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01.10.2015 | Original Article

ICAM1 depletion reduces spinal metastasis formation in vivo and improves neurological outcome

verfasst von: Thomas Broggini, Marcus Czabanka, Andras Piffko, Christoph Harms, Christian Hoffmann, Ralf Mrowka, Frank Wenke, Urban Deutsch, Carsten Grötzinger, Peter Vajkoczy

Erschienen in: European Spine Journal | Ausgabe 10/2015

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Abstract

Introduction

Clinical treatment of spinal metastasis is gaining in complexity while the underlying biology remains unknown. Insufficient biological understanding is due to a lack of suitable experimental animal models. Intercellular adhesion molecule-1 (ICAM1) has been implicated in metastasis formation. Its role in spinal metastasis remains unclear. It was the aim to generate a reliable spinal metastasis model in mice and to investigate metastasis formation under ICAM1 depletion.

Material and methods

B16 melanoma cells were infected with a lentivirus containing firefly luciferase (B16-luc). Stable cell clones (B16-luc) were injected retrogradely into the distal aortic arch. Spinal metastasis formation was monitored using in vivo bioluminescence imaging/MRI. Neurological deficits were monitored daily. In vivo selected, metastasized tumor cells were isolated (mB16-luc) and reinjected intraarterially. mB16-luc cells were injected intraarterially in ICAM1 KO mice. Metastasis distribution was analyzed using organ-specific fluorescence analysis.

Results

Intraarterial injection of B16-luc and metastatic mB16-luc reliably induced spinal metastasis formation with neurological deficits (B16-luc:26.5, mB16-luc:21 days, p < 0.05). In vivo selection increased the metastatic aggressiveness and led to a bone specific homing phenotype. Thus, mB16-luc cells demonstrated higher number (B16-luc: 1.2 ± 0.447, mB16-luc:3.2 ± 1.643) and increased total metastasis volume (B16-luc:2.87 ± 2.453 mm³, mB16-luc:11.19 ± 3.898 mm³, p < 0.05) in the spine. ICAM1 depletion leads to a significantly reduced number of spinal metastasis (mB16-luc:1.2 ± 0.84) with improved neurological outcome (29 days). General metastatic burden was significantly reduced under ICAM1 depletion (control: 3.47 × 10⁷ ± 1.66 × 10⁷; ICAM-1 ^−/−: 5.20 × 10⁴ ± 4.44 × 10⁴, p < 0.05 vs. control)

Conclusion

Applying a reliable animal model for spinal metastasis, ICAM1 depletion reduces spinal metastasis formation due to an organ-unspecific reduction of metastasis development.

Kitagawa K, Yagita Y, Sasaki T, Sugiura S, Omura-Matsuoka E, Mabuchi T, Matsushita K, Hori M (2005) Chronic mild reduction of cerebral perfusion pressure induces ischemic tolerance in focal cerebral ischemia. Stroke J Cereb Circ 36:2270–2274. doi:10.1161/01.STR.0000181075.77897.0e CrossRef

Klimo P Jr, Schmidt MH (2004) Surg Manage Spinal Metastases. Oncologist 9:188–196CrossRefPubMed

Ryken TC, Eichholz KM, Gerszten PC, Welch WC, Gokaslan ZL, Resnick DK (2003) Evidence-based review of the surgical management of vertebral column metastatic disease. Neurosurg Focus 15:E11CrossRefPubMed

Patchell RA, Tibbs PA, Regine WF, Payne R, Saris S, Kryscio RJ, Mohiuddin M, Young B (2005) Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet 366:643–648. doi:10.1016/S01406736(05)669541 CrossRefPubMed

Gay LJ, Felding-Habermann B (2011) Contribution of platelets to tumour metastasis. Nat Rev Cancer 11:123–134. doi:10.1038/nrc3004 CrossRefPubMed

Takahashi M, Furihata M, Akimitsu N, Watanabe M, Kaul S, Yumoto N, Okada T (2008) A highly bone marrow metastatic murine breast cancer model established through in vivo selection exhibits enhanced anchorage-independent growth and cell migration mediated by ICAM-1. Clin Exp Metastasis 25:517–529. doi:10.1007/s1058500891635 CrossRefPubMed

Aoudjit F, Potworowski EF, Springer TA, St-Pierre Y (1998) Protection from lymphoma cell metastasis in ICAM-1 mutant mice: a posthoming event. J Immunol 161:2333–2338PubMed

Hayes SH, Seigel GM (2009) Immunoreactivity of ICAM-1 in human tumors, metastases and normal tissues. Int J Clin Exp Pathol 2:553–560PubMedCentralPubMed

Rosette C, Roth RB, Oeth P, Braun A, Kammerer S, Ekblom J, Denissenko MF (2005) Role of ICAM1 in invasion of human breast cancer cells. Carcinogenesis 26:943–950. doi:10.1093/carcin/bgi070 CrossRefPubMed

10.

Datwyler AL, Lattig-Tunnemann G, Yang W, Paschen W, Lee SL, Dirnagl U, Endres M, Harms C (2011) SUMO2/3 conjugation is an endogenous neuroprotective mechanism. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 31:2152–2159. doi:10.1038/jcbfm.2011.112 CrossRef

11.

