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 1/2012

Open Access 01-12-2012 | Research article

Thrombospondin-1-derived 4N1K peptide expression is negatively associated with malignant aggressiveness and prognosis in urothelial carcinoma of the upper urinary tract

Authors: Yasuyoshi Miyata, Shin-ichi Watanabe, Hiroshi Kanetake, Hideki Sakai

Published in: BMC Cancer | Issue 1/2012

Login to get access

Abstract

Background

Thrombospondin (TSP) is a multi-functional protein that appears to have dual roles in cancer, that is, either as a promoter or a suppressor. 4N1K is a TSP-derived peptide that has been reported to be associated with neovascularity, cell survival, and invasion. There is a little information regarding its pathological roles in human cancer tissues. Our aim was to clarify clinical significance and prognostic value of 4N1K expression in patients with urothelial carcinoma of the upper urinary tract (UC-UUT).

Methods

We investigated 4N1K expression in 97 surgically excised, non-metastasized UC-UUT specimens and five normal tissues via immunohistochemistry. Microvessel density (MVD), lymph vessel density (LVD), cancer cell proliferation (PI), apoptotic index (AI), and matrix metalloproteinase (MMP)-9 expression was also determined. The relationships 4N1K expression and pT stage, grade, and prognosis were analysed. In addition, correlations with these cancer-related and TSP-related factors were also investigated.

Results

Strong and moderate 4N1K expression was found in normal urothelial tissues. Of the 97 specimens, 45 patients were positive for 4N1K expression, which was primarily located in the interstitial areas of the cancer tissue. 4N1K expression was negatively associated with pT stage (p = 0.003) and grade (p = 0.002). Survival analyses revealed that 4N1K is a predictor of metastasis-free (p = 0.036) and cause-specific survival (p = 0.009). 4N1K expression was closely associated with malignant behaviour, specifically MVD (p = 0.001), AI (p = 0.013), and MMP-9 expression (p = 0.036), but not PI and LVD, as determined via multivariate analysis models.

