Elucidation of novel pro-metastic functions of tumor-associated carbonic anhydrase IX and its cross-talk with pro-inflammatory response
Project leader: Jozef Bizik
Project duration: 2015 - 2019
Tumor microenvironment is a complex ecosystem consisting from components influencing each other - tumor cells, stromal cells, extracellular matrix and many soluble factors and cytokines. Characteristic feature of the tumor microenvironment-hypoxia is considered as indicator of bad prognosis. Among the most hypoxia-induced proteins is carbonic anhydrase IX (CA IX) whose increased expression in tissues is often correlated with high malignity and the main task of which is to maintain intracellular pH homeostasis linked with acidification of the extracellular space. It is known that many processes in cells are tightly controlled by the values of intracellular and extracellular pH. Such process is also the formation of invasive structures, so-called invadopodia, which represents an important step in tumor cells metastasizing. Intriguingly, CA IX protein can markedly affect their formation by its enzymatic activity. Our most recent results indicate that another mechanism by which CA IX could participate in the invasion process is its cross-talk with proteins such as Arp2/3, WASP and mDia, responsible for actin polymerization. The molecular mechanism of this interplay will be the subject of our research. Moreover, from the point of view of migration and invasion, the proteoglycan domain of CA IX has an interesting ability to bind ECM proteins, and hence promote dissemination of tumor cells. It was also proved that certain inflammatory mediators, such as COX-2 and IL-6, increase the expression of CA IX. Hypoxia, necrosis and inflammatory reaction are closely connected during malignant progression. Despite this fact it has not been elucidated yet how necrosis-related signaling modulates hypoxia at the molecular level. Therefore, by a detailed study of CA IX we would like to identify a functional link between necrosis-induced signaling molecules, hypoxia and invasive potential of tumor cells, and subsequently to search for possibilities of their influencing or inhibition.