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 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2010

Open Access 01-12-2010 | Research

Tetrathiomolybdate inhibits head and neck cancer metastasis by decreasing tumor cell motility, invasiveness and by promoting tumor cell anoikis

Authors: Pawan Kumar, Arti Yadav, Samip N Patel, Mozaffarul Islam, Quintin Pan, Sofia D Merajver, Theodoros N Teknos

Published in: Molecular Cancer | Issue 1/2010

Login to get access

Abstract

Background

The metastatic spread of solid tumors is directly or indirectly responsible for most cancer-related deaths. Tumor metastasis is very complex and this process requires a tumor cell to acquire enhanced motility, invasiveness and anoikis resistance to successfully establish a tumor at a distal site. Metastatic potential of tumor cells is directly correlated with the expression levels of several angiogenic cytokines. Copper is a mandatory cofactor for the function of many of these angiogenic mediators as well as other proteins that play an important role in tumor cell motility and invasiveness. We have previously shown that tetrathiomolybdate (TM) is a potent chelator of copper and it mediates its anti-tumor effects by suppressing tumor angiogenesis. However, very little is known about the effect of TM on tumor cell function and tumor metastasis. In this study, we explored the mechanisms underlying TM-mediated inhibition of tumor metastasis.

Results

We used two in vivo models to examine the effects of TM on tumor metastasis. Animals treated with TM showed a significant decrease in lung metastasis in both in vivo models as compared to the control group. In addition, tumor cells from the lungs of TM treated animals developed significantly smaller colonies and these colonies had significantly fewer tumor cells. TM treatment significantly decreased tumor cell motility and invasiveness by inhibiting lysyl oxidase (LOX) activity, FAK activation and MMP2 levels. Furthermore, TM treatment significantly enhanced tumor cell anoikis by activating p38 MAPK cell death pathway and by downregulating XIAP survival protein expression.

