Retinoid acid receptors in human colorectal cancer: An unexpected link with patient outcome.

International audienceThe status of the three retinoic acid receptors (RARs) α, β and γ in human colorectal cancer (CRC) has not as yet been examined. RARs are in part responsible for the actions of the retinoids (vitamin A and its derivatives), which are essential for human health and survival due to their extensive involvement in numerous cellular processes, in particular in epithelial morphology. The present study examined the expression of the three RARs in CRC using immunohistochemical analysis of paraffin-embedded tissue sections. RAR expression in tumor (T) and adjacent non-tumor (NT) specimens from stage I (n=6), stage II (n=34), stage III (n=26) and stage IV (n=14) CRC patients was compared with that in normal mucous membranes (n=10) from control individuals. The findings were correlated with tumor grade, treatment response (progression during treatment, remission, chemoresistance) and survival as clinicopathological parameters. RARα and γ expression was decreased with CRC stage in the T tissues (P=0.016 and P=0.052, respectively), suggesting that they may be used as predictive markers. RARβ expression in the NT tissues was associated with a more favorable prognosis (P=0.04). These results provide important information on the tumor microenvironment (the area adjacent to tumor cells)

Pharmacological targeting of the protein synthesis mTOR/4E-BP1 pathway in cancer-associated fibroblasts abrogates pancreatic tumourchemoresistance

International audiencePancreatic ductal adenocarcinoma (PDAC) is extremely stroma-rich. Cancer-associated fibroblasts (CAFs) secrete proteins that activate survival and promote chemoresistance of cancer cells. Our results demonstrate that CAF secretome-triggered chemoresistance is abolished upon inhibition of the protein synthesis mTOR/4E-BP1 regulatory pathway which we found highly activated in primary cultures of -SMA-positive CAFs, isolated from human PDAC resections. CAFs selectively express the sst1 somatostatin receptor. The SOM230 analogue (Pasireotide) activates the sst1 receptor and inhibits the mTOR/4E-BP1 pathway and the resultant synthesis of secreted proteins including IL-6. Consequently, tumour growth and chemoresistance in nude mice xenografted with pancreatic cancer cells and CAFs, or with pieces of resected human PDACs, are reduced when chemotherapy (gemcitabine) is combined with SOM230 treatment. While gemcitabine alone has marginal effects, SOM230 is permissive to gemcitabine-induced cancer cell apoptosis and acts as an antifibrotic agent. We propose that selective inhibition of CAF protein synthesis with sst1-directed pharmacological compounds represents an anti-stromal-targeted therapy with promising chemosensitization potential

Fine-Tuning Roles of Endogenous Brain-Derived Neurotrophic Factor, TrkB and Sortilin in Colorectal Cancer Cell Survival

International audienceBACKGROUND: Neurotrophin receptors were initially identified in neural cells. They were recently detected in some cancers in association with invasiveness, but the function of these tyrosine kinase receptors was not previously investigated in colorectal cancer (CRC) cells. METHODS AND FINDINGS: We report herein that human CRC cell lines synthesize the neural growth factor Brain-derived neurotrophic factor (BDNF) under stress conditions (serum starvation). In parallel, CRC cells expressed high- (TrkB) and low-affinity (p75(NTR)) receptors at the plasma membrane, whereas TrkA and TrkC, two other high affinity receptors for NGF and NT-3, respectively, were undetectable. We demonstrate that BDNF induced cell proliferation and had an anti-apoptotic effect mediated through TrkB, as assessed by K252a, a Trk pharmacologic inhibitor. It suppressed both cell proliferation and survival of CRC cells that do not express TrkA nor TrkC. In parallel to the increase of BDNF secretion, sortilin, a protein acting as a neurotrophin transporter as well as a co-receptor for p75(NTR), was increased in the cytoplasm of primary and metastatic CRC cells, which suggests that sortilin could regulate neurotrophin transport in these cells. However, pro-BDNF, also detected in CRC cells, was co-expressed with p75(NTR) at the cell membrane and co-localized with sortilin. In contrast to BDNF, exogenous pro-BDNF induced CRC apoptosis, which suggests that a counterbalance mechanism is involved in the control of CRC cell survival, through sortilin as the co-receptor for p75(NTR), the high affinity receptor for pro-neurotrophins. Likewise, we show that BDNF and TrkB transcripts (and not p75(NTR)) are overexpressed in the patients' tumors by comparison with their adjacent normal tissues, notably in advanced stages of CRC. CONCLUSION: Taken together, these results highlight that BDNF and TrkB are essential for CRC cell growth and survival in vitro and in tumors. This autocrine loop could be of major importance to define new targeted therapies

La place des connaissances scientifiques dans les décisions publiques : L’émergence du débat sur l'“Evidence Based Policy” dans le domaine agricole

