A paper from the group of Silvia Deaglio demonstrates that the enzymatic activities of the surface molecule CD38 regulate growth and trafficking of chronic lymphocytic leukemia B cells (CLL) paving the way for its therapeutic targeting in hematological malignancies.
CD38 is a cell surface molecule endowed with enzymatic and receptor functions. Its expression on chronic lymphocytic leukemia (CLL) cells correlates with a poor clinical outcome. Besides being a negative prognosticator, CD38 plays a critical role in the pathogenetic network underlying the disease, mediating proliferative and migratory signals. However, the molecular mechanisms at the basis of CD38 behavior in the leukemic context remain undetermined. In this paper published in Leukemia http://www.ncbi.nlm.nih.gov/pubmed/24990614, Tiziana Vaisitti and collegues demonstrate that the molecule in enzymatically active in primary CLL cells and that these functions are critical in the control of proliferation and migration, both in vitro and in vivo. Inhibition of the enzymatic activities of CD38 using kuromanin, a molecule belonging to the flavonoid family, reduces CLL chemotaxis and homing. Indeed, in short term xenograft experiments using primary leukemic cells, flavonoid treatment results in the trapping of CLL cells in the blood, thereby increasing responses to chemotherapy. These results suggest that the use of selective reagents able to interfere with CD38 enzymatic activities may represent a novel therapeutic approach for selected hematological malignancies.
A paper from the group of Federica Cavallo shows that adjuvant immunization with a xenogeneic DNA vaccine is effective for the treatment of surgically controlled staged II-III oral canine malignant melanoma, laying the foundation for its translation to a human clinical setting.
Due to the many similarities with its human counterpart, canine malignant melanoma (CMM) represents a valuable model to assess the efficacy of novel therapeutic strategies. In this study Federica Riccardo and coworkers (http://clincancerres.aacrjournals.org/cgi/content/abstract/1078-0432.CCR-13-3042) took advantage of this model to evaluate immunogenicity, safety and therapeutic efficacy of a human (h) chondroitin sulfate proteoglycan-4 (CSPG4) DNA-based vaccine. CSPG4 represents an attractive target for immunotherapy because of its high expression in a high percentage of human melanoma and CMM tumors and its restricted distribution in normal tissues. The high homology between human and canine CSPG4 has provided the rationale for testing the potential of a hCSPG4 DNA vaccine in dogs with stage II-III surgically resected CSPG4-positive oral CMM. Intramuscular plasmid administration followed by electroporation resulted in significantly longer overall and disease-free survival times in 14 vaccinated dogs as compared to 13 non-vaccinated controls. All vaccinated dogs developed antibodies against both human and canine CSPG4. The induction of CSPG4-specific antibodies is likely to inhibit CSPG4 oncogenic role in the biology of melanoma cells, interfering with the progression of the disease by inhibiting the proliferation of CSPG4-positive residual melanoma cells in canine patients. Thanks to the high translational value of CMM model, hopefully these finding will help improving treatment of human melanoma patients. Also in the fight against cancer, dogs may give a helping paw to humans.
A paper from the group of Emanuela Tolosano described a key role for the heme exporter FLVCR1a in hepatic heme metabolism and cytochrome P450 function.
The liver has one of the highest rate of synthesis of heme, 50% of of which is used to support the synthesis of cytochromes P450. These enzymes metabolize exogenous and endogenous compounds, including natural products, hormones, drugs, and carcinogens. FLVCR1a is a ubiquitously expressed plasma membrane heme exporter that has been shown to control intracellular heme content in hematopoietic lineages. In a recent paper published on Gastroenterology, Vinchi et al. addressed FLVCR1a function in the liver, by generating mice with conditional disruption of Flvcr1a in hepatocytes. With aging, these mice accumulated heme and iron in liver. As a mechanism to compensate for the lack of heme export, heme catabolism (HO-1) and iron storage (Ferritin) are increased. These findings highlight a crucial role for FLVCR1a in the maintenance of hepatic heme homeostasis. Flvcr1a export function was found closely associated with heme biosynthesis, required to sustain cytochrome induction. Hepatic heme accumulation in these mice causes the early inhibition of heme synthesis and increased degradation of heme, which finally reduced the expression and activity of cytochromes P450. As a consequence, these mice show a reduced ability to upregulate cytochrome P450 in response to drugs and xenobiotics. These observations suggest a direct implication of heme export in cytochromes P450 function and drug metabolism.
A paper from the group of Ferdinando Di Cunto uncovers the mechanisms by which the Down syndrome critical region gene TTC3 affects neuronal differentiation and neuronal Golgi architecture.
A crucial topic in Down Syndrome (DS) research is to establish how much dosage imbalance of single Chromosome 21 genes mapped to the Down Critical Region (DCR) are responsible for the intellectual disability (ID) which characterizes this disorder. Indeed, elucidating the molecular mechanisms that determine abnormal brain function in DS patients is fundamental to develop rational pharmacological strategies. TTC3 is one of the genes, located in the DCR, whose increased expression levels are suspected to play a significant role in determining ID. In this work Gaia Berto and colleagues have found that the dosage of the TTC3 gene is critically important for neurons, since a decrease or an increase of its levels can strongly affect the extension of neuronal processes and the structure of the neuronal Golgi apparatus, through modulation of the actin cytoskeleton. Moreover, they have characterized the complex molecular machinery linking TTC3 to actin rearrangements, which comprises drugable targets such as the protein kinase ROCK.
A paper from the group of Federica Cavallo discloses new roles of perforin in tumor immune surveillance and male mammary gland reabsorption during embryogenesis
Observational studies linked to clinical outcome analysis in cancer patients that have been carried out in recent years have displayed the prognostic and predictive value of the tumor microenvironment inflammatory state. This has generated a new wave of interest in the immunosurveillance phenomenon. Natural immune surveillance against the onset of cancer is one of the most important tenets in experimental tumor immunology. Perforin-mediated cytotoxicity is one of the principal immunosurveillance mechanisms involved in the fight against cancer. However, its importance in spontaneous epithelial cancer is still poorly defined. In a recent paper published on Journal of Immunology, Marco Macagno and colleagues provide further proof of the complex role that the immune system plays in the body and gives new insight into the pathogenesis ofepithelial tumors, demonstrating that the penetrance and malignancy of a tumor may be dramatically affected by pfp-dependent mechanisms. In addition, their findings unveiled the previously unsuspected involvement of pfp in male mammary gland reabsorption during embryogenesis.
Convenzione per l'attivazione di una Cell Factory presso l'Università di Torino (Torino, 28 novembre 2013).
Oggi nel Salone del Rettorato, il Rettore dell'Università degli Studi di Torino, Prof. Gianmaria Ajani, e il Responsabile Emea LA di Fresenius Medical Care, Prof. Emanuele Gatti, hanno firmato la Convenzione per l'attivazione di una Cell Factory presso l'Università di Torino per la produzione di cellule staminali finalizzate alla terapia dell'insufficienza renale ed epatica.