Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Diagnostic Pathology
Published in: Diagnostic Pathology 1/2013

Open Access 01-12-2013 | Research

Inducible nitric oxide synthase expression in gastric adenocarcinoma: impact on lymphangiogenesis and lymphatic metastasis

Authors: Nimet Karadayı, Nilufer Onak Kandemır, Dilek Yavuzer, Taner Korkmaz, Gonca Gecmen, Furuzan Kokturk

Published in: Diagnostic Pathology | Issue 1/2013

Login to get access

Abstract

Background

Lymphatic metastasis is the most important parameter in the spread of gastric carcinomas. Nitric oxide (NO) is a signaling molecule that plays an important role in inflammation and carcinogenesis. In this study, the possible link between inducible nitric oxide synthase (iNOS) expression with lymphangiogenesis and the clinicopathological parameters of gastric carcinomas was investigated.

Methods

In this study, iNOS expression and D2-40 (lymphatic endothelium-specific marker monoclonal antibody) reactivity were examined immunohistochemically in 41 gastric adenocarcinoma and 20 non-neoplastic gastric tissues. iNOS expression was scored semiquantitatively in the tumor parenchyma and stroma. D2-40-positive lymphatic vessels were used in the determination of lymphatic invasion and intratumoral and peritumoral lymphatic vascular density.

Results

iNOS expression was higher in gastric carcinoma tissue compared with non-neoplastic tissue. Particularly, iNOS expression in tumor cells was found to be closely related to lymphangiogenesis and lymphatic metastasis. The density of lymphatic invasion as well as intratumoral and peritumoral lymphatic vascular density were positively correlated with lymph node metastasis.

Conclusions

Our results suggest that iNOS-mediated NO formation plays an important role in gastric carcinogenesis, tumor lymphangiogenesis, and the development of lymphatic metastases. Inhibition of the NO pathway may be an alternative treatment of gastric carcinomas.

