive for Reg IV expression (P=0.042). On analysis of overall survival (OS) and disease‑free survival (DFS), VEGF-C and Reg IV expression had a correlation with poor prognosis, therefore, these factors were selected and applied to G-factor classifications so that cases negative for both could be classified as G0, cases positive for either of the factors could be classified as G1, and cases positive for both factors could be classified as G2. While no significant correlation was observed in the recurrence rates between G0 and G2, OS and DFS in stage II cases were significantly poorer for G2 cases in comparison with G0 or G1 cases. The survival curves of OS and DFS in stage II G2 were similar to that of stage III cases. According to these results, prognosis of VEGF-C/Reg IV both positive G2 cases in stage II colorectal cancer was found to be almost equal to the poor survival in stage III cases, and the advancement of one stage up migration based on G-factors may be supposed to be highly feasible for clinical application. In conclusion, the combination of VEGF-C and Reg IV may be a promising factor for clinical staging to supplement the classical TNM classification system, and it may suggest a good indication of adjuvant chemotherapy for G2 cases in stage II colorectal cancers.

View Figures

View References

1	Sobin LH: TNM, sixth edition: new developments in general concepts and rules. Semin Surg Oncol. 21:19–22. 2003. View Article : Google Scholar : PubMed/NCBI
2	Tanigawa N, Amaya H, Matsumura M and Shimomatsuya T: Correlation between expression of vascular endothelial growth factor and tumor vascularity, and patient outcome in human gastric carcinoma. J Clin Oncol. 15:826–832. 1997.
3	Maeda K, Kang SM, Onoda N, et al: Expression of p53 and vascular endothelial growth factor associated with tumor angiogenesis and prognosis in gastric cancer. Oncology. 55:594–599. 1998. View Article : Google Scholar : PubMed/NCBI
4	Maehara Y, Tomoda M, Hasuda S, et al: Prognostic value of p53 protein expression for patients with gastric cancer - a multivariate analysis. Br J Cancer. 79:1255–1261. 1999. View Article : Google Scholar : PubMed/NCBI
5	Kakeji Y, Koga T, Sumiyoshi Y, et al: Clinical significance of vascular endothelial growth factor expression in gastric cancer. J Exp Clin Cancer Res. 21:125–129. 2002.PubMed/NCBI
6	Fondevila C, Metges JP, Fuster J, et al: p53 and VEGF expression are independent predictors of tumour recurrence and survival following curative resection of gastric cancer. Br J Cancer. 90:206–215. 2004. View Article : Google Scholar : PubMed/NCBI
7	Resnick MB, Routhier J, Konkin T, Sabo E and Pricolo VE: Epidermal growth factor receptor, c-MET, beta-catenin, and p53 expression as prognostic indicators in stage II colon cancer: a tissue microarray study. Clin Cancer Res. 10:3069–3075. 2004. View Article : Google Scholar : PubMed/NCBI
8	White JD, Hewett PW, Kosuge D, et al: Vascular endothelial growth factor-D expression is an independent prognostic marker for survival in colorectal carcinoma. Cancer Res. 62:1669–1675. 2002.PubMed/NCBI
9	Des Guetz G, Uzzan B, Nicolas P, et al: Microvessel density and VEGF expression are prognostic factors in colorectal cancer. Meta-analysis of the literature. Br J Cancer. 94:1823–1832. 2006.PubMed/NCBI
10	Oue N, Kuniyasu H, Noguchi T, et al: Serum concentration of Reg IV in patients with colorectal cancer: overexpression and high serum levels of Reg IV are associated with liver metastasis. Oncology. 72:371–380. 2007. View Article : Google Scholar : PubMed/NCBI
11	Oue N, Mitani Y, Aung PP, et al: Expression and localization of Reg IV in human neoplastic and non-neoplastic tissues: Reg IV expression is associated with intestinal and neuroendocrine differentiation in gastric adenocarcinoma. J Pathol. 207:185–198. 2005. View Article : Google Scholar : PubMed/NCBI
12	Oue N, Sentani K, Noguchi T, et al: Serum olfactomedin 4 (GW112, hGC-1) in combination with Reg IV is a highly sensitive biomarker for gastric cancer patients. Int J Cancer. 125:2383–2392. 2009. View Article : Google Scholar : PubMed/NCBI
13	Sanada Y, Oue N, Mitani Y, Yoshida K, Nakayama H and Yasui W: Down-regulation of the claudin-18 gene, identified through serial analysis of gene expression data analysis, in gastric cancer with an intestinal phenotype. J Pathol. 208:633–642. 2006. View Article : Google Scholar : PubMed/NCBI
14	Ajisaka H, Yonemura Y and Miwa K: Correlation of lymph node metastases and expression of matrix metalloproteinase-7 in patients with gastric cancer. Hepatogastroenterology. 51:900–905. 2004.PubMed/NCBI
15	Japanese Society for Cancer of the Colon and Rectum. Japanese Classification of Colorectal Carcinoma. 7th edition. Kanehara; Tokyo: 2009
16	Mejia A, Schulz S, Hyslop T, Weinberg DS and Waldman SA: Molecular staging individualizing cancer management. J Surg Oncol. 105:468–474. 2012. View Article : Google Scholar : PubMed/NCBI
17	Eschrich S, Yang I, Bloom G, et al: Molecular staging for survival prediction of colorectal cancer patients. J Clin Oncol. 23:3526–3535. 2005. View Article : Google Scholar : PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

New molecular staging with G-factors (VEGF-C and Reg IV) by supplementing TNM classification in colorectal cancers

This article is mentioned in:

Abstract

Figure 1

Figure 2

Figure 3

Related Articles