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Effects of the disintegrin eristostatin on individual steps of hematogenous metastasis
V L Morris1, E E Schmidt, S Koop
1Department of Microbiology and Immunology, University of Western Ontario, London, Canada.
Abstract:
Adhesion molecules, including integrins, are important for interactions of cancer cells with vessel walls, a step leading to cancer metastasis. Disintegrins block the action of integrins by binding to them. We tested the hypothesis that the disintegrin eristostatin would block metastasis by interfering with cancer cell adhesion to vessel walls, thus preventing extravasation. Experimental metastasis assays, in which B16F1 melanoma cells (controls vs eristostatin-treated, 25 micrograms/ml) were injected via mesenteric veins of anesthetized C57BL/6 mice, showed that eristostatin reduced (P < 0.05) the mean number of liver metastases from 14.4 to 0.6 at 11 days postinjection (p.i.). We examined three different steps in metastasis at which eristostatin could have exerted its effect, namely, cell arrest, extravasation, and migration. Control and eristostatin-treated B16F1 cells were fluorescently labeled and examined by videomicroscopy in liver microcirculation in vivo at various times up to 14 days p.i. Measurements of vessel size in which cell arrest occurred and length/width ratio of arrested cells showed only small differences between control and eristostatin-treated cells. Eristostatin treatment did not prevent extravasation, and the timing and process of extravasation were similar for both treated and control cells; by 3-4 days p.i. more than 90% of the cells had extravasated or were in the process. Eristostatin also did not affect the ability of extravasated cells to migrate through the extracellular matrix to the subcapsular region where tumors later form. Therefore, we conclude that eristostatin exerted its primary effect by regulating the number of individual cancer cells that grow after extravasation.
Insights
The disintegrin eristostatin significantly reduced liver metastases in mice by impacting cancer cell growth post-extravasation, not by blocking initial adhesion or migration.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Integrins are key adhesion molecules mediating cancer cell interactions with blood vessels, a critical step in metastasis.
- Disintegrins, like eristostatin, inhibit integrin function by binding to them.
Purpose of the Study:
- To investigate the anti-metastatic potential of eristostatin.
- To determine if eristostatin blocks cancer cell adhesion to vessel walls and prevents extravasation.
Main Methods:
- Experimental metastasis assays using B16F1 melanoma cells injected into C57BL/6 mice.
- In vivo videomicroscopy to observe cancer cell arrest, extravasation, and migration in the liver microcirculation.
- Quantification of liver metastases at 11 days postinjection.
Main Results:
- Eristostatin treatment significantly reduced the mean number of liver metastases from 14.4 to 0.6.
- Eristostatin did not significantly alter cancer cell arrest in vessels or the extravasation process.
- Eristostatin did not impede the migration of extravasated cancer cells.
Conclusions:
- Eristostatin primarily acts by regulating the growth of individual cancer cells after they have extravasated from blood vessels.
- Eristostatin demonstrates potential as a therapeutic agent targeting cancer metastasis through a novel mechanism.