Virtual slides

The virtual slides for this article can be found here: http://​www.​diagnosticpathol​ogy.​diagnomx.​eu/​vs/​1713572940104388​.
Appendix
Available only for authorised users
Literature
1.
Yamaguchi T, Fujimori T, Tomita S, Ichikawa K, Mitomi H, Ohno K, Shida Y, Kato H: Clinical validation of the gastrointestinal NET grading system: Ki67 index criteria of the WHO 2010 classification is appropriate to predict metastasis or recurrence. Diagn Pathol. 2013, 22 (8): 65-CrossRef
2.
Ziche M, Morbidelli L: Molecular regulation of tumour angiogenesis by nitric oxide. Eur Cytokine Netw. 2009, 20 (4): 164-170.PubMed
3.
Singh S, Gupta AK: Nitric oxide: role in tumour biology and iNOS/NO-based anticancer therapies. Cancer Chemother Pharmacol. 2011, 67 (6): 1211-1224. 10.1007/s00280-011-1654-4.CrossRefPubMed
4.
Burke AJ, Sullivan FJ, Giles FJ, Glynn SA: The yin and yang of nitric oxide in cancer progression. Carcinogenesis. 2013, 34 (3): 503-512. 10.1093/carcin/bgt034.CrossRefPubMed
5.
Zhang W, He XJ, Ma YY, Wang HJ, Xia YJ, Zhao ZS, Ye ZY, Tao HQ: Inducible nitric oxide synthase expression correlates with angiogenesis, lymphangiogenesis, and poor prognosis in gastric cancer patients. Hum Pathol. 2011, 42 (9): 1275-1282. 10.1016/j.humpath.2010.09.020.CrossRefPubMed
6.
Lahdenranta J, Hagendoorn J, Padera TP, Hoshida T, Nelson G, Kashiwagi S, Jain RK, Fukumura D: Endothelial nitric oxide synthase mediates lymphangiogenesis and lymphatic metastasis. Cancer Res. 2009, 69 (7): 2801-2808. 10.1158/0008-5472.CAN-08-4051.PubMedCentralCrossRefPubMed
7.
Massi D, De Nisi MC, Franchi A, Mourmouras V, Baroni G, Panelos J, Santucci M, Miracco C: Inducible nitric oxide synthase expression in melanoma: implications in lymphangiogenesis. Mod Pathol. 2009, 22 (1): 21-30. 10.1038/modpathol.2008.128.CrossRefPubMed
8.
Franchi A, Massi D, Santucci M, Masini E, Rossi Degl’Innocenti D, Magnelli L, Fanti E, Naldini A, Ardinghi C, Carraro F, Gallo O: Inducible nitric oxide synthase activity correlates with lymphangiogenesis and vascular endothelial growth factor-C expression in head and neck squamous cell carcinoma. J Pathol. 2006, 208 (3): 439-445. 10.1002/path.1892.CrossRefPubMed
9.
Rajnakova A, Moochhala S, Goh PM, Ngoi S: Expression of nitric oxide synthase, cyclooxygenase, and p53 in different stages of human gastric cancer. Cancer Lett. 2001, 172: 177-185. 10.1016/S0304-3835(01)00645-0.CrossRefPubMed
10.
Feng CW, Wang LD, Jiao LH, Liu B, Zheng S, Xie XJ: Expression of p53, inducible nitric oxide synthase and vascular endothelial growth factor in gastric precancerous and cancerous lesions: correlation with clinical features. BMC Cancer. 2002, 2: 8-14. 10.1186/1471-2407-2-8.PubMedCentralCrossRefPubMed
11.
Wang YZ, Cao YQ, Wu JN, Chen M, Cha XY: Expression of nitric oxide synthase in human gastric carcinoma and its relation to p53, PCNA. World J Gastroenterol. 2005, 11 (1): 46-50.PubMedCentralCrossRefPubMed
12.
Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A: AJCC cancer staging manual. 2010, New York: Springer-Verlag, 299-323. 7
13.
Shan L, Ying J, Lu N: HER2 expression and relevant clinicopathological features in gastric and gastroesophageal junction adenocarcinoma in a Chinese population. Diagn Pathol. 2013, 9 (8): 76-CrossRef
14.
Bosman FT: World health organization; ınternational agency for research on cancer. WHO classification of tumours of the digestive system. 2010, Lyon: IARC Press, 4
15.
Sotoudeh K, Hashemi F, Madjd Z, Sadeghipour A, Molanaei S, Kalantary E: The clinicopathologic association of c-MET overexpression in Iranian gastric carcinomas; an immunohistochemical study of tissue microarrays. Diagn Pathol. 2012, 28 (7): 57-CrossRef
16.
Yamauchi C, Hasebe T, Iwasaki M, Imoto S, Wada N, Fukayama M, Ochiai A: Accurate assessment of lymph vessel tumor emboli in invasive ductal carcinoma of the breast according to tumor areas, and their prognostic significance. Hum Pathol. 2007, 38: 247-259. 10.1016/j.humpath.2006.07.017.CrossRefPubMed
17.
