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Tumor metastasis is tightly linked with invasive membrane protrusions, invadopodia, formed by actively invading tumor cells. Hypoxia and pH modulation play a role in the invadopodia formation and in their matrix degradation ability. Tumor-associated carbonic anhydrase IX (CAIX), induced by hypoxia, is essential for pH regulation and migration, predisposing it as an active component of invadopodia. To investigate this assumption, we employed silencing and inhibition of CA9, invadopodia isolation and matrix degradation assay. Quail chorioallantoic membranes with implanted tumor cells, and lung colonization assay in murine model were used to assess efficiency of in vivo invasion and the impact of CAIX targeting antibodies. We showed that CAIX co-distributes to invadopodia with cortactin, MMP14, NBCe1, and phospho-PKA. Suppression or enzymatic inhibition of CAIX leads to impaired invadopodia formation and matrix degradation. Loss of CAIX attenuated phosphorylation of Y421-cortactin and influenced molecular machinery coordinating actin polymerization essential for invadopodia growth. Treatment of tumor cells by CAIX-specific antibodies against carbonic or proteoglycan domains results in reduced invasion and extravasation in vivo . For the first time, we demonstrated in vivo localization of CAIX within invadopodia. Our findings confirm the key role of CAIX in the metastatic process and gives rationale for its targeting during anti-metastatic therapy.

Pyruvate dehydrogenase kinase 1 (PDHK1) and carbonic anhydrase IX (CAIX) are some of the most hypoxia-inducible proteins associated with tumors, implicated in glucose metabolism and pH regulation, respectively. They both appear to be necessary for model tumor growth, and their high level of expression in human tumors predicts poor patient outcome. Another thing they have in common is that hypoxia not only induces their expression but also their enzymatic activity. This work therefore simultaneously targets these two hypoxia-inducible proteins either pharmacologically or genetically in vitro and in vivo, leading to decreased cancer cell survival and significantly slower model tumor growth. It also suggests that CAIX and PDHK1 are important for cells originating from a colorectal primary tumor, as well as from its metastasis. Moreover, our analysis reveals a unique relationship between these two HIF-1 target genes. In conclusion, the attributes of PDHK1 and CAIX predict them to be promising targets for the design of new, specific inhibitors that could negatively influence tumor cell proliferation and survival, or increase efficacy of standard treatment regimens, and at the same time avoid normal tissue toxicity.

Pyruvate dehydrogenase kinase 1 (PDHK1) and carbonic anhydrase IX (CAIX) are some of the most hypoxia-inducible proteins associated with tumors, implicated in glucose metabolism and pH regulation, respectively. They both appear to be necessary for model tumor growth, and their high level of expression in human tumors predicts poor patient outcome. Another thing they have in common is that hypoxia not only induces their expression but also their enzymatic activity. This work therefore simultaneously targets these two hypoxia-inducible proteins either pharmacologically or genetically in vitro and in vivo, leading to decreased cancer cell survival and significantly slower model tumor growth. It also suggests that CAIX and PDHK1 are important for cells originating from a colorectal primary tumor, as well as from its metastasis. Moreover, our analysis reveals a unique relationship between these two HIF-1 target genes. In conclusion, the attributes of PDHK1 and CAIX predict them to be promising targets for the design of new, specific inhibitors that could negatively influence tumor cell proliferation and survival, or increase efficacy of standard treatment regimens, and at the same time avoid normal tissue toxicity. [ABSTRACT FROM AUTHOR]