Inducible Expression of Tissue Factor in Small-cell Lung Cancer: Impact on Morphology and Matrix Metalloproteinase Secretion

Overview

Journal J Cancer Res Clin Oncol

Specialty Oncology

Date 2012 Jan 13

PMID 22237453

Citations 9

Authors

Nicole Hahn

Margarethe Heiden

Rainer Seitz

Ursula Salge-Bartels

Affiliations

Soon will be listed here.

Abstract

Purpose: Tissue factor (TF), the transmembrane receptor for factor VIIa (FVIIa), has key regulatory functions in coagulation as well as in tumour progression and metastasis. Small-cell lung cancer (SCLC) metastasises more aggressively than non-small-cell lung cancer (NSCLC). Previously, we described the transition of SCLC cell line H69 to adherent growth and TF expression. Here, we explored the differential expression of TF and its functional impact on morphology and matrix metalloproteinase (MMP) secretion.

Methods: The constitutional TF expression was evaluated in a panel of established NSCLC and SCLC cell lines. Furthermore, in three stress-selected adherent SCLC H69 cells, TF and MMP expressions were determined by mRNA, protein, and activity measurements. RNA interference-mediated TF down-regulation and FVIIa stimulation were used to study the impact of TF on cellular functions.

Results: NSCLC cells expressed high TF antigen (median 3.75 ng/mg; range 0.31-65.2 ng/mg protein, n = 8), while SCLC expressed none or low TF (median 0.07 ng/mg; range 0-0.39 ng/mg protein, n = 6). However, selected H69 adherent cells markedly expressed TF (range: 4.8-44.3 ng/mg protein, n = 3) and secreted MMP-2 and MMP-9. FVIIa stimulated MMP-2 and MMP-9 secretion in H69adh cells, whereas TF down-regulation diminished MMP-2 and MMP-9 expression and promoted reversion to suspension growth.

Conclusions: Our data show the significance of TF expression in the reversible growth phenotype of H69. Because TF, MMP expression, and adherence are highly relevant to cancer metastasis, this study suggests a novel mechanism of adaptation, thereby adding to the understanding of SCLC biology and its aggressiveness.

Citing Articles

Role of Notch1 Signaling Pathway in Small Cell Lung Carcinoma.

Charbat M, Abdulhalim Y, Alrabeei M, Abdo Hassan W Iran J Pathol. 2025; 19(4):365-375.

PMID: 40034926 PMC: 11872034. DOI: 10.30699/IJP.2024.2013339.3184.

Targeting cancer-derived extracellular vesicles by combining CD147 inhibition with tissue factor pathway inhibitor for the management of urothelial cancer cells.

Boddu V, Zamzow P, Kramer M, Merseburger A, Gorantla S, Klinger M Cell Commun Signal. 2024; 22(1):129.

PMID: 38360687 PMC: 10870545. DOI: 10.1186/s12964-024-01508-x.

Small cell lung cancer: circulating tumor cell lines and expression of mediators of angiogenesis and coagulation.

Rath B, Plangger A, Klameth L, Hochmair M, Ulsperger E, Boeckx B Explor Target Antitumor Ther. 2023; 4(2):355-365.

PMID: 37205313 PMC: 10185438. DOI: 10.37349/etat.2023.00139.

Potential Coagulation Factor-Driven Pro-Inflammatory Responses in Ovarian Cancer Tissues Associated with Insufficient O₂ and Plasma Supply.

Koizume S, Miyagi Y Int J Mol Sci. 2017; 18(4).

PMID: 28417928 PMC: 5412393. DOI: 10.3390/ijms18040809.

Small cell lung cancer, an epithelial to mesenchymal transition (EMT)-like cancer: significance of inactive Notch signaling and expression of achaete-scute complex homologue 1.

Ito T, Kudoh S, Ichimura T, Fujino K, Hassan W, Udaka N Hum Cell. 2016; 30(1):1-10.

PMID: 27785690 DOI: 10.1007/s13577-016-0149-3.

References

Bogdanov V, Balasubramanian V, Hathcock J, Vele O, Lieb M, Nemerson Y . Alternatively spliced human tissue factor: a circulating, soluble, thrombogenic protein. Nat Med. 2003; 9(4):458-62. DOI: 10.1038/nm841. View

Bepler G, Rotsch M, Jaques G, Haeder M, Heymanns J, Hartogh G . Peptides and growth factors in small cell lung cancer: production, binding sites, and growth effects. J Cancer Res Clin Oncol. 1988; 114(3):235-44. DOI: 10.1007/BF00405828. View

Adamkiewicz J, Wimmel A, Schuermann M . Transition from SCLC to NSCLC phenotype is accompanied by an increased TRE-binding activity and recruitment of specific AP-1 proteins. Oncogene. 1998; 16(23):3057-68. DOI: 10.1038/sj.onc.1201845. View

