Publications

Publications du laboratoire sur l'ARN interférence et les cancers

Thrombospondin-1 Triggers Cell Migration and Development of Advanced Prostate Tumors

Firlej V, Mathieu JRR, Gilbert C, Lemonnier L, Nakhlé J, Gallou-Kabani C, Guarmit B, Morin A, Prevarskaya N, Barry-Delongchamps N and Cabon F

Cancer research 2011 71: 7649-7658

The antitumor effects of pharmacologic inhibitors of angiogenesis are hampered in patients by the rapid development of tumor resistance, notably through increased invasiveness and accelerated metastasis. Here, we reevaluated the role of the endogenous antiangiogenic thrombospondin 1 (TSP1) in prostate carcinomas in which angiogenesis is an active process. In xenografted tumors, we observed that TSP1 altogether inhibited angiogenesis and fostered tumor development. Our results show that TSP1 is a potent stimulator of prostate tumor cell migration. This effect required CD36, which also mediates TSP1 antiangiogenic activity, and was mimicked by an antiangiogenic TSP1-derived peptide. As suspected for pharmacologic inhibitors of angiogenesis, the TSP1 capacities to increase hypoxia and to trigger cell migration are thus inherently linked. Importantly, although antiangiogenic TSP1 increases hypoxia in vivo, our data show that, in turn, hypoxia induced TSP1, thus generating a vicious circle in prostate tumors. In radical prostatectomy specimens, we found TSP1 expression significantly associated with invasive tumors and with tumors which eventually recurred. TSP1 may thus help select patients at risk of prostate-specific antigen relapse. Together, the data suggest that intratumor disruption of the hypoxic cycle through TSP1 silencing will limit tumor invasion.

Systemic delivery and quantification of unformulated interfering RNAs in vivo.

Morin, A., C. Gallou-Kabani, J.R.R. Mathieu, and F. Cabon

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Current Topics in Medicinal Chemistry 2009 9:1117-1129.

Synthetic small interfering RNAs (siRNAs) open promising new therapeutic perspectives in acute and chronic pathologies. A number of experiments in mice demonstrated the ability of naked siRNAs injected under a normal pressure to trigger gene silencing in vivo, translating into a measurable phenotype. We focus in this review on the information that we can gain from these experiments, and discuss how the specificity of the gene silencing in vivo can be controlled. Because the activity of most drugs increases with the dosing, we are prone to consider that increasing the concentration of siRNAs within cells enhances the efficiency and the duration of the silencing. However, because RNAi is a saturable process, and because increasing the siRNA concentration into cells can induce undesirable side effects, this must be demonstrated. We compare in this review the methods used to quantify and study the biodistribution of siRNAs in living animals, and discuss how these methods can help in designing for each model and each siRNA the most adequate protocol to silence a cognate target gene in vivo.

SIRNA-Directed In Vivo Silencing of Androgen Receptor Inhibits the Growth of Castration-Resistant Prostate Carcinomas.

Compagno D, Merle C, Morin A, Gilbert C, Mathieu JR, Bozec A, Mauduit C, Benahmed M, Cabon F.

PLoS ONE. 2007 Oct 10;2(10):e1006.

Accès libre au texte intégral sur le site de l'éditeur

BACKGROUND: Prostate carcinomas are initially dependent on androgens, and castration or androgen antagonists inhibit their growth. After some time though, tumors become resistant and recur with a poor prognosis. The majority of resistant tumors still expresses a functional androgen receptor (AR), frequently amplified or mutated. METHODOLOGY/PRINCIPAL FINDINGS: To test the hypothesis that AR is not only expressed, but is still a key therapeutic target in advanced carcinomas, we injected siRNA targeting AR into mice bearing exponentially growing castration-resistant tumors. Quantification of siRNA into tumors and mouse tissues demonstrated their efficient uptake. This uptake silenced AR in the prostate, testes and tumors. AR silencing in tumors strongly inhibited their growth, and importantly, also markedly repressed the VEGF production and angiogenesis. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that carcinomas resistant to hormonal manipulations still depend on the expression of the androgen receptor for their development in vivo. The siRNA-directed silencing of AR, which allows targeting overexpressed as well as mutated isoforms, triggers a strong antitumoral and antiangiogenic effect. siRNA-directed silencing of this key gene in advanced and resistant prostate tumors opens promising new therapeutic perspectives and tools.

SiRNA-mediated inhibition of vascular endothelial growth factor severely limits tumor resistance to antiangiogenic thrombospondin-1 and slows tumor vascularization and growth.

Filleur S, Courtin A, Ait-Si-Ali S, Guglielmi J, Merle C, Harel-Bellan A, Clézardin P, Cabon F.

Cancer Res. 2003 Jul 15;63(14):3919-22.

In the past few years, several laboratories have developed antiangiogenic molecules that starve tumors by targeting their vasculature and we have shown that, when produced in tumors, the antiangiogenic molecule thrombospondin-1 (TSP1) reduces the vascularization and delays tumor onset. Yet over time, tumor cells producing active TSP1 do eventually form exponentially growing tumors. These tumors are composed of cells secreting unusually high amounts of the angiogenic stimulator vascular endothelial growth factor (VEGF) that are sufficient to overcome the inhibitory TSP1. Here, we use short double-stranded RNA (siRNA) to trigger RNA interference and thereby impair the synthesis of VEGF and ask if this inability to produce VEGF prevents the development of TSP1 resistance. Systemic in vivo administration of crude anti-VEGF siRNA reduced the growth of unaltered fibrosarcoma tumor cells, and when the anti-VEGF siRNA was expressed from tumor cells themselves, such inhibition was synergistic with the inhibitory effects derived from TSP1 secretion by the tumor cells. Anti-VEGF siRNA delayed the emergence of TSP1-resistant tumors and strikingly reduced their subsequent growth rate.