Abstract
Small cell lung cancer (SCLC) is an aggressive, rapidly metastazising neoplasm with a high propensity for marrow involvement. SCLC cells express high levels of functional CXCR4 receptors for the chemokine stromal-cell-derived factor-1 (SDF-1/CXCL12). Adhesion of SCLC cells to extracellular matrix or accessory cells within the tumor microenvironment confers resistance to chemotherapy via integrin signaling and thus may be responsible for residual disease and relapses commonly seen in SCLC. We examined the signaling mechanisms that regulate CXCL12-induced adhesion of SCLC cells to fibronectin, collagen and stromal cells and the effects on SCLC cell chemoresistance. We found that CXCL12-induced integrin activation which resulted in an increased adhesion of SCLC cells to fibronectin and collagen. This was mediated by α2, α4, α5 and β1 integrins along with CXCR4 activation, which could be inhibited by CXCR4 antagonists. Stromal cells protected SCLC cells from chemotherapy-induced apoptosis and this protection could also be antagonized by CXCR4 inhibitors. We conclude that activation of integrins and CXCR4 chemokine receptors co-operate in mediating adhesion and survival signals from the tumor microenvironment to SCLC cells. Therefore, CXCR4 antagonists in combination with cytotoxic drugs should be explored in SCLC to overcome CXCL12-mediated adhesion and survival signals in the tumor microenvironment.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Burger JA, Burger M and Kipps TJ . (1999). Blood, 94, 3658–3667.
Burger JA, Spoo A, Dwenger A, Burger M and Behringer D . (2003a). Br. J. Haematol., 122, 579–589.
Burger M, Glodek A, Hartmann T, Schmitt-Graff A, Silberstein LE, Fujii N, Kipps TJ and Burger JA . (2003b). Oncogene, 22, 8093–8101.
Campbell JJ, Hedrick J, Zlotnik A, Siani MA, Thompson DA and Butcher EC . (1998). Science, 279, 381–384.
Constantin G, Majeed M, Giagulli C, Piccio L, Kim JY, Butcher EC and Laudanna C . (2000). Immunity, 13, 759–769.
Duong LT and Rodan GA . (2000). Cell Motil. Cytoskeleton, 47, 174–188.
Fernandis AZ, Prasad A, Band H, Klosel R and Ganju RK . (2004). Oncogene, 23, 157–167.
Fujii N, Nakashima H and Tamamura H . (2003). Expert Opin. Invest. Drugs, 12, 185–195.
Ganju RK, Brubaker SA, Meyer J, Dutt P, Yang Y, Qin S, Newman W and Groopman JE . (1998). J. Biol. Chem., 273, 23169–23175.
Geminder H, Sagi-Assif O, Goldberg L, Meshel T, Rechavi G, Witz IP and Ben-Baruch A . (2001). J. Immunol., 167, 4747–4757.
Glodek AM, Honczarenko M, Le Y, Campbell JJ and Silberstein LE . (2003). J. Exp. Med., 197, 461–473.
Grabovsky V, Feigelson S, Chen C, Bleijs DA, Peled A, Cinamon G, Baleux F, Arenzana-Seisdedos F, Lapidot T, van Kooyk Y, Lobb RR and Alon R . (2000). J. Exp. Med., 192, 495–506.
Hamasaki K, Mimura T, Morino N, Furuya H, Nakamoto T, Aizawa S, Morimoto C, Yazaki Y, Hirai H and Nojima Y . (1996). Biochem. Biophys. Res. Commun., 222, 338–343.
Hazlehurst LA, Damiano JS, Buyuksal I, Pledger WJ and Dalton WS . (2000). Oncogene, 19, 4319–4327.
Hidalgo A, Sanz-Rodriguez F, Rodriguez-Fernandez JL, Albella B, Blaya C, Wright N, Cabanas C, Prosper F, Gutierrez-Ramos JC and Teixido J . (2001). Exp. Hematol., 29, 345–355.
Hoffman PC, Mauer AM and Vokes EE . (2000). Lancet, 355, 479–485.
Ihde DC . (1992). N. Engl. J. Med., 327, 1434–1441.
Kijima T, Maulik G, Ma PC, Tibaldi EV, Turner RE, Rollins B, Sattler M, Johnson BE and Salgia R . (2002). Cancer Res., 62, 6304–6311.
Kraus AC, Ferber I, Bachmann SO, Specht H, Wimmel A, Gross MW, Schlegel J, Suske G and Schuermann M . (2002). Oncogene, 21, 8683–8695.
Lassen U, Osterlind K, Hansen M, Dombernowsky P, Bergman B and Hansen HH . (1995). J. Clin. Oncol., 13, 1215–1220.
