Natural Killer cell control of mutant melanoma during targeted therapy.

Pharmacologic inhibition of the mutant BRAF protein in advanced BRAF melanoma results in a high proportion of patients that respond, but few with durable responses. We have recently revealed that Natural Killer (NK) cells play an essential role in the inhibitor control of melanoma metastases in mice that may be therapeutically exploited to help overcome drug resistance.

MicroRNA and ALK-positive anaplastic large cell lymphoma.

In this review we describe the current literature covering the role of microRNA in anaplastic large cell lymphoma (ALCL). MicroRNA is one of the best characterized subgroups of non-coding RNAs and it is now becoming clear that its importance in oncogenesis has been greatly underestimated. In ALCL the deregulation of a diverse range of microRNA has been demonstrated however much less is known about the physiological consequences of this deregulation.

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

Pancreatic 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 α-SMA-positive CAFs, isolated from human PDAC resections.

Stabilization of the G-quadruplex at the VEGF IRES represses cap-independent translation.

The activation of translation contributes to malignant transformation and is an emerging target for cancer therapies. RNA G-quadruplex structures are general inhibitors of cap-dependent mRNA translation and were recently shown to be targeted for oncoprotein translational activation. In contrast however, the G-quadruplex within the 5'UTR of the human vascular endothelial growth factor A (VEGF) has been shown to be essential for IRES-mediated translation.

DNAM-1 expression marks an alternative program of NK cell maturation.

Natural killer (NK) cells comprise a heterogeneous population of cells important for pathogen defense and cancer surveillance. However, the functional significance of this diversity is not fully understood. Here, we demonstrate through transcriptional profiling and functional studies that the activating receptor DNAM-1 (CD226) identifies two distinct NK cell functional subsets: DNAM-1(+) and DNAM-1(-) NK cells.

The E3 ubiquitin ligase thyroid hormone receptor-interacting protein 12 targets pancreas transcription factor 1a for proteasomal degradation.

Pancreas transcription factor 1a (PTF1a) plays a crucial role in the early development of the pancreas and in the maintenance of the acinar cell phenotype. Several transcriptional mechanisms regulating expression of PTF1a have been identified. However, regulation of PTF1a protein stability and degradation is still unexplored.

RUNX1-dependent RAG1 deposition instigates human TCR-δ locus rearrangement.

V(D)J recombination of TCR loci is regulated by chromatin accessibility to RAG1/2 proteins, rendering RAG1/2 targeting a potentially important regulator of lymphoid differentiation. We show that within the human TCR-α/δ locus, Dδ2-Dδ3 rearrangements occur at a very immature thymic, CD34(+)/CD1a(-)/CD7(+dim) stage, before Dδ2(Dδ3)-Jδ1 rearrangements. These strictly ordered rearrangements are regulated by mechanisms acting beyond chromatin accessibility.

Progastrin a new pro-angiogenic factor in colorectal cancer.

Angiogenesis is essential in tumor progression and metastatic process, and increased angiogenesis has been associated with poor prognosis and relapse of colorectal cancer (CRC). VEGF has become the main target of anti-angiogenic therapy. However, most patients relapse after an initial response or present a resistance to the treatment.

Bruton's tyrosine kinase inhibitors: lessons learned from bench-to-bedside (first) studies.

Purpose Of Review: Targeted inhibitors of B-cell receptor signaling have emerged as the most promising therapeutic options against non-Hodgkin's lymphoma. The inhibitor agents that target Bruton's tyrosine kinase (BTK) have elicited particularly high enthusiasm given the unprecedented positive responses observed in Phase I trials. The sheer amount of clinical data published since last year now requires reinterpretation in light of recently published findings on BTK.

Preclinical evidence that SSR128129E--a novel small-molecule multi-fibroblast growth factor receptor blocker--radiosensitises human glioblastoma.

Resistance of glioblastoma to radiotherapy is mainly due to tumour cell radioresistance, which is partially controlled by growth factors such as fibroblast growth factor (FGF). Because we have previously demonstrated the role of FGF-2 in tumour cell radioresistance, we investigate here whether inhibiting FGF-2 pathways by targeting fibroblast growth factor receptor (FGFR) may represent a new strategy to optimise the efficiency of radiotherapy in glioblastoma. Treating radioresistant U87 and SF763 glioblastoma cells with the FGFR inhibitor, SSR12819E, radiosensitises these cells while the survival after irradiation of the more radiosensitive U251 and SF767 cells was not affected.

Intercellular communication by exosomes in placenta: a possible role in cell fusion?

