| Abstract [eng] |
Despite recent breakthroughs in cancer treatment, the survival of pediatric patients presenting with advanced-stage or relapsed solid tumors remains poor. Tumors employ a variety of compensatory mechanisms to evade tumor killing. Tumor hypoxia and associated peritumoral acidosis significantly contribute to cancer progression and treatment resistance. CAIX, a hypoxia-induced enzyme, helps cancer cells overcome intracellular acidosis and survive whereas CCL2-CCR2 axis promotes immunosuppressive tumor microenvironment. Both, CAIX enzyme and CCL2-CCR2 chemokine signaling axis have become attractive targets in cancer therapy development. Our work highlights the compensatory mechanisms involved when CAIX or CCL2-CCR2 axis is inhibited in pediatric cancer solid tumor models, such as neuroblastoma and osteosarcoma. We demonstarte feasibilty of combining CAIX inhibition with CCR2 antagonist in neuroblastoma xenograft model. In addition, we evaluated the CAIX inhibitor synthetic compounds‘ suitability and limitations for CAIX expressing tumor's recognition in vivo. Additionally, we show how hypoxic conditions alter the expression of different cellular markers and impair CCR2 antagonist effects in the experimental 143B osteosarcoma model. All these findings can serve as a foundation for future hypoxic tumor niche recognition-based therapy and diagnostics development. |