Conclusions

4N1K expression appears to be associated with cancer cell progression and survival in UC-UUT patients via the regulation of angiogenesis, apoptosis, and MMP-9 expression. There is a possibility that the 4N1K-peptide may be a useful marker and novel therapeutic target in patients with UC-UUT.
Appendix
Available only for authorised users
Literature
1.
Hall MC, Womack S, Sagalowsky AI, Carmody T, Erickstad MD, Roehrborn CG: Prognostic factors, recurrence and survival in transitional cell carcinoma of the upper urinary tract: a 30-year experience in 252 patients. Urology. 1998, 52: 594-601. 10.1016/S0090-4295(98)00295-7.CrossRefPubMed
2.
Jeong IG, Kim SH, Jeon HG, Kim BK, Moon LC, Lee SE, Lee E: Prognostic value of apoptosis-related markers in urothelial cancer of the upper urinary tract. Hum Pathol. 2009, 40: 668-677. 10.1016/j.humpath.2008.10.010.CrossRefPubMed
3.
Folkman J: Angiogenesis in cancer, vascular, rheumatoid and other diseases. Nat Med. 1995, 1: 27-31. 10.1038/nm0195-27.CrossRefPubMed
4.
Miyata Y, Kanda S, Ohba K, et al: Lymphangiogenesis and angiogenesis in bladder cancer: prognostic implications and regulation by vascular endothelial growth factors-A, -C, and –D. Clin Cancer Res. 2006, 12: 800-806. 10.1158/1078-0432.CCR-05-1284.CrossRefPubMed
5.
Good DJ, Polverini PJ, Ranstinejad F, Le Beau MM, Lemons RS, Frazier WA, Bouck NP: A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment thrombospondin. Proc Natl Acad Sci USA. 1990, 87: 6624-6628. 10.1073/pnas.87.17.6624.CrossRefPubMedPubMedCentral
6.
Tolsma SS, Stack MS, Bouck N: Lumen formation and other angiogenic activities of cultured capillary endothelial cells are inhibited by thorombospondin-1. Microvasc Res. 1997, 54: 13-26. 10.1006/mvre.1997.2015.CrossRefPubMed
7.
Lawler J: thrombospondin-1 as an endogenous inhibitor of angiogenesis and tumor growth. J Cell Mol Med. 2002, 6: 1-12. 10.1111/j.1582-4934.2002.tb00307.x.CrossRefPubMed
8.
9.
Kasper HU, Ebert M, Malfertheiner P, Roessner A, Kirkpatrick CJ, Wolf HK: Expression of thrombospondin-1 in pancreatic carcinoma: correlation with microvessel density. Virchow Arch. 2001, 438: 116-120. 10.1007/s004280000302.CrossRef
10.
Nakao T, Kurita N, Komatsu M, Yoshikawa K, Iwata T, Utsunomiya T, Shimada M: Expression of thrombospondin-1 and Ski are prognostic factors in advanced gastric cancer. Int J Clin Oncol. 2011, 16: 145-152. 10.1007/s10147-010-0147-5.CrossRefPubMed
11.
Miyata Y, Kanda S, Ohba K, et al: Tumor lymphangiogenesis in transitional cell carcinoma of the upper urinary tract: association with clinicopathological features and prognosis. J Urol. 2006, 176: 348-353. 10.1016/S0022-5347(06)00520-9.CrossRefPubMed
12.
Zhou M, He Y, Zu X, Zhang H, Zeng H, Qi L: Lymph vessel density as a predictor of lymph node metastasis and its relationship with prognosis in urothelial carcinoma of the bladder. BJU Int. 2010, 107: 1930-1935.CrossRefPubMed
13.
Albo D, Shinohara T, Tuszynski GO: Up-regulation of matrix metalloproteinase 9 by thrombospondin 1 in gastric cancer. J Surg Res. 2002, 108: 51-60. 10.1006/jsre.2002.6452.CrossRefPubMed
14.
Shariat SF, Youssef RF, Gupta A, Chade DC, Karakiewicz PI, Isbarn H, Jeldres C, Sagalowsky AI, Ashfaq R, Lotan Y: Association of angiogenesis related markers with bladder cancer outcomes and other molecular markers. J Urol. 2010, 183: 1744-1750. 10.1016/j.juro.2010.01.018.CrossRefPubMed
15.
Qian X, Rothman VL, Nicosia RF, Tuszynski GP: Expression of therombospondin-1 in human pancreatic adenocarcinomas: role in matrix metalloproteinase-9 production. Pathol Oncol Res. 2001, 7: 251-259. 10.1007/BF03032381.CrossRefPubMed
16.
Donmez G, Sullu Y, Baris S, Yildiz L, Aydin O, Karagoz F, Kandemir B: Vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9), and thrombospondin-1 (TSP-1) expression in urothelial carcinomas. Pathol Res Pract. 2009, 205: 854-857. 10.1016/j.prp.2009.07.015.CrossRefPubMed
17.
Murphy G, Crabbe T: Gelatinases a and b. Mothods Enzymol. 1995, 248: 470-484.CrossRef
18.
Miyata Y, Kanda S, Nomata K, Hayashida Y, Kanetake H: Expression of metalloproteinase-2, metalloproteinase-9, and tissue inhibitor of metalloproteinase-1 in transitional cell carcinoma of upper urinary tract: correlation with tumor stage and survival. Urology. 2004, 63: 602-608. 10.1016/j.urology.2003.09.035.CrossRefPubMed
19.
