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Constitutive BR3 receptor signaling in diffuse, large B-cell lymphomas stabilizes nuclear factor-?B-inducing kinase while activating both canonical and alternative nuclear factor-?B pathways.

ABSTRACT: Aberrant nuclear factor ?B (NF-?B) signaling has been found to be of particular importance in diffuse, large B-cell lymphoma (DLBCL) cell survival and proliferation. Although the canonical NF-?B signaling pathway has been studied in some detail, activation of the alternative NF-?B pathway in DLBCL is not well characterized. Important insights into the regulation of the alternative NF-?B pathway in B lymphocytes has recently revealed the regulatory importance of the survival kinase NIK (NF-?B-inducing kinase) in genetically engineered murine models. Our studies demonstrate that both the canonical and alternative NF-?B pathways are constitutively activated in DLBCL. We also demonstrate that NIK kinase aberrantly accumulates in DLBCL cells due to constitutive activation of B-cell activation factor (BAFF)-R (BR3) through interaction with autochthonous B-lymphocyte stimulator (BLyS) ligand in DLBCL cells. Activation of BR3 in DLBCL induces recruitment and degradation of tumor necrosis factor receptor-associated factor 3, which results in NIK kinase accumulation, I?B? phosphorylation, and NF-?B p100 processing, thereby resulting in continuous activation of both NF-?B pathways in DLBCL cells, leading to autonomous lymphoma cell growth and survival. These results further elucidate mechanisms involved in abnormal NF-?B activation in DLBCL, and should contribute to better future therapeutic approaches for patients with DLBCL.

SUBMITTER: Pham LV

PROVIDER: S-EPMC3037744 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Constitutive BR3 receptor signaling in diffuse, large B-cell lymphomas stabilizes nuclear factor-κB-inducing kinase while activating both canonical and alternative nuclear factor-κB pathways.

Pham Lan V LV Fu Lingchen L Tamayo Archito T AT Bueso-Ramos Carlos C Drakos Elias E Vega Francisco F Medeiros L Jeffrey LJ Ford Richard J RJ

Blood 20101001 1

Aberrant nuclear factor κB (NF-κB) signaling has been found to be of particular importance in diffuse, large B-cell lymphoma (DLBCL) cell survival and proliferation. Although the canonical NF-κB signaling pathway has been studied in some detail, activation of the alternative NF-κB pathway in DLBCL is not well characterized. Important insights into the regulation of the alternative NF-κB pathway in B lymphocytes has recently revealed the regulatory importance of the survival kinase NIK (NF-κB-ind ...[more]

PMID: 20889926

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Project description:BackgroundSolid epidemiological evidences connect obesity with incidence, stage and survival in pancreatic cancer. However, the underlying mechanistic basis linking adipocytes to pancreatic cancer progression remain largely elusive. We hypothesized that factors secreted by adipocytes could be responsible for epithelial-to-mesenchymal transition (EMT) induction and, in turn, a more aggressive phenotype in models of pancreatic preneoplastic lesions.MethodsWe studied the role of factors secreted by two adipogenic model systems from primary human bone marrow stromal cells (hBMSCs) in an in vitro experimental cell transformation model system of human pancreatic ductal epithelial (HPDE) cell stably expressing activated KRAS (HPDE/KRAS),Results:We measured a significant induction of EMT and aggressiveness in HPDE and HPDE/KRAS cell lines when cultured with medium conditioned by fully differentiated adipocytes (ADIPOCM) if compared with the same cells cultured with medium conditioned by hBMSC (hBMSCCM) from two different healthy donors. Several genes coding for soluble modulators of the non-canonical WNT signaling pathway, including FRZB, SFRP2, RSPO1, WNT5A and 5B were significantly overexpressed in fully differentiated adipocytes than in their respective in hBMSC. ADIPOCM induced the overexpression and the nuclear translocation of the Frizzled family member receptor tyrosine kinase-like orphan receptor (Ror) 2 in HPDE and HPDE/KRAS cells. Vantictumab, an anti-Frizzled monoclonal antibody, reduced ROR2 nuclear translocation and in turn the EMT and aggressiveness in HPDE and HPDE/KRAS cells.ConclusionsWe demonstrated that adipocytes could induce EMT and aggressiveness in models of pancreatic preneoplastic lesions by orchestrating a complex paracrine signaling of soluble modulators of the non-canonical WNT signaling pathway that determine, in turn, the activation and nuclear translocation of ROR2. This signaling pathway could represent a novel target for pancreatic cancer chemoprevention. Most importantly, these factors could serve as novel biomarkers to select a risk population among obese subjects for screening and, thus, early diagnosis of pancreatic cancer.

Dataset Information

Constitutive BR3 receptor signaling in diffuse, large B-cell lymphomas stabilizes nuclear factor-?B-inducing kinase while activating both canonical and alternative nuclear factor-?B pathways.

Publications

Constitutive BR3 receptor signaling in diffuse, large B-cell lymphomas stabilizes nuclear factor-κB-inducing kinase while activating both canonical and alternative nuclear factor-κB pathways.

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