Cancer Science & Therapy

Background and purpose: Transplantable immunogenic breast tumors (EMT6) in CD200RKO mice, but not wild-type (WT) animals, are cured of local and metastatic tumor growth following surgical resection and immunization with irradiated cells in adjuvant. By contrast tumor growth of the poorly immunogenic 4THM breast cancer was actually enhanced in CD200R1KO mice by comparison with WT mice. A novel two-phase culture system in which tumor invasion from a liquid phase occurs into a collagen gel containing bone marrow mesenchymal stromal cells (BMMSCs) was described which could recapitulate many of the differences observed in vivo between EMT6 and 4THM tumor cells. Invasion of tumor cells into the gel layer was monitored after collagenase digestion and culture of tumor cells at limiting dilution. Aliquots of the digest were assayed for cytokine levels in ELISA.

Results: Growth of both EMT6 and 4THM tumor cells into the collagen matrix was increased in collagen gels impregnated with BMMSCs. TGFβ IL-6 and IL-17 were detected in both gel and liquid phases following addition of DLN cells to the matrix. While inclusion of IL-6 and IL-17 alone in the gel matrix increased EMT6 tumor cell invasiveness, this was actually attenuated by inclusion of Draining Lymph Node (DLN) cells from EMT6 immune mice into the gel. This attenuation was abolished by anti-TGFβ antibody, and re-established using recombinant TGFβ. Anti-TGFβ did not affect 4THM tumor invasion into collagen gels, though there was a trend to increased invasion with TGFβ added to the gel matrix.

Conclusion: Micro-environmental stromal elements and the cytokines IL-6/IL-17/TGFβ control local invasion of breast tumor cells. These effects are further differentially modulated in different tumors by the presence of additional inflammatory/immune responses.