Lemoine FM, Humphries RK, Abraham SD, Krystal G and Eaves CJ . (1988). Exp. Hematol., 16, 718–726.
Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verastegui E and Zlotnik A . (2001). Nature, 410, 50–56.
Murakami T, Maki W, Cardones AR, Fang H, Tun Kyi A, Nestle FO and Hwang ST . (2002). Cancer Res., 62, 7328–7334.
Nefedova Y, Landowski TH and Dalton WS . (2003). Leukemia, 17, 1175–1182.
Peled A, Grabovsky V, Habler L, Sandbank J, Arenzana-Seisdedos F, Petit I, Ben-Hur H, Lapidot T and Alon R . (1999). J. Clin. Invest., 104, 1199–1211.
Phillips RJ, Burdick MD, Lutz M, Belperio JA, Keane MP and Strieter RM . (2003). Am. J. Respir Crit. Care Med., 167, 1676–1686.
Robledo MM, Bartolome RA, Longo N, Rodriguez-Frade JM, Mellado M, Longo I, van Muijen GN, Sanchez-Mateos P and Teixido J . (2001). J. Biol. Chem., 276, 45098–45105.
Salgia R, Li JL, Ewaniuk DS, Wang YB, Sattler M, Chen WC, Richards W, Pisick E, Shapiro GI, Rollins BJ, Chen LB, Griffin JD and Sugarbaker DJ . (1999). Oncogene, 18, 67–77.
Sanz-Rodriguez F, Hidalgo A and Teixido J . (2001). Blood, 97, 346–351.
Schaller MD . (2001). Biochim. Biophys. Acta, 1540, 1–21.
Sethi T, Rintoul RC, Moore SM, MacKinnon AC, Salter D, Choo C, Chilvers ER, Dransfield I, Donnelly SC, Strieter R and Haslett C . (1999). Nat. Med., 5, 662–668.
Springer TA . (1994). Cell, 76, 301–314.
Taichman RS, Cooper C, Keller ET, Pienta KJ, Taichman NS and McCauley LK . (2002). Cancer Res., 62, 1832–1837.
Tamamura H, Omagari A, Hiramatsu K, Gotoh K, Kanamoto T, Xu Y, Kodama E, Matsuoka M, Hattori T, Yamamoto N, Nakashima H, Otaka A and Fujii N . (2001). Bioorg. Med. Chem. Lett., 11, 1897–1902.
Uhm JH, Dooley NP, Kyritsis AP, Rao JS and Gladson CL . (1999). Clin. Cancer Res., 5, 1587–1594.
Vicente-Manzanares M, Montoya MC, Mellado M, Frade JM, del Pozo MA, Nieto M, de Landazuri MO, Martinez AC and Sanchez-Madrid F . (1998). Eur. J. Immunol., 28, 2197–2207.
Wade R, Bohl J and Vande Pol S . (2002). Oncogene, 21, 96–107.
Wright N, Hidalgo A, Rodriguez-Frade JM, Soriano SF, Mellado M, Parmo-Cabanas M, Briskin MJ and Teixido J . (2002). J. Immunol., 168, 5268–5277.
Zipori D, Toledo J and von der Mark K . (1985). Blood, 66, 447–455.
Acknowledgements
The authors are grateful to Myriam Krome and Barbara Rogalsky for excellent technical assistance. Supported by the Deutsche Forschungsgemeinschaft (DFG) grant no. BU/1159/3-2 (to MB) and Deutsche Krebshilfe grant no. 10-1688-Bu (to JAB).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hartmann, T., Burger, J., Glodek, A. et al. CXCR4 chemokine receptor and integrin signaling co-operate in mediating adhesion and chemoresistance in small cell lung cancer (SCLC) cells. Oncogene 24, 4462–4471 (2005). https://doi.org/10.1038/sj.onc.1208621
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1208621
Keywords
This article is cited by
-
CXC chemokine receptor 4 (CXCR4) blockade in cancer treatment
Journal of Cancer Research and Clinical Oncology (2023)
-
Small-cell lung cancer
Nature Reviews Disease Primers (2021)
-
Single-cell microRNA sequencing method comparison and application to cell lines and circulating lung tumor cells
Nature Communications (2021)
-
Therapy-Induced Changes in CXCR4 Expression in Tumor Xenografts Can Be Monitored Noninvasively with N-[11C]Methyl-AMD3465 PET
Molecular Imaging and Biology (2020)
-
Colorectal cancer cell-derived CCL20 recruits regulatory T cells to promote chemoresistance via FOXO1/CEBPB/NF-κB signaling
Journal for ImmunoTherapy of Cancer (2019)