Rodriguez-Manzaneque JC, Lane TF, Ortega MA, Hynes RO, Lawler J, Iruela-Arispe ML: Thrombospondin-1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor. Proc Natl Acad Sci USA. 2001, 98: 12485-12490. 10.1073/pnas.171460498.CrossRefPubMedPubMedCentral
20.
Wei W, Kong B, Yang Q, Qu X: Hepatocyte growth factor enhances ovarian cancer cell invasion though down regulation of thrombospondin-1. Cancer Biol Ther. 2010, 9: 79-87.CrossRefPubMed
21.
Miyanaga K, Kato Y, Nakamura T, Matsumura M, Amaya H, Horiuchi T, Chiba Y, Tanaka K: Expression and role of thrombospondin-1 in colorectal cancer. Anticancer Res. 2002, 22: 3941-3948.PubMed
22.
Zubac DP, Bostad L, Kihl B, Seidal T, Wentzel-Lausen T, Haukaas SA: The expression of thrombospondin-1 and p53 in clear cell renal cell carcinoma: its relationship to agiogenesis, cell proliferation and cancer specific survival. J Urol. 2009, 182: 2144-2149. 10.1016/j.juro.2009.07.015.CrossRefPubMed
23.
Yamashita Y, Sendo S, Hosokawa T, Tuszynski G, Kurohiji T, Beppu R, Shinohara T, Kinugasa T, Shirakusa T: Exogenous thrombospondin stimulates the proliferation of non-thrombospondin-producing cells. Int J Oncol. 1998, 13: 355-359.PubMed
24.
Mateo V, Brown EJ, Biron G, et al: Mechanisms of CD47-induced caspase-independent cell death in normal and leukemia cells: link between phosphatidylserine exposure and cytoskeleton organization. Blood. 2002, 100: 2882-2890. 10.1182/blood-2001-12-0217.CrossRefPubMed
25.
Manna PP, Frazier WA: CD47 meidates killing of breast tumor cells via Gi-dependent inhibition of protein kinase A. Cancer Res. 2004, 64: 1026-1036. 10.1158/0008-5472.CAN-03-1708.CrossRefPubMed
26.
Rath GM, Schneider C, Dedieu S, Rothhut B, Soula-Rothhut M, Ghoneim C, Sid CB, Morjani H, El Btaouri H, Martiny L: The C-terminal CD47/IAP-binding domain of thrombospondin-1 prevents camptothecin- and doxorubicin-induced apoptosis in human thyroid carcinoma cells. Biochim Biophys Acta. 2006, 1763: 1125-1134. 10.1016/j.bbamcr.2006.08.001.CrossRefPubMed
27.
Grossfeld GD, Ginsberg DA, Stein P, et al: Thrombospondin-1 expression in bladder cancer: association with p53 alternations, tumor angiogenesis, and tumor progression. J Natl Cancer Inst. 1997, 89: 219-227. 10.1093/jnci/89.3.219.CrossRefPubMed
28.
Goddard JC, Sutton CD, Jones JL, OByrne KJ, Kochelbergh RC: Reduced thrombospondin-1 at presentation predicts disease progression in superficial bladder cancer. Eur Urol. 2002, 42: 464-468. 10.1016/S0302-2838(02)00372-X.CrossRefPubMed
29.
Pratt DA, Miller WR, Dawes J: Thrombospondin in malignant and non-malignant breast tissues. Eur J Cancer Clin Oncol. 1989, 25: 343-350. 10.1016/0277-5379(89)90028-X.CrossRefPubMed
30.
Poon RT, Chung KK, Cheung ST, et al: Clinical significance of thrombospondin 1 expression in hepatocellular carcinoma. Clin Cancer Res. 2004, 10: 4150-4157. 10.1158/1078-0432.CCR-03-0435.CrossRefPubMed
31.
Firlej V, Mathieu JRR, Gilbert C, Lemonnier L, Nakhlé J, Gallou-Kabani C, Guarmit B, Morin A, Prevarskaya N, Delongchamps NB, Cabon F: Thrombospondin-1 triggers cell migration and development of advanced prostate tumors. Cancer Res. 2011, 28: 7649-7658.CrossRef
32.
Miyata Y, Koga S, Takehara K, Kanetatke H, Kanda S: Expression of thrombospondin-derived 4N1K peptide-containing proteins in renal cell carcinoma tissues is associated with a decrease in tumor growth and angiogenesis. Clin Cancer Res. 2003, 9: 1734-1740.PubMed
33.
Qian X, Tuszynski GP: Expression of thrombospondin-1 in cancer: a role in tumor progression. Proc Soc Exp Biol Med. 1996, 212: 199-207.CrossRefPubMed
34.
Guo N-H, Krutzsch HC, Inman JK, Robert DD: Thrombospondin 1 and type I repeat peptides of thrombospondin 1 specifically induced apoptosis of endothelial cells. Cancer Res. 1997, 57: 1735-1742.PubMed
35.
Chandradekaran L, He CZ, Al-Barazi H, Krutzsch HC, Iruela-Arispe ML, Roberts DD: Cell contact-dependent activation of α2β1 intergrin modulated endothelial cell response to therombospondin-1. Mol Biol Cell. 2000, 11: 2885-2900.CrossRef
36.
Kanda S, Shono T, Tomasini-Johansson B, Klint P, Saito Y: Role of thrombospondin-1 derived peptide, 4N1K, in FGF-2-induced angiogenesis. Exp Cell Res. 1999, 252: 262-272. 10.1006/excr.1999.4622.CrossRefPubMed
37.
