ABSTRACT
Splenic marginal zone lymphoma (SMZL) is a B-cell neoplasm whose molecular pathogenesis remains fundamentally unexplained, requiring more precise diagnostic markers. Previous molecular studies have revealed 7q loss and mutations of nuclear factor κB (NF-κB), B-cell receptor (BCR) and Notch signalling genes. We performed whole-exome sequencing in a series of SMZL cases. Results confirmed that SMZL is an entity distinct from other low-grade B-cell lymphomas, and identified mutations in multiple genes involved in marginal zone development, and others involved in NF-κB, BCR, chromatin remodelling and the cytoskeleton.
Subject(s)
Biomarkers, Tumor/genetics , Cell Differentiation , Exome/genetics , High-Throughput Nucleotide Sequencing , Lymphoma, B-Cell, Marginal Zone/genetics , Lymphoma, B-Cell, Marginal Zone/pathology , Mutation/genetics , Splenic Neoplasms/genetics , Splenic Neoplasms/pathology , Chromatin Assembly and Disassembly , Cytoskeleton , Humans , NF-kappa B/genetics , Signal TransductionABSTRACT
A significant proportion of extracellular nucleic acids in plasma circulate highly protected in tumor-specific exosomes, but it is unclear how the release of exosomes is modulated in carcinogenesis. We quantified by cytometry exosomes in plasma of 91 colorectal cancer patients to evaluate their potential as a tumor indicator and their repercussions on diagnosis and prognosis. We examined the involvement of TSAP6, a TP53-regulated gene involved in the regulation of vesicular secretion, in levels of circulating exosomes in plasma of colorectal patients and in HCT116 TP53-(wild-type and null) human colorectal cancer cell lines. The fraction of exosomes in cancer patients was statistically higher than in healthy controls (mean rank » 53.93 vs. 24.35). High levels of exosomes in plasma of patients correlated with high levels of carcino-embryonic antigen (P » 0.029) and with poorly differentiated tumors (P » 0.039) and tended to have shorter overall survival than patients with low levels (P » 0.056). Release of exosomes did not correlate with TSAP6 expression; and regulation of TSAP6 by TP53 was not shown either in tumor samples or in HCT116 cell lines. Although it was not suggested that the TP53/TSAP6 pathway regulates the release of exosomes into the plasma of colorectal cancer patients, the level of circulating exosomes may be used as a tumor indicator, because it correlates with poor prognosis parameters and shorter survival.
Subject(s)
Colorectal Neoplasms/blood , Exosomes/metabolism , Biomarkers, Tumor , Carcinoembryonic Antigen/biosynthesis , Carcinoembryonic Antigen/blood , Cell Cycle Proteins , Cell Differentiation , Cell Line, Tumor , Colorectal Neoplasms/genetics , Colorectal Neoplasms/mortality , Exosomes/genetics , Female , Genes, p53 , HCT116 Cells , Humans , Male , Oncogene Proteins/genetics , Oncogene Proteins/metabolism , Oxidoreductases , Prognosis , RNA, Messenger/biosynthesis , Secretory Vesicles/metabolism , Tumor Suppressor Protein p53/metabolismABSTRACT
Identifying the molecular mechanisms responsible for the resistance of gliomas to anticancer treatments is an issue of great therapeutic interest. Δ(9)-Tetrahydrocannabinol (THC), the major active ingredient of marijuana, and other cannabinoids inhibit tumor growth in animal models of cancer, including glioma, an effect that relies, at least in part, on the stimulation of autophagy-mediated apoptosis in tumor cells. Here, by analyzing the gene expression profile of a large series of human glioma cells with different sensitivity to cannabinoid action, we have identified a subset of genes specifically associated to THC resistance. One of these genes, namely that encoding the growth factor midkine (Mdk), is directly involved in the resistance of glioma cells to cannabinoid treatment. We also show that Mdk mediates its protective effect via the anaplastic lymphoma kinase (ALK) receptor and that Mdk signaling through ALK interferes with cannabinoid-induced autophagic cell death. Furthermore, in vivo Mdk silencing or ALK pharmacological inhibition sensitizes cannabinod-resistant tumors to THC antitumoral action. Altogether, our findings identify Mdk as a pivotal factor involved in the resistance of glioma cells to THC pro-autophagic and antitumoral action, and suggest that selective targeting of the Mdk/ALK axis could help to improve the efficacy of antitumoral therapies for gliomas.
Subject(s)
Cannabinoids/pharmacology , Cytokines/metabolism , Dronabinol/pharmacology , Drug Resistance, Neoplasm/drug effects , Glioma/metabolism , Neoplasm Proteins/metabolism , Receptor Protein-Tyrosine Kinases/metabolism , Analgesics, Non-Narcotic/pharmacology , Anaplastic Lymphoma Kinase , Animals , Cell Line, Tumor , Cytokines/genetics , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic/drug effects , Glioma/drug therapy , Glioma/genetics , Humans , Midkine , Neoplasm Proteins/genetics , Receptor Protein-Tyrosine Kinases/geneticsABSTRACT
Clinical and biological studies on nodal marginal zone lymphoma (NMZL) are hampered by the lack of specific diagnostic markers and the low reproducibility of this diagnosis. A comparative expression-profiling study has shown a set of markers to be differentially expressed in NMZL compared with follicular lymphoma (FL), including myeloid cell nuclear differentiation antigen (MNDA), a nuclear protein expressed by myeloid cells and a subset of B-cells. The aim of this study was to characterize the expression of MNDA in normal and reactive human tissue, and in a large series of non-Hodgkin's B-cell lymphomas, with particular emphasis on NMZL and FL. Our results showed that MNDA is expressed in normal tissue by a subset of the marginal zone B cells. They also showed MNDA expression in subgroups of chronic lymphocytic leukemia, mantle-cell lymphoma, and diffuse large B-cell lymphoma, but MNDA was especially expressed by lymphomas derived from the marginal zone, such as mucosa-associated lymphoid-tissue lymphoma, splenic marginal-zone lymphoma and NMZL. MNDA expression was rarely observed in FL, a characteristic that is of potential value in distinguishing between NMZL and FL. MNDA expression is thus a useful tool for the recognition of NMZL.