Conclusions

Taken together, these results suggest that TM is a potent suppressor of head and neck tumor metastasis by modulating key regulators of tumor cell motility, invasiveness and anoikis resistance.
Appendix
Available only for authorised users
Literature
1.
Ragin CC, Modugno F, Gollin SM: The epidemiology and risk factors of head and neck cancer: a focus on human papillomavirus. J Dent Res. 2007, 86: 104-114. 10.1177/154405910708600202CrossRefPubMed
2.
Jemal A, Thomas A, Murray T, Thun M: Cancer statistics, 2002. CA Cancer J Clin. 2002, 52: 23-47. 10.3322/canjclin.52.1.23CrossRefPubMed
3.
Deschamps DR, Spencer HJ, Kokoska MS, Spring PM, Vural EA, Stack BC: Implications of head and neck cancer treatment failure in the neck. Otolaryngol Head Neck Surg. 142: 722-727.
4.
Ferlito A, Shaha AR, Silver CE, Rinaldo A, Mondin V: Incidence and Sites of Distant Metastases from Head and Neck Cancer. ORL. 2001, 63: 202-207. 10.1159/000055740CrossRefPubMed
5.
Teknos TN, Islam M, Arenberg DA, Pan Q, Carskadon SL, Abarbanell AM, Marcus B, Paul S, Vandenberg CD, Carron M: The effect of tetrathiomolybdate on cytokine expression, angiogenesis, and tumor growth in squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg. 2005, 131: 204-211. 10.1001/archotol.131.3.204CrossRefPubMed
6.
Lathers DM, Young MR: Increased aberrance of cytokine expression in plasma of patients with more advanced squamous cell carcinoma of the head and neck. Cytokine. 2004, 25: 220-228. 10.1016/j.cyto.2003.11.005CrossRefPubMed
7.
Chen Z, Malhotra PS, Thomas GR, Ondrey FG, Duffey DC, Smith CW, Enamorado I, Yeh NT, Kroog GS, Rudy S: Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer. Clin Cancer Res. 1999, 5: 1369-1379.PubMed
8.
Smith BD, Smith GL, Carter D, Sasaki CT, Haffty BG: Prognostic significance of vascular endothelial growth factor protein levels in oral and oropharyngeal squamous cell carcinoma. J Clin Oncol. 2000, 18: 2046-2052.PubMed
9.
Masuda M, Ruan HY, Ito A, Nakashima T, Toh S, Wakasaki T, Yasumatsu R, Kutratomi Y, Komune S, Weinstein IB: Signal transducers and activators of transcription 3 up-regulates vascular endothelial growth factor production and tumor angiogenesis in head and neck squamous cell carcinoma. Oral Oncol. 2007, 43: 785-790. 10.1016/j.oraloncology.2006.10.007CrossRefPubMed
10.
Sauter ER, Nesbit M, Watson JC, Klein-Szanto A, Litwin S, Herlyn M: Vascular endothelial growth factor is a marker of tumor invasion and metastasis in squamous cell carcinomas of the head and neck. Clin Cancer Res. 1999, 5: 775-782.PubMed
11.
Teknos TN, Cox C, Yoo S, Chepeha DB, Wolf GT, Bradford CR, Carey TE, Fisher SG: Elevated serum vascular endothelial growth factor and decreased survival in advanced laryngeal carcinoma. Head Neck. 2002, 24: 1004-1011. 10.1002/hed.10163CrossRefPubMed
12.
Kumar P, Miller AI, Polverini PJ: p38 MAPK mediates gamma-irradiation-induced endothelial cell apoptosis, and vascular endothelial growth factor protects endothelial cells through the phosphoinositide 3-kinase-Akt-Bcl-2 pathway. J Biol Chem. 2004, 279: 43352-43360. 10.1074/jbc.M405777200CrossRefPubMed
13.
Kumar P, Coltas IK, Kumar B, Chepeha DB, Bradford CR, Polverini PJ: Bcl-2 protects endothelial cells against gamma-radiation via a Raf-MEK-ERK-survivin signaling pathway that is independent of cytochrome c release. Cancer Res. 2007, 67: 1193-1202. 10.1158/0008-5472.CAN-06-2265CrossRefPubMed
14.
Kumar P, Ning Y, Polverini PJ: Endothelial cells expressing Bcl-2 promotes tumor metastasis by enhancing tumor angiogenesis, blood vessel leakiness and tumor invasion. Lab Invest. 2008, 88: 740-749. 10.1038/labinvest.2008.46CrossRefPubMed
15.
Ahmad A, Hart IR: Mechanisms of metastasis. Crit Rev Oncol Hematol. 1997, 26: 163-173. 10.1016/S1040-8428(97)10002-6CrossRefPubMed
16.
Manes S, Mira E, Gomez-Mouton C, Lacalle RA, Martinez C: Cells on the move: a dialogue between polarization and motility. IUBMB Life. 2000, 49: 89-96. 10.1080/15216540050022386CrossRefPubMed
17.
Maung K, Easty DJ, Hill SP, Bennett DC: Requirement for focal adhesion kinase in tumor cell adhesion. Oncogene. 1999, 18: 6824-6828. 10.1038/sj.onc.1203094CrossRefPubMed