Sawada M, Miyake S, Ohdama S, Matsubara O, Masuda S, Yakumaru K . Expression of tissue factor in non-small-cell lung cancers and its relationship to metastasis. Br J Cancer. 1999; 79(3-4):472-7. PMC: 2362438. DOI: 10.1038/sj.bjc.6690073. View

Regina S, Valentin J, Lachot S, Lemarie E, Rollin J, Gruel Y . Increased tissue factor expression is associated with reduced survival in non-small cell lung cancer and with mutations of TP53 and PTEN. Clin Chem. 2009; 55(10):1834-42. DOI: 10.1373/clinchem.2009.123695. View

Salge U, Seitz R, Wimmel A, Schuermann M, Daubner E, Heiden M . Transition from suspension to adherent growth is accompanied by tissue factor expression and matrix metalloproteinase secretion in a small cell lung cancer cell line. J Cancer Res Clin Oncol. 2001; 127(2):139-41. DOI: 10.1007/s004320000210. View

Versteeg H, Spek C, Richel D, Peppelenbosch M . Coagulation factors VIIa and Xa inhibit apoptosis and anoikis. Oncogene. 2004; 23(2):410-7. DOI: 10.1038/sj.onc.1207066. View

Michael M, Babic B, Khokha R, Tsao M, Ho J, Pintilie M . Expression and prognostic significance of metalloproteinases and their tissue inhibitors in patients with small-cell lung cancer. J Clin Oncol. 1999; 17(6):1802-8. DOI: 10.1200/JCO.1999.17.6.1802. View

Szotowski B, Goldin-Lang P, Antoniak S, Bogdanov V, Pathirana D, Pauschinger M . Alterations in myocardial tissue factor expression and cellular localization in dilated cardiomyopathy. J Am Coll Cardiol. 2005; 45(7):1081-9. DOI: 10.1016/j.jacc.2004.12.061. View

10.

Holen T, Amarzguioui M, Wiiger M, Babaie E, Prydz H . Positional effects of short interfering RNAs targeting the human coagulation trigger Tissue Factor. Nucleic Acids Res. 2002; 30(8):1757-66. PMC: 113209. DOI: 10.1093/nar/30.8.1757. View

11.

Haberland J, Bertz J, Wolf U, Ziese T, Kurth B . German cancer statistics 2004. BMC Cancer. 2010; 10:52. PMC: 2837012. DOI: 10.1186/1471-2407-10-52. View

12.

Xu C, Gui Q, Chen W, Wu L, Sun W, Zhang N . Small interference RNA targeting tissue factor inhibits human lung adenocarcinoma growth in vitro and in vivo. J Exp Clin Cancer Res. 2011; 30:63. PMC: 3118969. DOI: 10.1186/1756-9966-30-63. View

13.

Keller T, Salge U, Konig H, Dodt J, Heiden M, Seitz R . Tissue factor is the only activator of coagulation in cultured human lung cancer cells. Lung Cancer. 2001; 31(2-3):171-9. DOI: 10.1016/s0169-5002(00)00196-3. View

14.

Seitz R, Rappe N, Kraus M, Immel A, Wolf M, Maasberg M . Activation of coagulation and fibrinolysis in patients with lung cancer: relation to tumour stage and prognosis. Blood Coagul Fibrinolysis. 1993; 4(2):249-54. DOI: 10.1097/00001721-199304000-00006. View

15.

Seitz R, Heidtmann H, Wolf M, Immel A, Egbring R . Prognostic impact of an activation of coagulation in lung cancer. Ann Oncol. 1997; 8(8):781-4. DOI: 10.1023/a:1008240918434. View

16.

Versteeg H, Schaffner F, Kerver M, Petersen H, Ahamed J, Felding-Habermann B . Inhibition of tissue factor signaling suppresses tumor growth. Blood. 2007; 111(1):190-9. PMC: 2200804. DOI: 10.1182/blood-2007-07-101048. View

17.

Ohlmann C, Jung C, Jaques G . Is growth inhibition and induction of apoptosis in lung cancer cell lines by fenretinide [N-(4-hydroxyphenyl)retinamide] sufficient for cancer therapy?. Int J Cancer. 2002; 100(5):520-6. DOI: 10.1002/ijc.10525. View

18.

Heidtmann H, Salge U, Havemann K, KIRSCHKE H, Wiederanders B . Secretion of a latent, acid activatable cathepsin L precursor by human non-small cell lung cancer cell lines. Oncol Res. 1993; 5(10-11):441-51. View

19.

Wojtukiewicz M, Zacharski L, Memoli V, Kisiel W, Kudryk B, Rousseau S . Abnormal regulation of coagulation/fibrinolysis in small cell carcinoma of the lung. Cancer. 1990; 65(3):481-5. DOI: 10.1002/1097-0142(19900201)65:3<481::aid-cncr2820650318>3.0.co;2-u. View

20.

Ruf W, Yokota N, Schaffner F . Tissue factor in cancer progression and angiogenesis. Thromb Res. 2010; 125 Suppl 2:S36-8. PMC: 3827916. DOI: 10.1016/S0049-3848(10)70010-4. View