48 research outputs found
miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis
MicroRNAs (miRNAs) are increasingly implicated in regulating the malignant progression of cancer. Here we show that miR-9, which is upregulated in breast cancer cells, directly targets CDH1, the E-cadherin-encoding messenger RNA, leading to increased cell motility and invasiveness. miR-9-mediated E-cadherin downregulation results in the activation of β-catenin signalling, which contributes to upregulated expression of the gene encoding vascular endothelial growth factor (VEGF); this leads, in turn, to increased tumour angiogenesis. Overexpression of miR-9 in otherwise non-metastatic breast tumour cells enables these cells to form pulmonary micrometastases in mice. Conversely, inhibiting miR-9 by using a 'miRNA sponge' in highly malignant cells inhibits metastasis formation. Expression of miR-9 is activated by MYC and MYCN, both of which directly bind to the mir-9-3 locus. Significantly, in human cancers, miR-9 levels correlate with MYCN amplification, tumour grade and metastatic status. These findings uncover a regulatory and signalling pathway involving a metastasis-promoting miRNA that is predicted to directly target expression of the key metastasis-suppressing protein E-cadherin.Life Sciences Research Foundation FellowshipMargaret and Herman Sokol AwardNational Institutes of Health (U.S.) (Pathway to Independence Award (K99/R00))Howard Hughes Medical Institute (Undergraduate Fellowship)Breast Cancer Research Program (U.S.) (Predoctoral Fellowship)National Institutes of Health (U.S.) (Grant)Ludwig Center for Molecular Oncology at MI
High Expression Levels of Total IGF-1R and Sensitivity of NSCLC Cells In Vitro to an Anti-IGF-1R Antibody (R1507)
© 2009 Gong et al
The Eph-receptor A7 is a soluble tumor suppressor for follicular lymphoma
Insights into cancer genetics can lead to therapeutic opportunities. By cross-referencing chromosomal changes with an unbiased genetic screen we identify the ephrin receptor A7 (EPHA7) as a tumor suppressor in follicular lymphoma (FL). EPHA7 is a target of 6q deletions and inactivated in 72% of FLs. Knockdown of EPHA7 drives lymphoma development in a murine FL model. In analogy to its physiological function in brain development, a soluble splice variant of EPHA7 (EPHA7(TR)) interferes with another Eph-receptor and blocks oncogenic signals in lymphoma cells. Consistent with this drug-like activity, administration of the purified EPHA7(TR) protein produces antitumor effects against xenografted human lymphomas. Further, by fusing EPHA7(TR) to the anti-CD20 antibody (rituximab) we can directly target this tumor suppressor to lymphomas in vivo. Our study attests to the power of combining descriptive tumor genomics with functional screens and reveals EPHA7(TR) as tumor suppressor with immediate therapeutic potential
MicroRNA Profiling In Activated B-Cell and Germinal Center B-Cell Diffuse Large B-Cell Lymphoma Using Formalin Fixed, Paraffin Embedded Patient Biopsies
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The role of cytotoxic and regulatory T cells in relapsed/refractory Hodgkin lymphoma
Recent data suggests the presence of cytotoxic (TIA-1 and granzyme B+) and regulatory T-cells (FOXP3+) in classical Hodgkin lymphoma (cHL) tissues has been shown to correlate with poor overall survival in mainly diagnostic biopsies. By tissue microarray analyses, we extend this observation to a cohort of relapsed/refractory cHL tissue biopsies and analyze immunohistochemical expression of FOXP3, TIA-1, and granzyme B in the inflammatory background and the tumor microenvironment. High expression of TIA-1 (>50%) correlated with poor overall survival (P50%) and low FOXP3 (<25%) correlated with poor overall survival (P<0.0001). Expression of cytotoxic and regulatory T-cells shows prognostic significance in the relapsed/refractory clinical setting of cHL
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Intensive chemotherapy with cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) for human immunodeficiency virus-associated Burkitt lymphoma
In the era of highly active antiretroviral therapy (HAART), standard-dose chemotherapy for human immunodeficiency virus (HIV)-associated diffuse large B-cell lymphoma is becoming the standard of care. In contrast, the safety and efficacy of intensive regimens have not been established for Burkitt lymphoma (BL), a highly aggressive lymphoma for which moderate-dose chemotherapy is substandard in the HIV-negative population.
To evaluate the feasibility of intensive chemotherapy in HIV-associated BL, the authors retrospectively reviewed 14 HIV-positive adults with BL treated at their center between 1988 and 2000. Eight patients were treated between 1996 and 2000 with cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC), one of the currently preferred intensive-dose chemotherapy regimens for BL. Six received other chemotherapy. Outcomes were compared with those of 24 HIV-negative adult patients with BL who had similar patient characteristics and were treated concomitantly (13 with CODOX-M/IVAC; 11 with other regimens).
Of the 14 HIV-positive patients, 63% had a complete response after CODOX-M/IVAC treatment, compared with 67% of patients receiving other chemotherapy. The 2-year event-free survival (EFS) rates were 60% and 60% after CODOX-M/IVAC or other regimens, respectively. Similar outcomes were seen despite the fact that 88% of CODOX-M/IVAC-treated HIV-positive patients had Stage IV disease, compared with one-third of HIV-positive patients treated with other chemotherapy. HIV status did not adversely affect long-term EFS independent of the treatment regimen (P = 0.88). When EFS was evaluated according to chemotherapy regimen independent of HIV status, CODOX-M/IVAC was found to be associated with improved EFS (P = 0.05) in all patients, and particularly those at high risk. HIV-positive patients treated with CODOX-M/IVAC tolerated chemotherapy well with similar rates of myelosuppression and infectious complications as HIV-negative patients.
The current nonrandomized retrospective study suggested that intensive chemotherapy with CODOX-M/IVAC is feasible and well tolerated in HIV-positive adults with BL. In the post-HAART era, intensive chemotherapy such as CODOX-M/IVAC may be appropriate in all adult patients with BL, and especially those with poor prognostic factors, regardless of HIV status
Tumorigenic activity and therapeutic inhibition of Rheb GTPase
The AKT–mTOR pathway harbors several known and putative oncogenes and tumor suppressors. In a phenotypic screen for lymphomagenesis, we tested candidate genes acting upstream of and downstream from mTOR in vivo. We find that Rheb, a proximal activator of mTORC1, can produce rapid development of aggressive and drug-resistant lymphomas. Rheb causes mTORC1-dependent effects on apoptosis, senescence, and treatment responses that resemble those of Akt. Moreover, Rheb activity toward mTORC1 requires farnesylation and is readily blocked by a pharmacological inhibitor of farnesyltransferase (FTI). In Pten-deficient tumor cells, inhibition of Rheb by FTI is responsible for the drug’s anti-tumor effects, such that a farnesylation-independent mutant of Rheb renders these tumors resistant to FTI therapy. Notably, RHEB is highly expressed in some human lymphomas, resulting in mTORC1 activation and increased sensitivity to rapamycin and FTI. Downstream from mTOR, we examined translation initiation factors that have been implicated in transformation in vitro. Of these, only eIF4E was able to enhance lymphomagenesis in vivo. In summary, the Rheb GTPase is an oncogenic activity upstream of mTORC1 and eIF4E and a direct therapeutic target of farnesyltransferase inhibitors in cancer