18.
Schneider GB, Kurago Z, Zaharias R, Gruman LM, Schaller MD, Hendrix MJ: Elevated focal adhesion kinase expression facilitates oral tumor cell invasion. Cancer. 2002, 95: 2508-2515. 10.1002/cncr.10992CrossRefPubMed
19.
Hauck CR, Sieg DJ, Hsia DA, Loftus JC, Gaarde WA, Monia BP, Schlaepfer DD: Inhibition of focal adhesion kinase expression or activity disrupts epidermal growth factor-stimulated signaling promoting the migration of invasive human carcinoma cells. Cancer Res. 2001, 61: 7079-7090.PubMed
20.
Talvensaari-Mattila A, Pääkkö P, Höyhtyä M, Blanco-Sequeiros G, Turpeenniemi-Hujanen T: Matrix metalloproteinase-2 immunoreactive protein. Cancer. 1998, 83: 1153-1162. 10.1002/(SICI)1097-0142(19980915)83:6<1153::AID-CNCR14>3.0.CO;2-4CrossRefPubMed
21.
Väisänen A, Kallioinen M, Taskinen PJ, Turpeenniemi-Hujanen T: Prognostic value of MMP-2 immunoreactive protein (72 kD type IV collagenase) in primary skin melanoma. The Journal of Pathology. 1998, 186: 51-58. 10.1002/(SICI)1096-9896(199809)186:1<51::AID-PATH131>3.0.CO;2-PCrossRefPubMed
22.
Ruokolainen H, Paakko P, Turpeenniemi-Hujanen T: Tissue and circulating immunoreactive protein for MMP-2 and TIMP-2 in head and neck squamous cell carcinoma--tissue immunoreactivity predicts aggressive clinical course. Mod Pathol. 2005, 19: 208-217. 10.1038/modpathol.3800506.CrossRef
23.
Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE: Focal adhesion kinase gene silencing promotes anoikis and suppresses metastasis of human pancreatic adenocarcinoma cells. Surgery. 2004, 135: 555-562. 10.1016/j.surg.2003.10.017CrossRefPubMed
24.
Payne SL, Fogelgren B, Hess AR, Seftor EA, Wiley EL, Fong SF, Csiszar K, Hendrix MJ, Kirschmann DA: Lysyl oxidase regulates breast cancer cell migration and adhesion through a hydrogen peroxide-mediated mechanism. Cancer Res. 2005, 65: 11429-11436. 10.1158/0008-5472.CAN-05-1274CrossRefPubMed
25.
Brewer GJ: Copper control as an antiangiogenic anticancer therapy: lessons from treating Wilson's disease. Exp Biol Med (Maywood). 2001, 226: 665-673.
26.
Pan Q, Kleer CG, van Golen KL, Irani J, Bottema KM, Bias C, De Carvalho M, Mesri EA, Robins DM, Dick RD: Copper deficiency induced by tetrathiomolybdate suppresses tumor growth and angiogenesis. Cancer Res. 2002, 62: 4854-4859.PubMed
27.
McAuslan BR, Reilly W: Endothelial cell phagokinesis in response to specific metal ions. Exp Cell Res. 1980, 130: 147-157. 10.1016/0014-4827(80)90051-8CrossRefPubMed
28.
Hu GF: Copper stimulates proliferation of human endothelial cells under culture. J Cell Biochem. 1998, 69: 326-335. 10.1002/(SICI)1097-4644(19980601)69:3<326::AID-JCB10>3.0.CO;2-ACrossRefPubMed
29.
Hassouneh B, Islam M, Nagel T, Pan Q, Merajver SD, Teknos TN: Tetrathiomolybdate promotes tumor necrosis and prevents distant metastases by suppressing angiogenesis in head and neck cancer. Mol Cancer Ther. 2007, 6: 1039-1045. 10.1158/1535-7163.MCT-06-0524CrossRefPubMed
30.
Juarez JC, Betancourt O, Pirie-Shepherd SR, Guan X, Price ML, Shaw DE, Mazar AP, Donate F: Copper binding by tetrathiomolybdate attenuates angiogenesis and tumor cell proliferation through the inhibition of superoxide dismutase 1. Clin Cancer Res. 2006, 12: 4974-4982. 10.1158/1078-0432.CCR-06-0171CrossRefPubMed
31.
Goodman VL, Brewer GJ, Merajver SD: Control of copper status for cancer therapy. Curr Cancer Drug Targets. 2005, 5: 543-549. 10.2174/156800905774574066CrossRefPubMed
32.
Nor JE, Christensen J, Liu J, Peters M, Mooney DJ, Strieter RM, Polverini PJ: Up-Regulation of Bcl-2 in microvascular endothelial cells enhances intratumoral angiogenesis and accelerates tumor growth. Cancer Res. 2001, 61: 2183-2188.PubMed
33.
Zhang L, Lee KC, Bhojani MS, Khan AP, Shilman A, Holland EC, Ross BD, Rehemtulla A: Molecular imaging of Akt kinase activity. Nat Med. 2007, 13: 1114-1119. 10.1038/nm1608CrossRefPubMed
34.
Kumar P, Amin MA, Harlow LA, Polverini PJ, Koch AE: Src and phosphatidylinositol 3-kinase mediate soluble E-selectin-induced angiogenesis. Blood. 2003, 101: 3960-3968. 10.1182/blood-2002-04-1237CrossRefPubMed
35.
