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

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2010

Open Access 01-12-2010 | Research article

Angiotensin II type 2 receptor signaling significantly attenuates growth of murine pancreatic carcinoma grafts in syngeneic mice

Authors: Chiyo Doi, Noboru Egashira, Atsushi Kawabata, Dharmendra Kumar Maurya, Naomi Ohta, Deepthi Uppalapati, Rie Ayuzawa, Lara Pickel, Yuka Isayama, Deryl Troyer, Susumu Takekoshi, Masaaki Tamura

Published in: BMC Cancer | Issue 1/2010

Login to get access

Abstract

Background

Pancreatic cancer is one of the most aggressive human malignancies, with a very poor prognosis. To evaluate the effect of angiotensin II (Ang II) type 2 receptor (AT2) expression in the host's body on the growth of pancreatic carcinoma, we have investigated the growth of mouse pancreatic ductal carcinoma grafts in syngeneic wild type and AT2 receptor-deficient (AT2-KO) mice.

Methods

The role of AT2 receptor-signaling in stromal cells on the growth of murine pancreatic carcinoma cells (PAN02) was studied using various in vitro and in vivo assays. In vivo cell proliferation, apoptosis, and vasculature in tumors were monitored by Ki-67 immunostaining, TUNEL assay, and von Willebrand factor immunostaining, respectively. In the co-culture study, cell proliferation was measured by MTT cell viability assay. All the data were analyzed using t-test and data were treated as significant when p < 0.05.

Results

Our results show that the growth of subcutaneously transplanted syngeneic xenografts of PAN02 cells, mouse pancreatic ductal carcinoma cells derived from the C57/BL6 strain, was significantly faster in AT2-KO mice compared to control wild type mice. Immunohistochemical analysis of tumor tissue revealed significantly more Ki-67 positive cells in xenografts grown in AT2-KO mice than in wild type mice. The index of apoptosis is slightly higher in wild type mice than in AT2-KO mice as evaluated by TUNEL assay. Tumor vasculature number was significantly higher in AT2-KO mice than in wild type mice. In vitro co-culture studies revealed that the growth of PAN02 cells was significantly decreased when grown with AT2 receptor gene transfected wild type and AT2-KO mouse-derived fibroblasts. Faster tumor growth in AT2-KO mice may be associated with higher VEGF production in stromal cells.

