Autocrine- and paracrine-activated receptor tyrosine kinases in classic Hodgkin lymphoma

Renné, Christoph; Willenbrock, Klaus; Küppers, Ralf; Hansmann, Martin‐Leo; Bräuninger, Andreas

doi:10.1182/blood-2004-10-4008

Cited by 116 publications

(118 citation statements)

References 54 publications

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“…15 The antibodies used, dilutions and providers are listed in Supplementary Table 1. Antigen unmasking was performed for 2 min in a pressure cooker in TRIS-EDTA at pH 8.0.…”

Section: Immunohistochemistry Quantification and Statisticsmentioning

confidence: 99%

Spindle-shaped CD163+ rosetting macrophages replace CD4+ T-cells in HIV-related classical Hodgkin lymphoma

et al. 2013

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Combination antiretroviral therapy is highly effective in HIV infection, leading to decreased incidences of AIDSdefining neoplasms. However, HIV patients still have a 10-fold increased risk of developing classical Hodgkin lymphoma compared with the general population. As Hodgkin-and Reed-Sternberg cells represent only a minority in the tumor infiltrate, the aim of the present study was to characterize the microenvironment of HIV-related classical Hodgkin lymphoma and compare it with classical Hodgkin lymphoma cases of immunocompetent individuals. The major morphologic differences were the presence of necrotic foci and the absence of epithelioid cell formation in HIV-related Hodgkin lymphoma. We observed a significantly decreased number of CD4 þ T-cells and a significantly increased number of CD163 þ macrophages in HIVrelated Hodgkin lymphoma. Cases exhibiting a 'sarcomatoid' pattern of the reactive infiltrate exhibited significantly greater numbers of macrophages, associating the 'sarcomatoid' pattern to the presence of spindle-shaped macrophages. Whereas, rosetting of CD4 þ T-cells around Hodgkin-and Reed-Sternberg cells was frequently observed in classical Hodgkin lymphoma in immunocompetent persons; rosetting in a subset of HIV-related Hodgkin lymphoma cases appeared to involve cytoplasmic protrusions of spindle-shaped macrophages. HIV-related Hodgkin lymphoma, therefore, is characterized by unique morphologic features, which should be recognized by pathologists.

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“…15 The antibodies used, dilutions and providers are listed in Supplementary Table 1. Antigen unmasking was performed for 2 min in a pressure cooker in TRIS-EDTA at pH 8.0.…”

Section: Immunohistochemistry Quantification and Statisticsmentioning

confidence: 99%

Spindle-shaped CD163+ rosetting macrophages replace CD4+ T-cells in HIV-related classical Hodgkin lymphoma

et al. 2013

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“…Several different RTKs are expressed and activated in HRS cells of Hodgkin lymphoma (5), and the inhibition of these RTKs with TKIs could be a novel option for treatment. In a screening of 9 TKIs, we found that all HRS cell lines tested were sensitive toward the TKIs sorafenib and lestaurtinib at concentrations achievable in patients.…”

Section: Discussionmentioning

confidence: 99%

“…In previous experiments, the PDGFRa inhibitor imatinib and K-252a (5,13), an inhibitor of TRKA, caused decreases of HRS cell proliferation indicating that also HRS cells could be sensitive to tyrosine kinase inhibition although so far no tyrosine kinase-activating mutations have been observed. Therefore, we chose 9 TKIs, either already approved for cancer therapy or in late stages of clinical trials, to examine their effects on HRS cell lines.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, HRS cells express 8 RTKs, platelet-derived growth factor receptor (PDGFR) a, DDR2, EPHB1, RON, TRKA, TRKB, TIE1, and CSF1R, in varying patterns, and PDGFRa and TRKA have been shown to be activated in primary cases (5)(6)(7). As mutations affecting RTKs could not be detected in HRS cell lines and as activating ligands were frequently co-expressed in HRS cells or expressed by surrounding cells in the infiltrate of primary Hodgkin lymphoma cases (5), the receptors are presumed to be activated in an autocrine or paracrine fashion.…”