Kumar P, Benedict R, Urzua F, Fischbach C, Mooney D, Polverini P: Combination treatment significantly enhances the efficacy of antitumor therapy by preferentially targeting angiogenesis. Lab Invest. 2005, 85: 756-767. 10.1038/labinvest.3700272CrossRefPubMed
36.
Ferlito A, Rinaldo A, Buckley JG, Mondin V: General Considerations on Distant Metastases from Head and Neck Cancer. ORL. 2001, 63: 189-191. 10.1159/000055738CrossRefPubMed
37.
Kalavrezos N, Bhandari R: Current trends and future perspectives in the surgical management of oral cancer. Oral Oncol. 46: 429-432.
38.
Turski ML, Thiele DJ: New roles for copper metabolism in cell proliferation, signaling, and disease. J Biol Chem. 2009, 284: 717-721. 10.1074/jbc.R800055200PubMedCentralCrossRefPubMed
39.
Schlaepfer DD, Mitra SK: Multiple connections link FAK to cell motility and invasion. Curr Opin Genet Dev. 2004, 14: 92-101. 10.1016/j.gde.2003.12.002CrossRefPubMed
40.
Kagan HM, Li W: Lysyl oxidase: properties, specificity, and biological roles inside and outside of the cell. J Cell Biochem. 2003, 88: 660-672. 10.1002/jcb.10413CrossRefPubMed
41.
Lazarus HM, Cruikshank WW, Narasimhan N, Kagan HM, Center DM: Induction of human monocyte motility by lysyl oxidase. Matrix Biol. 1995, 14: 727-731. 10.1016/S0945-053X(05)80015-0CrossRefPubMed
42.
Patel BP, Shah SV, Shukla SN, Shah PM, Patel PS: Clinical significance of MMP-2 and MMP-9 in patients with oral cancer. Head Neck. 2007, 29: 564-572. 10.1002/hed.20561CrossRefPubMed
43.
Kawata R, Shimada T, Maruyama S, Hisa Y, Takenaka H, Murakami Y: Enhanced production of matrix metalloproteinase-2 in human head and neck carcinomas is correlated with lymph node metastasis. Acta Otolaryngol. 2002, 122: 101-106. 10.1080/00016480252775823CrossRefPubMed
44.
Hauck CR, Hsia DA, Puente XS, Cheresh DA, Schlaepfer DD: FRNK blocks v-Src-stimulated invasion and experimental metastases without effects on cell motility or growth. Embo J. 2002, 21: 6289-6302. 10.1093/emboj/cdf631PubMedCentralCrossRefPubMed
45.
Zhang Y, Thant AA, Hiraiwa Y, Naito Y, Sein TT, Sohara Y, Matsuda S, Hamaguchi M: A role for focal adhesion kinase in hyluronan-dependent MMP-2 secretion in a human small-cell lung carcinoma cell line, QG90. Biochem Biophys Res Commun. 2002, 290: 1123-1127. 10.1006/bbrc.2001.6321CrossRefPubMed
46.
Wilkinson JC, Wilkinson AS, Galban S, Csomos RA, Duckett CS: Apoptosis-inducing factor is a target for ubiquitination through interaction with XIAP. Mol Cell Biol. 2008, 28: 237-247. 10.1128/MCB.01065-07PubMedCentralCrossRefPubMed
47.
Rhee SG: Cell signaling. H2O2, a necessary evil for cell signaling. Science. 2006, 312: 1882-1883. 10.1126/science.1130481CrossRefPubMed
48.
Riedl SJ, Renatus M, Schwarzenbacher R, Zhou Q, Sun C, Fesik SW, Liddington RC, Salvesen GS: Structural basis for the inhibition of caspase-3 by XIAP. Cell. 2001, 104: 791-800. 10.1016/S0092-8674(01)00274-4CrossRefPubMed
Metadata
Title
Tetrathiomolybdate inhibits head and neck cancer metastasis by decreasing tumor cell motility, invasiveness and by promoting tumor cell anoikis
Authors
Pawan Kumar
Arti Yadav
Samip N Patel
Mozaffarul Islam
Quintin Pan
Sofia D Merajver
Theodoros N Teknos
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2010
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-9-206

Other articles of this Issue 1/2010

Molecular Cancer 1/2010 Go to the issue

Research

Tasquinimod (ABR-215050), a quinoline-3-carboxamide anti-angiogenic agent, modulates the expression of thrombospondin-1 in human prostate tumors

Research

NOTCH2 in breast cancer: association of SNP rs11249433 with gene expression in ER-positive breast tumors without TP53 mutations

Research

EBV-positive Hodgkin lymphoma is associated with suppression of p21cip1/waf1 and a worse prognosis

Research

Epigenetic control of the basal-like gene expression profile via Interleukin-6 in breast cancer cells

Research

Increased accumulation of hypoxia-inducible factor-1α with reduced transcriptional activity mediates the antitumor effect of triptolide

Research

NF-κB activation enhances cell death by antimitotic drugs in human prostate cancer cells
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