Lois C, Hong EJ, Pease S, Brown EJ, Baltimore D (2002) Germline transmission and tissue-specific expression of transgenes delivered by lentiviral vectors. Science 295:868–872. doi:10.1126/science.1067081 CrossRefPubMed

12.

Dittgen T, Nimmerjahn A, Komai S, Licznerski P, Waters J, Margrie TW, Helmchen F, Denk W, Brecht M, Osten P (2004) Lentivirus-based genetic manipulations of cortical neurons and their optical and electrophysiological monitoring in vivo. Proc Natl Acad Sci USA 101:18206–18211. doi:10.1073/pnas.0407976101 PubMedCentralCrossRefPubMed

13.

Heroult M, Schaffner F, Pfaff D, Prahst C, Kirmse R, Kutschera S, Riedel M, Ludwig T, Vajkoczy P, Graeser R, Augustin HG (2010) EphB4 promotes site-specific metastatic tumor cell dissemination by interacting with endothelial cell-expressed ephrinB2. Mol Cancer Res MCR 8:1297–1309. doi:10.1158/15417786.MCR090453 CrossRefPubMed

14.

Arguello F, Baggs RB, Frantz CN (1988) A murine model of experimental metastasis to bone and bone marrow. Cancer Res 48:6876–6881PubMed

15.

Hecht N, He J, Kremenetskaia I, Nieminen M, Vajkoczy P, Woitzik J (2012) Cerebral hemodynamic reserve and vascular remodeling in C57/BL6 mice are influenced by age Stroke. a journal of cerebral circulation 43:3052–3062. doi:10.1161/STROKEAHA.112.653204 CrossRef

16.

Stackpole CW, Alterman AL, Valle EF (1991) B16 melanoma variants selected by one or more cycles of spontaneous metastasis to the same organ fail to exhibit organ specificity. Clin Exp Metastasis 9:319–332CrossRefPubMed

17.

Natali P, Nicotra MR, Cavaliere R, Bigotti A, Romano G, Temponi M, Ferrone S (1990) Differential expression of intercellular adhesion molecule 1 in primary and metastatic melanoma lesions. Cancer Res 50:1271–1278PubMed

18.

Lalancette M, Aoudjit F, Potworowski EF, St-Pierre Y (2000) Resistance of ICAM-1-deficient mice to metastasis overcome by increased aggressiveness of lymphoma cells. Blood 95:314–319PubMed

19.

Roland CL, Harken AH, Sarr MG, Barnett CC Jr (2007) ICAM-1 expression determines malignant potential of cancer. Surgery 141:705–707. doi:10.1016/j.surg.2007.01.016 CrossRefPubMed

20.

Takahashi M, Miyazaki H, Furihata M, Sakai H, Konakahara T, Watanabe M, Okada T (2009) Chemokine CCL2/MCP-1 negatively regulates metastasis in a highly bone marrow-metastatic mouse breast cancer model. Clin Exp Metastasis 26:817–828. doi:10.1007/s1058500992818 CrossRefPubMed

21.

Aherne NJ, ETC, Wang JH, Redmond KC, Kelly J, Richardson D, Redmond HP (2002) Bone marrow micrometastases have upregulation of ICAM-1 and αVβ3 integrins: a putative survival mechanism for tumour dissemination? Irish J Med Sci 171:2. doi:10.1007/BF03170404

22.

Ell B, Mercatali L, Ibrahim T, Campbell N, Schwarzenbach H, Pantel K, Amadori D, Kang Y (2013) Tumor-induced osteoclast miRNA changes as regulators and biomarkers of osteolytic bone metastasis. Cancer Cell 24:542–556. doi:10.1016/j.ccr.2013.09.008 CrossRefPubMed

23.

Lavigne P, Benderdour M, Shi Q, Lajeunesse D, Fernandes JC (2005) Involvement of ICAM-1 in bone metabolism: a potential target in the treatment of bone diseases? Expert Opin Biol Ther 5:313–320. doi:10.1517/14712598.5.3.313 CrossRefPubMed

24.

Zhang P, Goodrich C, Fu C, Dong C (2014) Melanoma upregulates ICAM-1 expression on endothelial cells through engagement of tumor CD44 with endothelial E-selectin and activation of a PKCalpha-p38-SP-1 pathway. FASEB J Off Publ Fed Am Soc Exp Biol 28:4591–4609. doi:10.1096/fj.11202747

Titel: ICAM1 depletion reduces spinal metastasis formation in vivo and improves neurological outcome
verfasst von: Thomas Broggini
Marcus Czabanka
Andras Piffko
Christoph Harms
Christian Hoffmann
Ralf Mrowka
Frank Wenke
Urban Deutsch
Carsten Grötzinger
Peter Vajkoczy
Publikationsdatum: 01.10.2015
Verlag: Springer Berlin Heidelberg
Erschienen in: European Spine Journal / Ausgabe 10/2015
Print ISSN: 0940-6719
Elektronische ISSN: 1432-0932
DOI: https://doi.org/10.1007/s00586-015-3811-7

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Abstract

Introduction

Material and methods

Results

Conclusion

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