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 plastiacity 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.
> video on basic research on collaboration between immune system & cancer - Massimiliano Mazzone
- ©VIB, 2015
Macrophage Metabolism Controls Tumor Blood Vessel Morphogenesis and MetastasisWenes M, Shang M, di Matteo M, Goveia J, Martin Perez R, Serneels J, Prenen H, Ghesquière B, Carmeliet P, Mazzone MCell Metabolism, 24, 701-715, 2016 MET is required for the recruitment of anti-tumoural neutrophilsFinisguerra V, Di Conza G, di Matteo M, Serneels J, Costa S, Thompson A, Wauters E, Walmsley S, Prenen H, Granot Z, Casazza A, Mazzone MNATURE, 522, 349-53, 2015 PHD1 regulates p53-mediated colorectal cancer chemoresistanceDeschoemaeker S, Di Conza G, Lilla S, Martin Perez R, Mennerich D, Boon L, Hendrikx S, Maddocks O, Marx C, Radhakrishnan P, Prenen H, Schneider M, Myllyharju J, Kietzmann T, Vousden K, Zanivan S, Mazzone MEMBO Molecular Medicine, 7, 1350-65, 2015 Impeding Macrophage Entry into Hypoxic Tumor Areas by Sema3A/Nrp1 Signaling Blockade Inhibits Angiogenesis and Restores Antitumor ImmunityCasazza A, Laoui D, Wenes M, Rizzolio S, Bassani N, Mambretti M, Deschoemaeker S, Van Ginderachter J, Tamagnone L, Mazzone MCANCER CELL, 24, 695-709, 2013 Macrophage skewing by Phd2 haplodeficiency prevents ischaemia by inducing arteriogenesisTakeda Y, Costa S, Delamarre E, Roncal C, Leite de Oliveira R, Squadrito M, Finisguerra V, Deschoemaeker S, Bruyere F, Wenes M, Hamm A, Serneels J, Magat J, Bhattacharyya T, Anisimov A, Jordan B, Alitalo K, Maxwell P, Gallez B, Zhuang Z, Saito Y, Simons M, De Palma M, Mazzone MNATURE, 479, 122-126, 2011
14/02/2017 - Scientists at VIB-KU Leuven have identified a new mechanism that impacts tumor growth. The typical lack of oxygen in tumors doesn’t only stimulate proliferation, but also offsets the important role of the protein PHD2 as ‘cancer cell killer’.
20/10/2016 - Scientists at VIB and KU Leuven discovered a crucial factor in the spread of cancer. A team led by Massimiliano Mazzone has demonstrated that the metabolism of macrophages can be attuned to prevent the spread of cancer.
19/08/2015 - Scientists at VIB and KU Leuven have shown that blocking the PHD1 oxygen sensor hinders the activation of p53, a transcription factor that aids colorectal cancer (CRC) cells in repairing themselves and thus resisting chemotherapy.
25/06/2015 - One of the things Max Mazzone (Vesalius Research Center) focuses on is the role of our immune system in cancer. And this has recently lead to two important breakthroughs published in Nature and Gut.
18/05/2015 - The MET-proto-oncogene is involved in the pathogenesis of several tumors and therefore represents an interesting target for future therapies currently tested in dozens of clinical trials.
27/03/2015 - Researchers from VIB and KU Leuven have identified bio-markers that can be incorporated in a new diagnostic test. This should make it possible to detect colorectal cancer in an early stage using a simple blood test.
10/12/2013 - The Leuven-based VIB researchers have revealed a mechanism that explains why the anti-tumor activity of specific immune cells called macrophages is suppressed during tumor growth.
26/09/2013 - Occlusion of the main arterial route redirects blood flow to the collateral circulation. Max Mazzone, VIB Vesalius Research Center, KU Leuven, investigates the genetic and molecular mechanisms that are responsible for reestablishing the blood flow.
14/08/2012 - Researchers in Leuven (VIB/KU Leuven) have confirmed their hypothesis that normalizing blood vessels by blocking oxygen sensor PHD2 would make chemotherapy more effective.
10/10/2011 - In Nature, VIB-K.U.Leuven researchers describe a new mechanism to enhance the restoration of the blood flow in ischemic diseases, which are among the leading causes of death worldwide.
03/02/2011 - The Fournier-Majoie Foundation for Innovation (FFMI) has awarded Max Mazzone of VIB-K.U.Leuven a grant for research into a new method of early detection of colon cancer.
12/02/2009 - Our blood vessels have a built-in rescue-mechanism that springs into action when there is insufficient oxygen in our tissues. VIB scientists at K.U.Leuven have now discovered that this mechanism can be mobilized in the battle against cancer.
PhD: Univ. of Torino, Torino, Italy, 2007
Postdoc Fellow at VIB, Vesalius Research Center, Univ. of Leuven, Leuven, Belgium, 2006-09
VIB Group leader since February 2009