The tyrosine kinase receptor Met and its ligand HGF are co-expressed and functionally active in HHV-8 positive primary effusion lymphoma

Capello, Daniela; Gaïdano, Gianluca; Gallicchio, Margherita; Gloghini, Annunziata; Medico, Enzo; Vivenza, Daniela; Buonaiuto, Daniela; Fassone, Lucia; Avanzi, Giancarlo; Saglio, Giuseppe; Prat, María; Carbone, Antonino

doi:10.1038/sj.leu.2401666

Cited by 32 publications

(29 citation statements)

References 44 publications

(64 reference statements)

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“…Six cytokines (IL-6, IL-10, IP-10, HGF, MIG, and VEGF) were secreted to high levels in the growth medium of BC-1 cells consistent with earlier observations. 41,42 NVP-BEZ235 dramatically reduced secretion of all these cytokines 72 hours after treatment. The other Akt/mTOR pathway inhibitors exhibited weaker, more differential phenotypes.…”

Section: Discussionmentioning

confidence: 96%

Dual inhibition of PI3K and mTOR inhibits autocrine and paracrine proliferative loops in PI3K/Akt/mTOR-addicted lymphomas

Bhatt

Bhende

Sin

et al. 2010

Blood

131

126

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Primary effusion lymphoma (PEL) constitutes a subset of non-Hodgkin lymphoma whose incidence is highly increased in the context of HIV infection. Kaposi sarcomaassociated herpesvirus is the causative agent of PEL. The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays a critical role in cell proliferation and survival, and this pathway is dysregulated in many different cancers, including PEL, which display activated PI3K, Akt, and mammalian target of rapamycin (mTOR) kinases. PELs rely heavily on PI3K/Akt/mTOR signaling, are dependent on autocrine and paracrine growth factors, and also have a poor prognosis with reported median survival times of less than 6 months. We compared different compounds that inhibit the PI3K/Akt/mTOR pathway in PEL. Although compounds that modulated activity of only a single pathway member inhibited PEL proliferation, the use of a novel compound, NVP-BEZ235, that dually inhibits both PI3K and mTOR kinases was significantly more efficacious in culture and in a PEL xenograft tumor model. NVP-BEZ235 was effective at low nanomolar concentrations and has oral bioavailability. We also report a novel mechanism for NVP-BEZ235 involving the suppression of multiple autocrine and paracrine growth factors required for lymphoma survival. IntroductionThe phosphatidylinositol 3-kinase (PI3K) signaling pathway plays a critical role in cell proliferation and cell survival. PI3K activation stimulates the production of phosphatidylinositol 3,4,5-triphosphate, which results in activation of the kinases PDK1 and Akt. The lipid phosphatase and tensin homolog deleted on chromosome 10 (PTEN) protein is a negative regulator of this pathway. Akt kinase promotes cell survival by phosphorylating, and thereby inactivating, proapoptotic factors, such as the FOXO transcription factor family, GSK-3␤, caspase-9, and Bad. [1][2][3][4] Phosphorylation of Bad and the FOXO transactivators prevent apoptosis. Akt also phosphorylates p27, a negative regulator of the cell cycle, thereby preventing cell cycle arrest. In addition, Akt activation leads to phosphorylation and activation of the mammalian target of rapamycin (mTOR), a kinase that stimulates protein synthesis and cell proliferation.Activated mTOR protein can associate with raptor and mLST8/G␤L to form the mTORC1 complex. The mTORC1 complex induces phosphorylation of p70 S6 kinase (S6K), leading to phosphorylation and activation of the ribosomal protein S6. mTORC1 also inhibits 4E-BP1, a repressor of eukaryotic initiation factor eIF4E. This arm of the mTOR pathway is rapamycin-sensitive. In contrast, the mTORC2 complex, which consists of mTOR, mLST8/G␤L, mSin1, and Rictor, is insensitive to the effects of rapamycin. mTORC2 functions in a feedback loop that phosphorylates and activates Akt by phosphorylation at Ser473. 5 Hence, inhibitors of PI3K/Akt probably have broader effects than mTOR inhibitors.The nutrient sensor, AMP activated kinase (AMPK), is a negative regulator of mTORC1. 6 AMPK controls cellular homeostasis by regulating energy production withi...

