Based upon previous research on the in vivo effects of cytokines, our group uses molecular technology (e.g. transgenesis) to study the molecular mechanisms of inflammatory and vascular reactions at the level of the organism (mouse models). The ultimate goal is to identify and validate new molecular targets, particularly those modulating the NO/sGC/cGMP pathway, and to establish new cancer treatments disrupting the neovasculature.
NO-related research includes a mouse transgenic approach for the target validation of sGC (cytosolic guanylate cyclase) and its isoforms. Target identification and validation in the NO-dependent and NO–independent pathways involved in various forms of shock is the second branch of this program. The interaction between this pathway and oxidative stress is a hot topic in this field.
Our group provided proofs of principle that the remarkably effective antitumour activities of TNF (also observed in patients in locoregional treatment) are not inevitably linked to the shock-inducing effects. Currently, the molecular mechanisms of this in vivo antitumour activity, which is essentially a selective disruption of the tumour vasculature, are dissected in detail, in order to identify downstream targets enabling selective induction of these antitumour effects, without inducing shock.
Area of expertise
- Cytokines (Tumor Necrosis Factor, Interferons,…)
- Mouse models of cancer and systemic inflammation (sepsis, SIRS, anaphylaxis)
- Mouse (conditional) transgenesis, knockout and knock-in, bone marrow chimaeras
- Nitric oxide, soluble guanylate cyclase, cGMP
- Phenotyping of transgenic mice
Technology transfer potential
- Molecular targets for anticancer therapy disrupting the vasculature
- Molecular targets in inflammation and cardiovascular biology
- sGC (conditional) knockout mice, NO resistant sGC knock-in mice
- Telemetric measurements in mice
- Sepsis models
Blood vessels in a Lewis lung carcinoma
- Cauwels et al., Nitrite protects against morbidity and mortality associated with TNF- or LPS- induced shock in mice in an sGC dependent manner.
J Exp Med, 206, 2915-2924, 2009.
- Vermeersch et al., Soluble guanylate cyclase-alpha1 deficiency selectively inhibits the pulmonary vasodilator response to nitric oxide and increases the pulmonary vascular remodeling response to chronic hypoxia.
Circulation 116, 936-943, 2007.
- Cauwels et al., Anaphylactic shock depends on PI3K and eNOS-derived NO.
J Clin Invest 116:2244-2251, 2006
- Brouckaert et al., Tumour Necrosis Factor-alpha augmented tumour response in B16BL6 melanoma-bearing mice treated with Stealth liposomal doxorubicin (Doxil) correlates with altered Doxil pharmacokinetics.
Int J Cancer 109, 442-448, 2004.
- Cauwels et al., Caspase inhibition causes hyperacute tumor necrosis factor-induced shock via oxidative stress and phospholipase A2.
Nature Immunol 4, 387-393, 2003.