Klintrup K, Mäkinen JM, Kauppila S, Väre PO, Melkko J, Tuominen H, Tuppurainen K, Mäkelä J, Karttunen TJ, Mäkinen MJ: Inflammation and prognosis in colorectal cancer. Eur J Cancer. 2005, 41 (17): 2645-2654. 10.1016/j.ejca.2005.07.017.CrossRefPubMed
18.
Li LG, Xu HM: Inducible nitric oxide synthase, nitrotyrosine and apoptosis in gastric adenocarcinomas and their correlation with a poor survival. World J Gastroenterol. 2005, 11 (17): 2539-2544.PubMedCentralCrossRefPubMed
19.
Koh E, Noh SH, Lee YD, Lee HY, Han JW, Lee HW, Hong S: Differential expression of nitric oxide synthase in human stomach cancer. Cancer Lett. 1999, 146 (2): 173-180. 10.1016/S0304-3835(99)00265-7.CrossRefPubMed
20.
Puhakka A, Kinnula V, Näpänkangas U, Säily M, Koistinen P, Pääkkö P, Soini Y: High expression of nitric oxide synthases is a favorable prognostic sign in non-small cell lung carcinoma. APMIS. 2003, 111 (12): 1137-1146. 10.1111/j.1600-0463.2003.apm1111210.x.CrossRefPubMed
21.
Grossklaus DJ, Coffey CS, Shappell SB, Jack GS, Chang SS, Cookson MS: Percent of cancer in the biopsy set predicts pathological findings after prostatectomy. J Urol. 2002, 167: 2032-2035. 10.1016/S0022-5347(05)65077-X.CrossRefPubMed
22.
Weidner N: Current pathologic methods for measuring intratumoral microvessel density within breast carcinoma and other solid tumors. Breast Cancer Res Treat. 1995, 36: 169-180. 10.1007/BF00666038.CrossRefPubMed
23.
Vermeulen PB, Gasparini G, Fox SB, Colpaert C, Marson LP, Gion M, Beliën JA, de Waal RM, Van Marck E, Magnani E, Weidner N, Harris AL, Dirix LY: Second international consensus on the methodology and criteria of evaluation of angiogenesis quantification in solid human tumours. Eur J Cancer. 2002, 38 (12): 1564-1579. 10.1016/S0959-8049(02)00094-1.CrossRefPubMed
24.
Van der Auwera I, Cao Y, Tille JC, Pepper MS, Jackson DG, Fox SB, Harris AL, Dirix LY, Vermeulen PB: First international consensus on the methodology of lymphangiogenesis quantification in solid human tumours. Br J Cancer. 2006, 95 (12): 1611-1625. 10.1038/sj.bjc.6603445.PubMedCentralCrossRefPubMed
25.
Kawamura L, Carvalho FM, Alves BG, Bacchi CE, Goes JC, Calil MA, Baracat EC, Carvalho JP: Association between intratumoral lymphatic microvessel density (LMVD) and clinicopathologic features in endometrial cancer: a retrospective cohort study. World J Surg Oncol. 2010, 8: 89-10.1186/1477-7819-8-89. doi:10.1186/1477-7819-8-89PubMedCentralCrossRefPubMed
26.
Kandemir NO, Barut F, Bektas S, Ozdamar SO: Can lymphatic vascular density be used in determining metastatic spreading potential of tumor in invasive ductal carcinomas?. Pathol Oncol Res. 2012, 18 (2): 253-262. 10.1007/s12253-011-9436-1.CrossRefPubMed
27.
Jin J, Jin T, Quan M, Piao Y, Lin Z: Ezrin overexpression predicts the poor prognosis of gastric adenocarcinoma. Diagn Pathol. 2012, 5 (7): 135-CrossRef
28.
Brabletz T, Hlubek F, Spaderna S, Schmalhofer O, Hiendlmeyer E, Jung A, Kirchner T: EMT: ınvasion and metastasis in colorectal cancer: epithelial-mesenchymal transition, mesenchymal-epithelial transition, stem cells and β-catenin. Cells Tissues Organs. 2005, 179: 56-65. 10.1159/000084509.CrossRefPubMed
29.
Thomsen LL, Miles DW: Role of nitric oxide in tumour progression: lessons from human tumours. Cancer Metastasis Rev. 1998, 17 (1): 107-118. 10.1023/A:1005912906436.CrossRefPubMed
30.
Rinderknecht M, Detmar M: Tumor lymphangiogenesis and melanoma metastasis. J Cell Physiol. 2008, 216 (2): 347-354. 10.1002/jcp.21494.CrossRefPubMed
31.
Weryńska B, Dziegiel P, Jankowska R: Role of lymphangiogenesis in lung cancer. Folia Histochem Cytobiol. 2009, 47 (3): 333-342.PubMed
32.
Khromova N, Kopnin P, Rybko V, Kopnin BP: Downregulation of VEGF-C expression in lung and colon cancer cells decelerates tumor growth and inhibits metastasis via multiple mechanisms. Oncogene. 2012, 31 (11): 1389-1397. 10.1038/onc.2011.330.CrossRefPubMed
33.
Van der Auwera I, Van den Eynden GG, Colpaert CG, Van Laere SJ, van Dam P, Van Marck EA, Dirix LY, Vermeulen PB: Tumor lymphangiogenesis in inflammatory breast carcinoma: a histomorphometric study. Clin Cancer Res. 2005, 11 (21): 7637-7642. 10.1158/1078-0432.CCR-05-1142.CrossRefPubMed
34.
