Clear Cell Renal Cell Carcinoma as a Model of Pathological Angiogenesis: Which Actors to Target for Treatment?
Pp. 112-131 (20)
Caroline Hilmi and Gilles Pagès
Angiogenesis is a physiological phenomenon that establishes the vascular
tree during development and maintains the supply of oxygen and nutrients to organs
during adult life. A tight balance exists between several pro- or anti-angiogenic actors.
The level of these molecules determines de novo angiogenesis or a highly controlled
steady-state. Hence, a slight modification of this equilibrium inducing an increase of
angiogenesis may provoke pathological angiogenesis in particular favouring
aggressiveness of cancers by contributing to tumour growth and metastasis. Disruption
of the angiogenic balance is a result of over production of chemokines, in particular the
Vascular Endothelial Growth Factor (VEGF) or members of the ELR+CXCL family
(ELR for glutamic acid (E), leucine (L) and arginin (R)), which are major proangiogenic
factors. Their receptors (VEGFR or CXCR) present at the surface of
endothelial and tumour cells are also essential to drive angiogenesis through activation
of signalling pathways (RAS/RAF/MEK/ERK and PI3 Kinase/AKT/mTOR). Both
signalling pathways drive cell proliferation, survival, and production of angiogenic and
inflammatory cytokines. In this context, clear cell renal cell carcinomas (ccRCC)
represent a paradigm of deregulated angiogenesis. Thus, ccRCC have been widely used
to better understand pathological angiogenesis leading to over vascularization and it
will be discussed in this revue the different approaches used by companies to study the
implication of angiogenesis in cancers and to develop antibodies or pharmacological
inhibitors targeting major receptors or cytokines. Although some therapeutic
compounds are used in the clinic, they have given disappointing results particularly on
the improvement of global survival. Hence the current challenge is to improve the
existing therapeutics or to stratify the patients that will really benefit from them in order
to tend to a more personalized therapy.
Angiogenesis, clear cell renal cell carcinoma, ELR+CXCL,
immunotherapy, tyrosine kinase receptors, VEGF.
Centre Antoine Lacassagne, 33 Avenue de Valombrose 06189 Nice France.