Exosomes are nanovesicles released from viable cells and have attracted increasing interest due to their role in intercellular communication and biological functions. More recently exosomes have been shown to be released by trophoblasts and to carry molecules involved in placental physiology. This involves proteins such as fibronectin, syncytin, Wnt/βcatenin-related molecules, galectin-3, and HLA-G, but also bioactive lipids such as the immunosuppressive PGE2, the PPARγ ligand 15d-PGJ2, or microRNAs that appear as immunomodulators in pregnancy and are able to confer viral resistance.

miR-219-1-3p is a negative regulator of the mucin MUC4 expression and is a tumor suppressor in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers in the world with one of the worst outcome. The oncogenic mucin MUC4 has been identified as an actor of pancreatic carcinogenesis as it is involved in many processes regulating pancreatic cancer cell biology. MUC4 is not expressed in healthy pancreas whereas it is expressed very early in pancreatic carcinogenesis.

Activation of pro-oncogenic pathways in colorectal hyperplastic polyps.

Background: In contrast to sessile serrated adenomas and traditional serrated adenomas which are associated with a significant cancer risk, the role of hyperplastic polyps (HP) in colorectal carcinogenesis as well as the molecular mechanisms underlying their development remain controversial and still need to be clarified. Several reports suggest that a subset of HP may represent precursor lesions of some colorectal cancers. However, biomarkers are needed to identify the subset of HP that may have a malignant potential.

Exosomes as new vesicular lipid transporters involved in cell-cell communication and various pathophysiologies.

Exosomes are nanovesicles that have emerged as a new intercellular communication system between an intracellular compartment of a donor cell towards the periphery or an internal compartment of a recipient cell. The bioactivity of exosomes resides not only in their protein and RNA contents but also in their lipidic molecules. Exosomes display original lipids organized in a bilayer membrane and along with the lipid carriers such as fatty acid binding proteins that they contain, exosomes transport bioactive lipids.

E2F1 activates p53 transcription through its distal site and participates in apoptosis induction in HPV-positive cells.

The p53 tumor suppressor protein, one of the most extensively studied proteins, plays a pivotal role in cellular checkpoints that respond to DNA damage to prevent tumorigenesis. However, the transcriptional control of the p53 gene has not been fully characterized. We report that the transcription factor E2F1 binds only to the E2F1 distal site of the p53 promoter in the human papillomavirus positive carcinoma HeLa cell line.

Emerging concepts on the role of exosomes in lipid metabolic diseases.

Dysregulation of lipid metabolism involves cellular communication mediated by cell contacts or exchange of bioactive lipids bound to soluble carriers or to lipoproteins. An increasing field is that of cellular communication mediated by nanovesicles called exosomes. Those vesicles are released from an internal compartment of viable cells, circulate in all biological fluids and can transfer material from cell-to-cells.

The rescue of miR-148a expression in pancreatic cancer: an inappropriate therapeutic tool.

MicroRNAs are small non-coding RNAs that physiologically modulate proteins expression, and regulate numerous cellular mechanisms. Alteration of microRNA expression has been described in cancer and is associated to tumor initiation and progression. The microRNA 148a (miR-148a) is frequently down-regulated in cancer.

4E-BP restrains eIF4E phosphorylation.

In eukaryotes, mRNA translation is dependent on the cap-binding protein eIF4E. Through its simultaneous interaction with the mRNA cap structure and with the ribosome-associated eIF4G adaptor protein, eIF4E physically posits the ribosome at the 5' extremity of capped mRNA. eIF4E activity is regulated by phosphorylation on a unique site by the eIF4G-associated kinase MNK.

A new biomarker that predicts colonic neoplasia outcome in patients with hyperplastic colonic polyps.

The most frequently occurring lesions in the colon are the hyperplastic polyps. Hyperplastic polyps have long been considered as lesions with no malignant potential and colonoscopy for these patients is not recommended. However, recent works suggest that hyperplastic polyps may represent precursor lesions of some sporadic colorectal cancers.

Genetic and epigenetic alterations in pancreatic carcinogenesis.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Despite significant progresses in the last decades, the origin of this cancer remains unclear and no efficient therapy exists. PDAC does not arise de novo: three remarkable different types of pancreatic lesions can evolve towards pancreatic cancer.

Mitochondrial respiratory chain complexes: apoptosis sensors mutated in cancer?

Mutations in cancer cells affecting subunits of the respiratory chain (RC) indicate a central role of oxidative phosphorylation for tumourigenesis. Recent studies have suggested that such mutations of RC complexes impact apoptosis induction. We review here the evidence for this hypothesis, which in particular emerged from work on how complex I and II mediate signals for apoptosis.