A major risk factor of developing colorectal cancer (CRC) is the presence of chronic inflammation in the colon. In order to understand how inflammation contributes to CRC development, the present study focused on SHP-2, a tyrosine phosphatase encoded by PTPN11 gene in which polymorphisms have been shown to be markers of colitis susceptibility. Conversely, gain-of-function mutations in PTPN11 gene (E76 residue) have been found in certain sporadic CRC. Results shown herein demonstrate that SHP-2 expression was markedly increased in sporadic human adenomas but not in advanced colorectal tumors. SHP-2 silencing inhibited proliferative, invasive and tumoral properties of both intestinal epithelial cells (IECs) transformed by oncogenic KRAS and of human CRC cells. IEC-specific expression of a SHP-2E76K activated mutant in mice was not sufficient to induce tumorigenesis but markedly promoted tumor growth under the ApcMin/+ background. Conversely, mice with a conditional deletion of SHP-2 in IECs developed colitis-associated adenocarcinomas with age, associated with sustained activation of Wnt/β-catenin, NFκB and STAT3 signalings in the colonic mucosae. Moreover, SHP-2 epithelial deficiency considerably increased tumor load in ApcMin/+ mice, shifting tumor incidence toward the colon. Overall, these results reveal that SHP-2 can exert opposing functions in the large intestine: it can promote or inhibit tumorigenesis depending of the inflammatory context.

The RIG-I like receptor pathway is stimulated during RNA virus infection by interaction between cytosolic RIG-I and viral RNA structures that contain short hairpin dsRNA and 5' triphosphate (5'ppp) terminal structure. In the present study, an RNA agonist of RIG-I was synthesized in vitro and shown to stimulate RIG-I-dependent antiviral responses at concentrations in the picomolar range. In human lung epithelial A549 cells, 5'pppRNA specifically stimulated multiple parameters of the innate antiviral response, including IRF3, IRF7 and STAT1 activation, and induction of inflammatory and interferon stimulated genes - hallmarks of a fully functional antiviral response. Evaluation of the magnitude and duration of gene expression by transcriptional profiling identified a robust, sustained and diversified antiviral and inflammatory response characterized by enhanced pathogen recognition and interferon (IFN) signaling. Bioinformatics analysis further identified a transcriptional signature uniquely induced by 5'pppRNA, and not by IFNα-2b, that included a constellation of IRF7 and NF-kB target genes capable of mobilizing multiple arms of the innate and adaptive immune response. Treatment of primary PBMCs or lung epithelial A549 cells with 5'pppRNA provided significant protection against a spectrum of RNA and DNA viruses. In C57Bl/6 mice, intravenous administration of 5'pppRNA protected animals from a lethal challenge with H1N1 Influenza, reduced virus titers in mouse lungs and protected animals from virus-induced pneumonia. Strikingly, the RIG-I-specific transcriptional response afforded partial protection from influenza challenge, even in the absence of type I interferon signaling. This systems approach provides transcriptional, biochemical, and in vivo analysis of the antiviral efficacy of 5'pppRNA and highlights the therapeutic potential associated with the use of RIG-I agonists as broad spectrum antiviral agents.

Receptor of Activated NF-kappaB Ligand (RANKL) is implicated as one of a number of effector molecules that mediate progesterone and prolactin signaling in the murine mammary epithelium. Using a mouse transgenic approach, we demonstrate that installation of the RANKL signaling axis into the mammary epithelium results in precocious ductal side-branching and alveologenesis in the virgin animal. These morphological changes occur due to RANKL-induced mammary epithelial proliferation, which is accompanied by increases in expression of activated NF-kB and cyclin D1. With age, prolonged RANKL exposure elicits limited mammary epithelial hyperplasia. While these transgenics exhibit RANKL-induced salivary gland adenocarcinomas, palpable mammary tumors are not observed due to RANKL-suppression of its own signaling receptor (RANK) in the mammary epithelium. Together, these studies reveal not only that the RANKL signaling axis can program many of the normal epithelial changes attributed to progesterone and prolactin action in the normal mammary gland during early pregnancy, but underscore the necessity for tight control of this signaling molecule to avoid unwarranted developmental changes that could lead to mammary hyperplasia in later life.

Chemotherapy-induced hair loss (alopecia) (CIA) is one of the most feared side effects of chemotherapy among cancer patients. There is currently no pharmacological approach to minimize CIA, although one strategy that has been proposed involves protecting normal cells from chemotherapy by transiently inducing cell cycle arrest. Proof-of-concept for this approach, known as cyclotherapy, has been demonstrated in cell culture settings.

This study establishes a proof-of-concept that a tattoo device can target intra-dermal drug delivery against cutaneous leishmaniasis (CL). The selected drug is oleylphosphocholine (OlPC) formulated as liposomes, particles known to be prone to macrophage ingestion. We first show that treatment of cultured Leishmania-infected macrophages with OlPC-liposomes results in a direct dose-dependent killing of intracellular parasites. Based on this, in vivo efficacy is demonstrated using a 10 day tattooing-mediated treatment in mice infected with L. major and L. mexicana. In both models this regimen results in rapid clinical recovery with complete regression of skin lesions by Day 28. Parasite counts and histopathology examination confirm high treatment efficacy at the parasitic level. Low amount of drug required for tattooing combined with fast clinical recovery may have a positive impact on CL patient management. This first example of tattoo-mediated drug delivery could open to new therapeutic interventions in the treatment of skin diseases.

eIF4E, the mRNA 5' cap-binding translation initiation factor, is overexpressed in numerous cancers and is implicated in mechanisms underlying oncogenesis and senescence. 4E-BPs (eIF4E-binding proteins) inhibit eIF4E activity, and thereby act as suppressors of eIF4E-dependent pathways. Here, we show that tumorigenesis is increased in p53 knockout mice that lack 4E-BP1 and 4E-BP2. However, primary fibroblasts lacking 4E-BPs, but expressing p53, undergo premature senescence and resist oncogene-driven transformation. Thus, the p53 status governs 4E-BP-dependent senescence and transformation. Intriguingly, the 4E-BPs engage in senescence via translational control of the p53-stabilizing protein, Gas2. Our data demonstrate a role for 4E-BPs in senescence and tumorigenesis and highlight a p53-mediated mechanism of senescence through a 4E-BP-dependent pathway.