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Home page > Tumoral signaling Team > Integrins and Cancer

Integrins and Cancer

Head : M. Dontenwill

Last update 12 December 2013

Integrins are αβ heterodimeric transmembrane proteins implicated in numerous physiological processes including adhesion to the extracellular matrix, proliferation, survival, migration and, differentiation. Integrins activate numerous signaling pathways inside the cell.

Our work is focused on α5β1 integrin (the fibronectin receptor), which emerged recently as a pertinent therapeutic target for several solid tumors1 [1] including brain tumors.We explore the molecular characteristics and functions of this integrin and its regulators (caveolin-1, EGFR, other integrins …) in relationship with clinical data. Our aim is to define the mechanisms involved in the pro-tumoral effects of α5β1 integrin in solid tumors, which may translate in the development of new targeted therapeutic opportunities.

Our models include tumor cell lines, human tumors xenografted into nude mice and human tumor biopsies along with clinical data.

1. Integrin α5β1 is a diagnostic marker and a therapeutic target in brain tumors (I. Lelong-Rebel, F. Schaffner, M. Dontenwill).

By in vitro and in vivo experiments, we validated α5β1 integrin as a pertinent prognostic and diagnostic marker for brain tumors[2]. We could show that α5β1 integrin is overexpressed in relation with the grade of human brain tumors and we highlighted potential patient subpopulations, which may respond to an integrin-targeted therapy (Figure 1).

Figure 1 : High expression level of α5 integrin is associated with high grade brain tumors. (Janouskova et al, 2012)

Human glioblastoma cell lines, genetically manipulated to overexpress or repress the α5 integrin subunit, were used to confirm the important role of α5β1 integrin in tumor aggressivity. We also put in evidence a negative crosstalk between α5β1 integrin and the tumor suppressor p53 pathways [2,3,4].

Antagonists of α5β1 integrin were able to activate the p53 pathway after chemotherapy, and consequently ledding to a switch from premature senescence towards tumoral cell apoptosis [5]. Inhibition of α5β1 integrin by specific non-peptidic antagonists (available in the laboratory) blocks the tumoral progression in relationship with the α5 subunit expression level [6,7]. Signaling pathways activated/inhibited by the integrin antagonists are currently under investigation with a particular focus on the p53 pathways. The combination of integrin antagonists with currently available therapies may improve the therapeutic answer for a selected population of patients expressing high level of α5β1 integrin and a wild type p53 protein. We also investigate the role of α5β1 integrin in the cancer stem cell biology.

2. Characterization of original antagonists of α5β1 integrin (M. Dontenwill, L. Choulier).

Very few antagonists are currently available for α5β1 integrin. The great majority are RGD-like molecules selected for their capability to inhibit the integrin adhesion on fibronectin. We are studying these RGD-like antagonists [6,7] in parallel with the development of new original antagonists.

Figure 2 : Migration of single cells in absence (left) or presence (right) of α5β1 integrin antagonists.

We developed an in silico approach to screen chemical libraries and to select efficient new antagonists. Lead molecules have been identified which are currently under investigations. Other innovative methods to characterize new integrin ligands are under investigation as well. The putative antagonists are investigated for their ability to block adhesion, migration (wound healing assays and single cell tracking- Figure 2), invasion, proliferation/survival and signaling pathways in different cell-based assays developed in the laboratory

3. Caveolin-1: an endogenous regulator of α5β1 integrin (S. Martin).

Caveolin-1 is a structural protein of specialized lipid rafts, the caveoles. Our studies demonstrated that caveolin-1 impact on glioma tumoral phenotype (cell growth, clonogenicity, invasion) through α5β1 integrin repression [7]. The balance caveolin-1/integrin α5β1 is predictive of the tumor behaviour and of the glioma response to α5β1 integrin antagonists [7,8] (Figure 3).

Figure 3 : Caveolin-1 and α5β1 integrin in the control of glioma aggressiveness.

We could show that α5β1 integrin expression is under the control of the TGFβ pathway activation [8]and that brain tumor biopsies can be stratified according to their caveolin1/integrin α5β1/TGFβR expression level [7] Expression of caveolin-1 appears highly heterogeneous even in one given tumor, which is, presumably, also the case for α5β1 integrin. We are currently exploring the role of caveolin-1 in other solid tumors.