Rao SR, Correa JJ, Sexton WJ, Pow-Sang JM, Dickinson SI, Lin HY, Spiess PE: Prospective clinical trial of the feasibility and safety of modified retroperitoneal lymph node dissection at time of nephroureterectomy for upper tract urothelial carcinoma. BJU Int. 2012, in press
38.
Cosentino M, Palou J, Gaya JM, Breda A, Rodriguez-Faba O, Villavicencio-Mavrich H: Upper urinary tract urothelial cell carcinoma: location as a predictive factor for concomitant bladder carcinoma. World J Urol. 2012, in press
39.
Miyata Y, Koga S, Kanda S, Nishikido M, Hayashi T, Kanetake H: Expression of cyclooxygenase-2 in renal cell carcinoma: correlation with tumor cell proliferation, apoptosis, angiogenesis, expression of matrix metalloproteinase-2, and survival. Clin Cancer Res. 2003, 9: 1741-1749.PubMed
40.
Albo D, Rothman VL, Roberts DD, Tuszynski GP: Tumour cell thrombospondin-1 regulates tumour cell adhesion and invasion through the urokinase plasminogen activator receptor. Br J Cancer. 2000, 83: 298-306. 10.1054/bjoc.2000.1268.CrossRefPubMedPubMedCentral
41.
Nicosia RF, Tuszynski GP: Matrix-bound thrombospondin promotes angiogenesis in vitro. J Cell Biol. 1994, 124: 183-193. 10.1083/jcb.124.1.183.CrossRefPubMed
42.
Ioachim E, Michael MC, Salmas M, Damala K, Tsanou E, Michael MM, Malamou-Mitsi V, Stavropoulos NE: Thrombospondin-1 expression in urothelial carcinoma: prognostic significance and association with p53 alterations, tumour angiogenesis and extracellular matrix components. BMC Cancer. 2006, 6: 140-10.1186/1471-2407-6-140.CrossRefPubMedPubMedCentral
43.
Campbell SC, Volpert OV, Ivanovich M, Bouck NP: Molecular mediator of angiogenesis in bladder cancer. Cancer Res. 1998, 58: 1298-1304.PubMed
44.
Beecken WC, Engl T, Jonas D, Blaheta RA: Expression of angiogenesis inhibitors in human bladder cancer may explain rapid metastatic progression after radical cystectomy. Int J Mol Med. 2009, 23: 261-266.PubMed
45.
Hawighorst T, Oura H, Streit M, Janes L, Nguyen L, Brown LF, Oliver G, Jackson DG, Detmar M: Thrombospondin-1 selectively inhbits early-stage carcinogenesis and angiogenesis but not tumor lymphangiogenesis and lymphatic metastasis in transgenic mice. Oncogene. 2002, 21: 7945-7956. 10.1038/sj.onc.1205956.CrossRefPubMed
46.
Friedl P, Vischer P, Freyberg MA: The role of thrombospondin-1 in apoptosis. Cell Mol Life Sci. 2002, 59: 1347-1357. 10.1007/s00018-002-8512-9.CrossRefPubMed
47.
Johansson U, Higginbottom K, Londei M: CD47 ligation induces a rapid caspase-independent apoptosis-like cell death in human monocytes and dendritic cells. Scand J Immunol. 2004, 59: 40-49. 10.1111/j.0300-9475.2004.01355.x.CrossRefPubMed
48.
Qian X, Wang TN, Rothman VL, Nicosia RF, Tuszynski GP: Thrombospondin-1 modulates angiogenesis in vitro by upregulation of matrix metalloproteinase-9 in endothelial cells. Exp Cell Res. 1997, 235: 403-412. 10.1006/excr.1997.3681.CrossRefPubMed
49.
Xing C, Arai K, Park K-P, Lo EH: Induction of vascular endothelial growth factor and matrix metalloproteinase-9 via CD34 signaling in neurovascular cells. Neurochem Res. 2010, 35: 1092-1097. 10.1007/s11064-010-0159-6.CrossRefPubMedPubMedCentral
Metadata
Title
Thrombospondin-1-derived 4N1K peptide expression is negatively associated with malignant aggressiveness and prognosis in urothelial carcinoma of the upper urinary tract
Authors
Yasuyoshi Miyata
Shin-ichi Watanabe
Hiroshi Kanetake
Hideki Sakai
Publication date
01-12-2012
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2012
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-12-372

Other articles of this Issue 1/2012

BMC Cancer 1/2012 Go to the issue

Research article

Prognostic impact of detecting viable circulating tumour cells in gastric cancer patients using a telomerase-specific viral agent: a prospective study

Research article

Prognostic impact of mRNA levels of osteopontin splice variants in soft tissue sarcoma patients

Research article

The role of brevican in glioma: promoting tumor cell motility in vitro and in vivo

Study protocol

Metformin efficacy and safety for colorectal polyps: a double-blind randomized controlled trial

Research article

Use of a chemically induced-colon carcinogenesis-prone Apc-mutant rat in a chemotherapeutic bioassay

Study protocol

Hypofractionated helical intensity-modulated radiotherapy of the prostate bed after prostatectomy with or without the pelvic lymph nodes - the PRIAMOS trial
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