Conclusions

These results suggest that Ang II regulates the growth of pancreatic carcinoma cells through modulating functions of host stromal cells; Moreover, Ang II AT2 receptor signaling is a negative regulator in the growth of pancreatic carcinoma cells. These findings indicate that the AT2 receptor in stromal fibroblasts is a potentially important target for chemotherapy for pancreatic cancer.
Appendix
Available only for authorised users
Literature
1.
2.
Hezel AF, Kimmelman AC, Stanger BZ, Bardeesy N, Depinho RA: Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 2006, 20 (10): 1218-1249. 10.1101/gad.1415606.CrossRefPubMed
3.
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ: Cancer Statistics, 2009. CA Cancer J Clin. 2009, 59 (4): 225-49. 10.3322/caac.20006.CrossRefPubMed
4.
5.
McKenna S, Eatock M: The medical management of pancreatic cancer: a review. Oncologist. 2003, 8 (2): 149-160. 10.1634/theoncologist.8-2-149.CrossRefPubMed
6.
Kleeff J, Reiser C, Hinz U, Bachmann J, Debus J, Jaeger D, Friess H, Buchler MW: Surgery for recurrent pancreatic ductal adenocarcinoma. Ann Surg. 2007, 245 (4): 566-572. 10.1097/01.sla.0000245845.06772.7d.CrossRefPubMedPubMedCentral
7.
Stoll M, Unger T: Angiotensin and its AT2 receptor: new insights into an old system. Regul Pept. 2001, 99 (2-3): 175-182. 10.1016/S0167-0115(01)00246-4.CrossRefPubMed
8.
Thomas WGMF: Molecules in Focus Angiotensin receptors: form and distribution. IJBCB. 2003, 35: 774-779.
9.
Timmermans PB, Wong PC, Chiu AT, Herblin WF, Benfield P, Carini DJ, Lee RJ, Wexler RR, Saye JA, Smith RD: Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev. 1993, 45 (2): 205-251.PubMed
10.
Berry C, Touyz R, Dominiczak AF, Webb RC, Johns DG: Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide. Am J Physiol Heart Circ Physiol. 2001, 281 (6): H2337-2365.PubMed
11.
Fyhrquist F, Saijonmaa O: Renin-angiotensin system revisited. J Intern Med. 2008, 264 (3): 224-236. 10.1111/j.1365-2796.2008.01981.x.CrossRefPubMed
12.
Hunyady L, Catt KJ: Pleiotropic AT1 receptor signaling pathways mediating physiological and pathogenic actions of angiotensin II. Mol Endocrinol. 2006, 20 (5): 953-970. 10.1210/me.2004-0536.CrossRefPubMed
13.
Grady EF, Sechi LA, Griffin CA, Schambelan M, Kalinyak JE: Expression of AT2 receptors in the developing rat fetus. J Clin Invest. 1991, 88 (3): 921-933. 10.1172/JCI115395.CrossRefPubMedPubMedCentral
14.
Prowse KR, Greider CW: Developmental and tissue-specific regulation of mouse telomerase and telomere length. Proc Natl Acad Sci USA. 1995, 92 (11): 4818-4822. 10.1073/pnas.92.11.4818.CrossRefPubMedPubMedCentral
15.
Kanehira T, Tani T, Takagi T, Nakano Y, Howard EF, Tamura M: Angiotensin II type 2 receptor gene deficiency attenuates susceptibility to tobacco-specific nitrosamine-induced lung tumorigenesis: involvement of transforming growth factor-beta-dependent cell growth attenuation. Cancer Res. 2005, 65 (17): 7660-7665.PubMed
16.
Puolakkainen PA, Brekken RA, Muneer S, Sage EH: Enhanced growth of pancreatic tumors in SPARC-null mice is associated with decreased deposition of extracellular matrix and reduced tumor cell apoptosis. Molecular Cancer Research. 2004, 2 (4): 215-224.PubMed
17.
Teicher BA: Tumor Models in Cancer Research. 2002, Human Press, NJ
18.
Mazzolini G, Narvaiza I, Martinez-Cruz LA, Arina A, Barajas M, Galofré JC, Qian C, Mato JM, Prieto J, Melero I: Pancreatic cancer escape variants that evade immunogene therapy through loss of sensitivity to IFNgamma-induced apoptosis. Gene Therapy. 2003, 10 (13): 1067-1078. 10.1038/sj.gt.3301957.CrossRefPubMed
19.
Fujita M, Hayashi I, Yamashina S, Fukamizu A, Itoman M, Majima M: Angiotensin type 1a receptor signaling-dependent induction of vascular endothelial growth factor in stroma is relevant to tumor-associated angiogenesis and tumor growth. Carcinogenesis. 2005, 26 (2): 271-279. 10.1093/carcin/bgh324.CrossRefPubMed
20.
Cao Z, Kelly DJ, Cox A, Casley D, Forbes JM, Martinello P, Dean R, Gilbert RE, Cooper ME: Angiotensin type 2 receptor is expressed in the adult rat kidney and promotes cellular proliferation and apoptosis. Kidney Int. 2000, 58: 2437-2451. 10.1046/j.1523-1755.2000.00427.x.CrossRefPubMed
21.
Antus B, Mucsi I, Rosivall L: Apoptosis induction and inhibition of cellular proliferation by angiotensin II: possible implication and perspectives. Acta Physiol Hung. 2000, 87 (1): 5-24. 10.1556/APhysiol.87.2000.1.2.CrossRefPubMed
