gms | German Medical Science

Objective: Cerebral breast and lung cancer metastases are the most common secondary malignancies in the brain and are often associated with a devastating prognosis. Dormancy is a mechanism of therapy resistance, in which tumor cells transverse into a non-proliferating, immunologically silent phenotype, which easily survive chemotherapy and are considered a source of recurrence. The NKG2D system consists of NKG2D ligands (NKG2DL), which are expressed on tumor cells, and NKG2D receptors, which are expressed on immune effector cells like NK cells and cytotoxic T cells. These usually can detect and eliminate NKG2D carrying tumor cells. We investigated, how dormancy marker and NKG2DL expression changes in brain metastases after chemotherapeutic treatment and if dormant cells have the ability to form a tumor in a cerebral microenvironment.

Methods: We analyzed the dormancy marker (DM) and NKG2DL expression in the murine breast cancer cell line E0771 and the lung cancer cell line LLC by qrtPCR and immunocytochemistry in vitro. Cells received a chemotheraopeutic treatment with Cyclosphosphamid or Cisplatin, were analyzed concerning their DM and NKG2DL expression again and where then stereotactically implanted into the brains of naïve C57BL6 mice. As a control, we implanted non-treated cells. Next, size, invasiveness and marker expression were analyzed using immunohistochemistry.

Results: In-vitro chemotherapeutic treatment with Cyclophosphamid and Cisplatin led to an upregulation of DM and NKG2DL in a dose and time dependent fashion. When implanting equal amounts of treated (dormant) and non-treated (non dormant) cells into the right striatum of naïve mice, non-dormant tumors grew significantly bigger and more invasive compared to dormant tumors.

Conclusion: Although chemotherapy induced a potentially more tumorigenic cell phenotype with overexpression of DM, dormant tumors were smaller and less invasive than non-dormant tumors. We therefore conclude, that dormant cells, although being chemo resistant, do not have the ability to sufficiently form tumors in a cerebral microenvironment. A possible reason could be the overexpression of NKG2DL, which also was induced by chemotherapeutic treatment. For future therapeutic approaches against brain metastases, addressing the NKG2D system might be promising, whereas dormancy as a mechanism of tumor surveillance might not be as relevant in brain metastases.