Miyahara M, Tanuma J, Sugihara K, Semba I: Tumor lymphangiogenesis correlates with lymph node metastasis and clinicopathologic parameters in oral squamous cell carcinoma. Cancer. 2007, 110 (6): 1287-1294. 10.1002/cncr.22900.CrossRefPubMed
35.
Agarwal B, Saxena R, Morimiya A, Mehrotra S, Badve S: Lymphangiogenesis does not occur in breast cancer. Am J Surg Pathol. 2005, 29 (11): 1449-1455. 10.1097/01.pas.0000174269.99459.9d.CrossRefPubMed
36.
van der Schaft DW, Pauwels P, Hulsmans S, Zimmermann M, van de Poll-Franse LV, Griffioen AW: Absence of lymphangiogenesis in ductal breast cancer at the primary tumor site. Cancer Lett. 2007, 254 (1): 128-136. 10.1016/j.canlet.2007.03.001.CrossRefPubMed
37.
Zhao YC, Ni XJ, Li Y, Dai M, Yuan ZX, Zhu YY, Luo CY: Peritumoral lymphangiogenesis induced by vascular endothelial growth factor C and D promotes lymph node metastasis in breast cancer patients. World J Surg Oncol. 2012, 10: 165-10.1186/1477-7819-10-165.PubMedCentralCrossRefPubMed
38.
Weiss L: The pathobiology of metastasis within the lymphatic system. Surg Oncol Clin N Am. 1996, 5 (1): 15-24.PubMed
39.
Alitalo A, Detmar M: Interaction of tumor cells and lymphatic vessels in cancer progression. Oncogene. 2012, 31 (42): 4499-4508. 10.1038/onc.2011.602.CrossRefPubMed
40.
Ogiya A, Kahn HJ, Marks A: A new monoclonal antibody, D2-40, for detection of lymphatic invasion in primary tumors. Lab Invest. 2002, 82: 1255-1257. 10.1097/01.LAB.0000028824.03032.AB.CrossRef
41.
Schulte-Merker S, Sabine A, Petrova TV: Lymphatic vascular morphogenesis in development, physiology, and disease. J Cell Biol. 2011, 193 (4): 607-618. 10.1083/jcb.201012094.PubMedCentralCrossRefPubMed
42.
Wang XL, Fang JP, Tang RY, Chen XM: Different significance between intratumoral and peritumoral lymphatic vessel density in gastric cancer: a retrospective study of 123 cases. BMC Cancer. 2010, 10: 299-10.1186/1471-2407-10-299.PubMedCentralCrossRefPubMed
43.
Gao P, Zhou GY, Zhang QH, Xiang L, Zhang SL, Li C, Sun YL: Clinicopathological significance of peritumoral lymphatic vessel density in gastric carcinoma. Cancer Lett. 2008, 263 (2): 223-230. 10.1016/j.canlet.2008.01.017.CrossRefPubMed
44.
Lin M, Ma SP, Lin HZ, Ji P, Xie D, Yu JX: Intratumoral as well as peritumoral lymphatic vessel invasion correlates with lymph node metastasis and unfavourable outcome in colorectal cancer. Clin Exp Metastasis. 2010, 27 (3): 123-132. 10.1007/s10585-010-9309-0.CrossRefPubMed
45.
Coşkun U, Akyürek N, Dursun A, Yamaç D: Peritumoral lymphatic microvessel density associated with tumor progression and poor prognosis in gastric carcinoma. J Surg Res. 2010, 164 (1): 110-115. 10.1016/j.jss.2009.03.081.CrossRefPubMed
46.
Lee K, Park Do J, Choe G, Kim HH, Kim WH, Lee HS: Increased intratumoral lymphatic vessel density correlates with lymph node metastasis in early gastric carcinoma. Ann Surg Oncol. 2010, 17 (1): 73-80. 10.1245/s10434-009-0707-y.CrossRefPubMed
Metadata
Title
Inducible nitric oxide synthase expression in gastric adenocarcinoma: impact on lymphangiogenesis and lymphatic metastasis
Authors
Nimet Karadayı
Nilufer Onak Kandemır
Dilek Yavuzer
Taner Korkmaz
Gonca Gecmen
Furuzan Kokturk
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Diagnostic Pathology / Issue 1/2013
Electronic ISSN: 1746-1596
DOI
https://doi.org/10.1186/1746-1596-8-151

Other articles of this Issue 1/2013

Diagnostic Pathology 1/2013 Go to the issue

Research

Usefulness and limitations of E-cadherin and β-catenin in the classification of breast carcinomas in situ with mixed pattern

Case Report

A 17 year old male with a testicular fibrothecoma: a case report

Research

HER2 expression and relevant clinicopathological features in gastric and gastroesophageal junction adenocarcinoma in a Chinese population

Case Report

Multicentric paraspinal neuroglial heterotopia with Müllerian and renal agenesis: a variant of Mayer-Rokitansky-Küster-Hauser syndrome?

Research

The distinct expression patterns of claudin-2, -6, and −11 between human gastric neoplasms and adjacent non-neoplastic tissues

Case Report

A case of adenocarcinoma of the rete testis accompanied by focal adenomatous hyperplasia