The ambition of the VIB Center for Cancer Biology (CCB) is to contribute to a better understanding of the biology that underlies cancer initiation, progression and metastatic dissemination with the ultimate goal to develop more effective and specific anti-cancer (combination) therapies.
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Laboratory of Tumor Inflammation and Angiogenesis
A lot of effort has been done to study how cancer cells react to oxygen shortage, a condition known as hypoxia. Indeed, abnormal and dysfunctional blood vessels in the tumor are incapable to restore oxygenation, therefore perpetuating hypoxia, which, in turn, will fuel tumor progression, metastasis and resistance to antitumor therapies.
This means that hypoxia can elicit complex and sometimes opposing responses in cancer cells and in the different stromal tumor components; therefore mechanisms to cope with low oxygen tensions can be systematically discovered in tumor microenvironment. These mechanisms rely on a family of oxygen-sensing prolyl hydroxylases, composed of three isoforms (PHD1, PHD2, and PHD3), which utilize oxygen to hydroxylate prolyl residues in the alpha subunit of the hypoxia-inducible transcription factor (HIF)-1a and HIF-2a, thus preventing HIF accumulation. We have previously shown that genetic inactivation of PHD2 induces tumor vessel normalization, thus reducing metastasis and improving chemotherapeutic drug delivery (Mazzone et al., Cell, 2009; Leite de Oliveira et al., Cancer Cell, 2012).
In addition, besides negatively regulating HIF accumulation, PHDs have functions that extend beyond oxygen sensing as observed by our lab in macrophages wherein PHD2 can control the activity of NF-aB, a key signaling molecule for inflammation, which lead macrophage skewing towards a proarteriogenic phenotype (Takeda et al., Nature, 20011; Hamm et al., EMBO Mol Med, 2013).
The control of NF-aB by PHDs can be both dependent and independent of the hydroxylase activity and therefore the presence of oxygen. In addition, cytokine driven downregulation of PHD expression levels also results in their reduced enzymatic activity independently of oxygen availability and thus triggers a “hypoxia-like” response.
Hence, it appears evident that the identification of upstream and downstream PHD regulators will increase our knowledge on how the hypoxia-response is regulated in both cancer cells and stromal compartment and how it affects their plasticity thus enlightening novel and yet unrecognized therapeutic targets and provide proof-of-feasibility for cell-based therapies. Importantly, although numerous studies examined how hypoxia initiates inflammation, much less attention has been paid on how oxygen tension shapes the inflammatory response of inflammatory cells and modulates specific differentiation states. Nevertheless, these are critical processes since, once recruited to the wounded region, inflammatory cells and in particular macrophages promote growth and expansion of blood vessels by directly stimulating endothelial cells and smooth muscle cells/pericytes, and by remodeling the extracellular matrix. Recently we described a Neuropilin-1-dependent guidance mechanism by which macrophages enter hypoxic tumor areas where they elicit their proangiogenic and immune suppressive functions. Thus, blocking Neuropilin-1 was sufficient to entrap macrophages in vascularized normoxic tumor areas and thus restore their anti-tumor capacity and prevent angiogenesis (Casazza et al., Cancer Cell, 2013). Based on these findings, understanding the molecular pathways underlying macrophage responses to reduced oxygen availability will shed light on the relation between hypoxia induced signaling and plasticity of inflammatory cells.
De facto, main research topics of the lab span the fields of cancer and inflammation, focusing on functional characterization of the hypoxia-response in differentiation and metabolism of tumor stromal cells, cancer progression and response to chemotherapy. In particular, we are using genetic, cell biological, biochemical and structural methods to better understand how the molecular specification of the hypoxia-driven response is orchestrated in different tumor microenvironments. We take advantage of tissue-specific gene targeting approaches in mice and combine the phenotype discovery with biochemical as well as cell biological techniques. At the molecular level, we are interested in dissecting the partners participating in the hypoxia response and determining how and what is conferring the specificity of this response in different cell types. Our proposed investigations will increase the knowledge on the molecular and cellular partners controlling inflammatory cell skewing and its significance in cancer. Hopefully our findings will offer novel therapeutic opportunities for those conditions where imbalanced or insufficient growth of blood vessels contributes to the pathogenesis of deadly disorders, such as cancer and ischemic diseases, unmet medical problems to date.