L’approche « Evidence Based Policy » (EBP) vise à un usage le plus judicieux possible des connaissances scientifiques disponibles pour prendre des décisions publiques : il s’agit de concevoir un cadre analytique utile pour évaluer le degré de fiabilité des connaissances disponibles, réfléchir à leur hiérarchisation et à la conception d’outils qui permettraient d’en faciliter l’usage et la communication entre scientifiques et praticiens. Cette méthode émerge dans de nombreux secteurs, dans les institutions internationales comme dans certains pays. Dans le domaine agricole, les études qui se revendiquent de l'EBP sont moins nombreuses mais se développement également. S'interroger sur les avantages et limites d’EBP permet de se pencher sur les difficultés que rencontre la décision publique pour l'utilisation des connaissances disponibles. Ce papier porte plus précisément sur les décisions publiques dans le domaine agricole. Il s’appuie notamment sur des exemples puisés dans les enquêtes menées sur des dispositifs agro-environnementaux dans le cadre d'un programme de recherche « EBP-Biosoc ». Deux questions sont abordées : d'une part le problème du choix et de la hiérarchisation des preuves, d'autre part la « dépolitisation » possible des décisions publiques selon leur rapport aux connaissances

O debate sobre as abordagens Evidence-based ou Evidence-aware policy no campo da agricultura

(O debate sobre as abordagens Evidence-based ou Evidence-aware policy no campo da agricultura). O recurso às abordagens da evidence-based ou evidence-aware policy se estende por vários setores (saúde, educação etc.). Na agricultura, essas abordagens são menos numerosas, mas se desenvolvem igualmente. O exame dos debates que acompanham esse movimento permite precisar a natureza das dificuldades enfrentadas por aqueles que tomam decisão pública quando buscam utilizar os conhecimentos científicos disponíveis. Entre as numerosas questões, então levantadas, três são especificamente abordadas aqui: (i) o problema da concorrência das provas; (ii) o papel que os instrumentos de racionalização podem exercer em uma possível “despolitização” das decisões públicas; (iii) a necessidade de não se renunciar a uma reflexão sobre as provas

O debate sobre as abordagens Evidence-based ou Evidence-aware policy no campo da agricultura

The use of evidence-based or evidence-aware policy perspectives extends over several sectors (health, education etc.). In agriculture, these approaches are less numerous but are also increasingly undertaken. The examination of the debates that followed this trend allows specification of the nature of difficulties faced by those who make public decisions when seeking to use available scientific knowledge. Among the vast range of issues raised thereby, three are specifically addressed here: (i) the problem of competition among sources of evidence, (ii) the role that the instruments of rationalization can exert over a possible “depoliticization” of public decisions; and (iii) the need to avoid abandonment of reflection on the evidence.O recurso às abordagens da evidence-based ou evidence-aware policy se estende por vários setores (saúde, educação etc.). Na agricultura, essas abordagens são menos numerosas, mas se desenvolvem igualmente. O exame dos debates que acompanham esse movimento permite precisar a natureza das dificuldades enfrentadas por aqueles que tomam decisão pública quando buscam utilizar os conhecimentos científicos disponíveis. Entre as numerosas questões, então levantadas, três são especificamente abordadas aqui: (i) o problema da concorrência das provas; (ii) o papel que os instrumentos de racionalização podem exercer em uma possível “despolitização” das decisões públicas; (iii) a necessidade de não se renunciar a uma reflexão sobre as provas

O debate sobre as abordagens Evidence-based ou Evidence-aware policy no campo da agricultura

(O debate sobre as abordagens Evidence-based ou Evidence-aware policy no campo da agricultura). O recurso às abordagens da evidence-based ou evidence-aware policy se estende por vários setores (saúde, educação etc.). Na agricultura, essas abordagens são menos numerosas, mas se desenvolvem igualmente. O exame dos debates que acompanham esse movimento permite precisar a natureza das dificuldades enfrentadas por aqueles que tomam decisão pública quando buscam utilizar os conhecimentos científicos disponíveis. Entre as numerosas questões, então levantadas, três são especificamente abordadas aqui: (i) o problema da concorrência das provas; (ii) o papel que os instrumentos de racionalização podem exercer em uma possível “despolitização” das decisões públicas; (iii) a necessidade de não se renunciar a uma reflexão sobre as provas

Tropomyosin-related kinase B/brain derived-neurotrophic factor signaling pathway as a potential therapeutic target for colorectal cancer

International audienc

Autophagy and Extracellular Vesicles in Colorectal Cancer: Interactions and Common Actors?

Autophagy is a homeostatic process involved in the degradation of disabled proteins and organelles using lysosomes. This mechanism requires the recruitment of specialized proteins for vesicle trafficking, that may also be involved in other types of machinery such as the biogenesis and secretion of extracellular vesicles (EVs), and particularly small EVs called exosomes. Among these proteins, Rab-GTPases may operate in both pathways, thus representing an interesting avenue for further study regarding the interaction between autophagy and extracellular vesicle machinery. Both mechanisms are involved in the development of colorectal cancer (CRC), particularly in cancer stem cell (CSC) survival and communication, although they are not specific to CRC or CSCs. This highlights the importance of studying the crosstalk between autophagy and EVs biogenesis and release

INVOLVEMENT OF NEUROTENSIN AND NEUROTROPHINS PATHWAYS IN HUMAN COLORECTAL CANCER CELLS 5-FLUOROURACIL TREATMENT RESISTANCE

International audienc