4. The α5β1 integrin is implicated in the resistance to targeted therapies (M. Lehmann, N. Etienne-Selloum).

Integrins and growth factor receptors (receptor tyrosine kinase – RTK) are actively cooperating to integrate numerous signaling pathways in the cell. In cancer cells, this cooperation induces an increase in the oncogenic potential of RTK. Extracellular matrix activation of integrins may induce resistance of cancer cells to RTK inhibitors.

Figure 4 : Molecular complexes of α5/EGFR detected by FRET-FLIM.

Our objective is to characterize the molecular and functional interactions between integrin α5 and EGF (HER1 /EGFR/ErbB1) and VEGF (VEGFR) receptors. For example, we are studying with high resolution imaging technologies (FRET/FLIM - Figure 4), the formation of integrin/RTK complexes in order to compare this complex formation with the resistance to RTK inhibitors. We also evaluate the effects of treatments associating integrin antagonists with RTK inhibitors (already in use in the human clinic). These preclinical studies will allow the proposition of new therapeutic associations of drugs for fighting preselected tumors with defined molecular characteristics.

Publications

1. SCHAFFNER F, RAY AM and M DONTENWILL, Integrin α5β1, the fibronectin receptor, as a pertinent therapeutic target in solid tumors. Cancers, 2013, 5:27-47.

2. JANOUSKOVA H, MAGLOTT A, LEGER DY, BOSSERT C, NOULET F, GUERIN E, GUENOT D, PINEL S, CHASTAGNER P, PLENAT F, ENTZ-WERLE N, LEHMANN-CHE J, GODET J, MARTIN S, TEISINGER J AND DONTENWILL M. Integrin α5β1 plays a critical role in resistance to temozolomide by interfering with the p53 pathway in high grade glioma. Cancer Res, 2012, 72: 3463-3470

3. MARTIN S, JANOUSKOVA H and M. DONTENWILL, integrins and p53 pathways in glioblastoma resistance to temozolomide, Frontiers, Frontiers in radiation oncology, 2012, doi: 10.3389/fonc.2012.00157.

4. JANOUSKOVA H, AM RAY, I LELONG-REBEL, CHOULIER L, SCHAFFNER F, M LEHMANN, S MARTIN and M DONTENWILL. Activation of p53 pathway by Nutlin-3a inhibits the expression of the therapeutic target α5 integrin in colon cancer cells. Cancer Letters, 2013, 336(2) : 307-318.

5. E. MARTINKOVA, A. MAGLOTT, D.Y. LEGER, D. BONNET, M. STIBOROVA, K. TAKEDA, S. MARTIN & M. DONTENWILL. Alpha5beta1 integrin antagonists reduce chemotherapy-induced premature senescence and facilitate apoptosis in human glioblastoma cells. Int. J. Cancer, 2010, 127, 1240-1248.

6. A. MAGLOTT, P. BARTIK, S. COSGUN, P. KLOTZ, P. RONDÉ, G. FUHRMANN, K. TAKEDA, S. MARTIN AND M. DONTENWILL. The small α5β1 integrin antagonist, SJ749, reduces proliferation and clonogenicity of human astrocytoma cells. Cancer Research, 2006, 66 : 6002-6007.

7. S. MARTIN, E. COSSET, J. TERRAND, A. MAGLOTT, K. TAKEDA AND M. DONTENWILL. Caveolin-1 regulates glioma aggressiveness through the control of α5β1 integrin expression and modulates glioblastoma responsiveness to SJ749, an α5β1 integrin antagonist. BBA, Mol Cell Res, 2009, 1793 : 354-367.

8. E.C. COSSET, J. GODET, N. ENTZ-WERLE, E. GUERIN, D. GUENOT, S. FROELICH, D. BONNET, S. PINEL, F. PLENAT, P. CHASTAGNER, M. DONTENWILL & S. MARTIN. Involvement of the TGFβ pathway in the regulation of α5β1 integrins by caveolin-1 in human glioblastoma. Int. J. Cancer, 2012, 131, 601-611, 2012