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ICAM1 depletion reduces spinal metastasis formation in vivo and improves neurological outcome
Thomas Broggini1, Marcus Czabanka2, Andras Piffko1
1Department of Neurosurgery, Universitätsmedizin Charite, Augustenburger Platz 1, 13353, Berlin, Germany.
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: 3.47×10(7)±1.66×10(7); ICAM-1-/-: 5.20×10(4)±4.44×10(4), 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.
Insights
This study developed a reliable mouse model for spinal metastasis. Depleting Intercellular Adhesion Molecule-1 (ICAM1) significantly reduced spinal metastasis and improved neurological outcomes.
Area of Science:
- Oncology
- Translational Medicine
- Animal Models
Background:
- Clinical treatment of spinal metastasis lacks biological understanding due to inadequate experimental models.
- Intercellular Adhesion Molecule-1 (ICAM1) role in spinal metastasis is unclear.
- Development of a reliable mouse model is crucial for studying spinal metastasis.
Purpose of the Study:
- To establish a reliable mouse model for spinal metastasis.
- To investigate the role of ICAM1 in spinal metastasis formation.
- To evaluate the effect of ICAM1 depletion on metastasis development and neurological deficits.
Main Methods:
- B16 melanoma cells (B16-luc) were injected retrogradely into the aortic arch of mice.
- Spinal metastasis was monitored using bioluminescence imaging and MRI.
- In vivo selected metastatic cells (mB16-luc) were used to study ICAM1 knockout (KO) mice.
Main Results:
- Intraarterial injection reliably induced spinal metastasis with neurological deficits.
- In vivo selection enhanced metastatic aggressiveness and bone homing.
- ICAM1 depletion significantly reduced spinal metastasis number, volume, and overall metastatic burden, improving neurological outcomes.
Conclusions:
- A reliable animal model for spinal metastasis was established.
- ICAM1 depletion effectively reduces spinal metastasis formation.
- ICAM1 plays a significant role in the development of spinal metastasis.