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Section: Discussionmentioning

confidence: 96%

Dual inhibition of PI3K and mTOR inhibits autocrine and paracrine proliferative loops in PI3K/Akt/mTOR-addicted lymphomas

Bhatt

Bhende

Sin

et al. 2010

Blood

131

126

View full text Add to dashboard Cite

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“…The expression of MET has been demonstrated in MMs and a subset of nonHodgkin's lymphomas. Activation of the pathway in these tumors may involve autocrine stimulation, because coexpression of HGF and MET has been observed (35,(41)(42)(43). In MMs, MET activation promotes proliferation and survival (37).…”

Section: Discussionmentioning

confidence: 99%

Follicular Dendritic Cells Catalyze Hepatocyte Growth Factor (HGF) Activation in the Germinal Center Microenvironment by Secreting the Serine Protease HGF Activator

Tjin

Bende

Derksen

et al. 2005

The Journal of Immunology

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Ag-specific B cell differentiation, the process that gives rise to plasma cells and memory B cells, involves the formation of germinal centers (GC). Within the GC microenvironment, multiple steps of B cell proliferation, selection, and maturation take place, which are controlled by the BCR in concert with cytokines and contact-dependent signals from follicular dendritic cells (FDCs) and T cells. Signaling by the multifunctional cytokine hepatocyte growth factor (HGF) and its receptor MET has been shown to induce integrin-mediated adhesion of B cells to VCAM-1, which is expressed by FDCs. In the present study we have examined the expression of regulatory components of the HGF/MET pathway, including HGF activator (HGFA), within the secondary lymphoid organ microenvironment. We show that MET is expressed by both centroblasts and plasma cells, and that HGFA is expressed by plasma cells. Because we have shown that HGF is a potent growth and survival factor for malignant plasma cells, HGF may also serve as a survival factor for normal plasma cells. Furthermore, we demonstrate that FDCs are the major source for HGF and its activator within the GC microenvironment. Both HGF and HGFA are expressed by FDCs in the GC dark zone (CD21high/CD23low), but not in the light zone (CD21high/CD23high). These findings suggest that HGF and HGFA provided by dark zone FDCs help to regulate the proliferation, survival, and/or adhesion of MET-positive centroblasts.

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“…In primary effusion lymphoma, as well as in MM, co-expression of HGF and Met has been observed, suggesting autocrine stimulation. 10,11,14 Since BM stromal cells produce HGF, 15 paracrine stimulation of MM cells within the BM microenvironment can also take place. Consistent with a role for HGF/Met in MM progression, high serum levels of HGF were reported to be associated with unfavorable prognosis in patients with MM.…”

Section: Introductionmentioning

confidence: 99%

The hepatocyte growth factor/Met pathway controls proliferation and apoptosis in multiple myeloma

et al. 2003

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The evolution of multiple myeloma (MM) depends on complex signals from the bone marrow (BM) microenvironment, supporting the proliferation and survival of malignant plasma cells. An interesting candidate signal is hepatocyte growth factor/ scatter factor (HGF), since its receptor Met is expressed on MM cells, while HGF is produced by BM stromal cells and by some MM cell lines, enabling para-or autocrine interaction. To explore this hypothesis, we studied the biological effects of HGF stimulation on MM cell lines and on primary MMs. We observed that Met is expressed by the majority of MM cell lines and by approximately half of the primary plasma cell neoplasms tested. Stimulation of MM cells with HGF led to the activation of the RAS/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/protein kinase B (PI3K/PKB) pathways, signaling routes that have been implicated in the regulation of cell proliferation and survival. Indeed, functional studies demonstrated that HGF has strong proliferative and antiapoptotic effects on both MM cell lines and primary MM cells. Furthermore, by applying specific signal-transduction inhibitors, we demonstrated that MEK is required for HGF-induced proliferation, whereas activation of PI3K is required for both HGF-induced proliferation and for rescue of MM cells from apoptosis. Taken together, our data indicate that HGF is a potent myeloma growth and survival factor and suggest that the HGF/Met pathway is a potential therapeutic target in MM.

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The tyrosine kinase receptor Met and its ligand HGF are co-expressed and functionally active in HHV-8 positive primary effusion lymphoma

Abstract: Primary effusion lymphoma (PEL) harbors consistent infection by human herpesvirus-8, preferentially develops in immuno-

Cited by 32 publications

References 44 publications

Dual inhibition of PI3K and mTOR inhibits autocrine and paracrine proliferative loops in PI3K/Akt/mTOR-addicted lymphomas

Dual inhibition of PI3K and mTOR inhibits autocrine and paracrine proliferative loops in PI3K/Akt/mTOR-addicted lymphomas

Follicular Dendritic Cells Catalyze Hepatocyte Growth Factor (HGF) Activation in the Germinal Center Microenvironment by Secreting the Serine Protease HGF Activator

The hepatocyte growth factor/Met pathway controls proliferation and apoptosis in multiple myeloma

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