Section: Introductionmentioning

confidence: 99%

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Induction of Endoplasmic Reticulum Stress by Sorafenib and Activation of NF-κB by Lestaurtinib as a Novel Resistance Mechanism in Hodgkin Lymphoma Cell Lines

Holz

Janning

Renné

et al. 2013

Molecular Cancer Therapeutics

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Hodgkin-Reed/Sternberg (HRS) cells of classical Hodgkin lymphoma show aberrant expression and activation of several receptor tyrosine kinases (RTK) in the majority of cases. Therefore, we tested whether tyrosine kinase inhibitors (TKI) already in clinical use or late stages of clinical trials have antiproliferative effects on HRS cell lines and evaluated the targets, affected signaling pathways, and mechanisms of cell death and resistance. Sorafenib and lestaurtinib had antiproliferative effects on HRS cell lines at concentrations achievable in patients. Sorafenib inhibited platelet-derived growth factor receptor (PDGFR) a, TRKA and RON, caused decreases in total and phosphorylated amounts of several signaling molecules, and provoked caspase-3-independent cell death, most likely due to endoplasmic reticulum stress as indicated by upregulation of GADD34 and GADD153 and phosphorylation of PERK. Lestaurtinib inhibited TRKA, PDGFRa, RON, and JAK2 and had only a cytostatic effect. Besides deactivation, lestaurtinib also caused activation of signaling pathways. It caused increases in CD30L and TRAIL expression, and CD30L/CD30 signaling likely led to the observed concomitant activation of extracellular signal-regulated kinase 1/2 and the alternative NF-kB pathway. These data disclose the possible use of sorafenib for the treatment of Hodgkin lymphoma and highlight NF-kB activation as a potential novel mechanism of resistance toward TKIs.

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“…It is conceivable that TrkB plays some role in cellular processes, since MAP kinase and PI3K pathways were known to be correlated with cell survival through tumor-associated gene expression. Furthermore, BDNF has also been reported to induce the expression of tumor-associated genes (5,10).…”

Section: Introductionmentioning

confidence: 99%

Neurotrophic receptor tyrosine kinase B sxinduces c-fos-associated cell survival

Hayashi

Nakatani²,

Nishioka³

et al. 2009

Int J Mol Med

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Abstract. The neurotrophic receptor tyrosine kinase B (TrkB) is a cell surface receptor for brain-derived neurotrophic factor (BDNF) with kinase activity. This protein is expressed in various tumors and thought to participate in various cellular processes. In this study, we established 293T cells stably expressing human TrkB to elucidate its intracellular functions. Using this cell system, we examined the biological roles of TrkB and its downstream target molecules. The TrkB expressing cells showed an increased survival rate through increased c-fos mRNA expression by BDNF, which were completely suppressed by TrkB inhibitor. Moreover, the combination of inhibitors of mitogen-activated protein kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) partially reduced both the cell survival rate and c-fos mRNA expression, whereas monotreatment of these reagents could not affect cell survival nor c-fos mRNA expression. These results suggested that TrkB could play a role in c-fos-associated cell survival through both MEK and PI3K pathway. It is conceivable that activation of TrkB has a significant impact on tumorigenesis and metastasis.

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Autocrine- and paracrine-activated receptor tyrosine kinases in classic Hodgkin lymphoma

Cited by 116 publications

References 54 publications

Spindle-shaped CD163+ rosetting macrophages replace CD4+ T-cells in HIV-related classical Hodgkin lymphoma

Spindle-shaped CD163+ rosetting macrophages replace CD4+ T-cells in HIV-related classical Hodgkin lymphoma

Induction of Endoplasmic Reticulum Stress by Sorafenib and Activation of NF-κB by Lestaurtinib as a Novel Resistance Mechanism in Hodgkin Lymphoma Cell Lines

Neurotrophic receptor tyrosine kinase B sxinduces c-fos-associated cell survival

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