22.
Takagi T, Nakano Y, Takekoshi S, Inagami T, Tamura M: Hemizygous mice for the angiotensin II type 2 receptor gene have attenuated susceptibility to azoxymethane-induced colon tumorigenesis. Carcinogenesis. 2002, 23 (7): 1235-1241. 10.1093/carcin/23.7.1235.CrossRefPubMed
23.
Steckelings UM, Henz BM, Wiehstutz S, Unger T, Artuc M: Differential expression of angiotensin receptors in human cutaneous wound healing. Br J Dermatol. 2005, 153 (5): 887-893. 10.1111/j.1365-2133.2005.06806.x.CrossRefPubMed
24.
Utsunomiya H, Nakamura M, Kakudo K, Inagami T, Tamura M: Angiotensin II AT2 receptor localization in cardiovascular tissues by its antibody developed in AT2 gene-deleted mice. Regul Pept. 2005, 126 (3): 155-161. 10.1016/j.regpep.2004.09.004.CrossRefPubMed
25.
Ulmasov B, Xu Z, Tetri LH, Inagami T, Neuschwander-Tetri BA: Protective role of angiotensin II type 2 receptor signaling in a mouse model of pancreatic fibrosis. Am J Physiol Gastrointest Liver Physiol. 2009, 296 (2): G284-294. 10.1152/ajpgi.90409.2008.CrossRefPubMed
26.
Reddy MK, Baskaran K, Molteni A: Inhibitors of angiotensin-converting enzyme modulate mitosis and gene expression in pancreatic cancer cells. Proc Soc Exp Biol Med. 1995, 210 (3): 221-226.CrossRefPubMed
27.
Volpert OV, Ward WF, Lingen MW, Chesler L, Solt DB, Johnson MD, Molteni A, Polverini PJ, Bouck NP: Captopril inhibits angiogenesis and slows the growth of experimental tumors in rats. J Clin Invest. 1996, 98 (3): 671-679. 10.1172/JCI118838.CrossRefPubMedPubMedCentral
28.
Hii SI, Nicol DL, Gotley DC, Thompson LC, Green MK, Jonsson JR: Captopril inhibits tumour growth in a xenograft model of human renal cell carcinoma. Br J Cancer. 1998, 77 (6): 880-883.CrossRefPubMedPubMedCentral
29.
Prontera C, Mariani B, Rossi C, Poggi A, Rotilio D: Inhibition of gelatinase A (MMP-2) by batimastat and captopril reduces tumor growth and lung metastases in mice bearing Lewis lung carcinoma. Int J Cancer. 1999, 81 (5): 761-766. 10.1002/(SICI)1097-0215(19990531)81:5<761::AID-IJC16>3.0.CO;2-1.CrossRefPubMed
30.
Yoshiji H, Kuriyama S, Kawata M, Yoshii J, Ikenaka Y, Noguchi R, Nakatani T, Tsujinoue H, Fukui H: The angiotensin-I-converting enzyme inhibitor perindopril suppresses tumor growth and angiogenesis: possible role of the vascular endothelial growth factor. Clin Cancer Res. 2001, 7 (4): 1073-1078.PubMed
31.
Lever AF, Hole DJ, Gillis CR, McCallum IR, McInnes GT, MacKinnon PL, Meredith PA, Murray LS, Reid JL, Robertson JW: Do inhibitors of angiotensin-I-converting enzyme protect against risk of cancer?. Lancet. 1998, 352 (9123): 179-184. 10.1016/S0140-6736(98)03228-0.CrossRefPubMed
32.
Kambayashi Y, Bardhan S, Takahashi K, Tsuzuki S, Inui H, Hamakubo T, Inagami T: Molecular cloning of a novel angiotensin II receptor isoform involved in phosphotyrosine phosphatase inhibition. J Biol Chem. 1993, 268 (33): 24543-24546.PubMed
33.
Ayuzawa A, Doi C, Rachakatla RS, Pyle MM, Maurya DK, Troyer D, Tamura M: Naïve human umbilical cord matrix derived stem cells significantly attenuate growth of human breast cancer cells in vitro and in vivo. Cancer letters. 2009, 280 (1): 31-37. 10.1016/j.canlet.2009.02.011.CrossRefPubMedPubMedCentral
34.
Ichiki T, Kambayashi Y, Inagami T: Differential inducibility of angiotensin II AT2 receptor between SHR and WKY vascular smooth muscle cells. Kidney Int Suppl. 1996, 55: S14-17.PubMed
35.
Egami K, Murohara T, Shimada T, Sasaki K, Shintani S, Sugaya T, Ishii M, Akagi T, Ikeda H, Matsuishi T, et al: Role of host angiotensin II type 1 receptor in tumor angiogenesis and growth. J Clin Invest. 2003, 112 (1): 67-75.CrossRefPubMedPubMedCentral
36.
Suganuma T, Ino K, Shibata K, Kajiyama H, Nagasaka T, Mizutani S, Kikkawa F: Functional expression of the angiotensin II type 1 receptor in human ovarian carcinoma cells and its blockade therapy resulting in suppression of tumor invasion, angiogenesis, and peritoneal dissemination. Clin Cancer Res. 2005, 11 (7): 2686-2694. 10.1158/1078-0432.CCR-04-1946.CrossRefPubMed
37.
Ino K, Shibata K, Kajiyama H, Yamamoto E, Nagasaka T, Nawa A, Nomura S, Kikkawa F: Angiotensin II type 1 receptor expression in ovarian cancer and its correlation with tumour angiogenesis and patient survival. Br J Cancer. 2006, 94 (4): 552-560. 10.1038/sj.bjc.6602961.CrossRefPubMedPubMedCentral
38.
Anandanadesan R, Gong Q, Chipitsyna G, Witkiewicz A, Yeo CJ, Arafat HA: Angiotensin II induces vascular endothelial growth factor in pancreatic cancer cells through an angiotensin II type 1 receptor and ERK1/2 signaling. J Gastrointest Surg. 2008, 12 (1): 57-66. 10.1007/s11605-007-0403-9.CrossRefPubMed
39.
Fujimoto Y, Sasaki T, Tsuchida A, Chayama K: Angiotensin II type 1 receptor expression in human pancreatic cancer and growth inhibition by angiotensin II type 1 receptor antagonist. FEBS Lett. 2001, 495 (3): 197-200. 10.1016/S0014-5793(01)02377-8.CrossRefPubMed
40.
Ino K, Shibata K, Kajiyama H, Nawa A, Nomura S, Kikkawa F: Manipulating the angiotensin system--new approaches to the treatment of solid tumours. Expert Opin Biol Ther. 2006, 6 (3): 243-255. 10.1517/14712598.6.3.243.CrossRefPubMed
41.
Stoll M, Steckelings UM, Paul M, Bottari SP, Metzger R, Unger T: The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothelial cells. J Clin Invest. 1995, 95 (2): 651-657. 10.1172/JCI117710.CrossRefPubMedPubMedCentral
42.
Munzenmaier DH, Greene AS: Opposing actions of angiotensin II on microvascular growth and arterial blood pressure. Hypertension. 1996, 27 (3 Pt 2): 760-765.CrossRefPubMed
43.
Hanahan D, Weinberg RA: The hallmarks of cancer. Cell. 2000, 100 (1): 57-70. 10.1016/S0092-8674(00)81683-9.CrossRefPubMed
44.
Hwang RF, Moore T, Arumugam T, Ramachandran V, Amos KD, Rivera A, Ji B, Evans DB, Logsdon CD: Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res. 2008, 68 (3): 918-926. 10.1158/0008-5472.CAN-07-5714.CrossRefPubMedPubMedCentral
45.
Sugimoto T, Takiguchi Y, Kurosu K, Kasahara Y, Tanabe N, Tatsumi K, Hiroshima K, Minamihisamatsu M, Miyamoto T, Kuriyama T: Growth factor-mediated interaction between tumor cells and stromal fibroblasts in an experimental model of human small-cell lung cancer. Oncology Report. 2005, 14: 823-830.
46.
Rosendorff C: The renin-angiotensin system and vascular hypertrophy. J Am Coll Cardiol. 1996, 28 (4): 803-812. 10.1016/S0735-1097(96)00251-3.CrossRefPubMed
47.
Wolf G, Harendza S, Schroeder R, Wenzel U, Zahner G, Butzmann U, Freeman RS, Stahl RA: Angiotensin II's antiproliferative effects mediated through AT2-receptors depend on down-regulation of SM-20. Lab Invest. 2002, 82: 1305-1317.CrossRefPubMed
48.
Carnovali M: The role of the selective blocking of angiotensin II receptors in the treatment of cardiovascular diseases. Clin Ter. 2001, 152 (2): 103-106.PubMed
49.
Miura S, Karnik SS: Ligand-independent signals from angiotensin II type 2 receptor induce apoptosis. Embo J. 2000, 19 (15): 4026-4035. 10.1093/emboj/19.15.4026.CrossRefPubMedPubMedCentral
50.
Wolf G, Harendza S, Schroeder R, Wenzel U, Zahner G, Butzmann U, Freeman RS, Stahl RA: Angiotensin II's antiproliferative effects mediated through AT2-receptors depend on down-regulation of SM-20. Lab Invest. 2002, 82 (10): 1305-1317.CrossRefPubMed
51.
Xoriuchi M, Hamai M, Cui TX, Iwai M, Minokoshi Y: Cross talk between angiotensin II type 1 and type 2 receptors: cellular mechanism of angiotensin type 2 receptor-mediated cell growth inhibition. Hypertens Res. 1999, 22 (2): 67-74. 10.1291/hypres.22.67.CrossRefPubMed
Metadata
Title
Angiotensin II type 2 receptor signaling significantly attenuates growth of murine pancreatic carcinoma grafts in syngeneic mice
Authors
Chiyo Doi
Noboru Egashira
Atsushi Kawabata
Dharmendra Kumar Maurya
Naomi Ohta
Deepthi Uppalapati
Rie Ayuzawa
Lara Pickel
Yuka Isayama
Deryl Troyer
Susumu Takekoshi
Masaaki Tamura
Publication date
01-12-2010
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2010
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-10-67

Other articles of this Issue 1/2010

BMC Cancer 1/2010 Go to the issue

Research article

Differential CARM1 expression in prostate and colorectal cancers

Research article

An association between anti-platelet drug use and reduced cancer prevalence in diabetic patients: results from the Vermont Diabetes Information System Study

Research article

Oncological outcome and patient satisfaction with skin-sparing mastectomy and immediate breast reconstruction: a prospective observational study

Technical advance

Clinical array-based karyotyping of breast cancer with equivocal HER2 status resolves gene copy number and reveals chromosome 17 complexity

Research article

Modeling the Aneuploidy Control of Cancer

Research article

Identification of hypoxanthine as a urine marker for non-Hodgkin lymphoma by low-mass-ion profiling
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits