Hepatocyte growth factor promotes migration of human myeloma cells

Holt, Randi Utne; Fagerli, Unn-Merete; Baykov, Vadim; Rø, Torstein Baade; Hov, Håkon; Waage, Anders; Sundan, Anders; Børset, Magne

doi:10.3324/haematol.11867

Cited by 42 publications

(34 citation statements)

References 21 publications

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“…15,[29][30][31][32] Its cytoreductive activity was also demonstrated in a gastric carcinoma xenograft model. 29) These in vitro and in vivo studies support the therapeutic potential of targeting MET in cancers where MET plays a role in tumor growth or metastasis.…”

Section: Met-targeted Therapymentioning

confidence: 99%

Receptor Tyrosine Kinases and Targeted Cancer Therapeutics

Takeuchi

Ito

2011

Biological & Pharmaceutical Bulletin

144

113

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The majority of growth factor receptors are composed of extracellular, transmembrane, and cytoplasmic tyrosine kinase (TK) domains. Receptor tyrosine kinase (RTK) activation regulates many key processes including cell growth and survival. However, dysregulation of RTK has been found in a wide range of cancers, and it has been shown to correlate with the development and progression of numerous cancers. Therefore, RTK has become an attractive therapeutic target. One way to effectively block signaling from RTK is inhibition of its catalytic activity with small-molecule inhibitors. Low-molecular-weight TK inhibitors (TKIs), such as imatinib, targeting tumors with mutant c-Kit, and gefitinib, targeting non-small cell lung cancer with mutant epidermal growth factor receptor (EGFR), have received marketing approval in Japan. MET, fibroblast growth factor receptor (FGFR), and insulin-like growth factor-I receptor (IGF-IR) are frequently genetically altered in advanced cancers. TKIs of these receptors have not yet appeared on the market, but many anticancer drug candidates are currently undergoing clinical trials. Most of these TKIs were designed to compete with ATP at the ATP-binding site within the TK domain. This review will focus on small-molecule TKIs targeting MET, FGFR, and IGF-IR and discuss the merits and demerits of two types of agents, i.e., those with only one or a few targets and those directed at multiple targets. Targeting agents specifically inhibiting the target kinase were previously searched for based on the hypothesis that a narrow target window might reduce unexpected side effects, but agents with multiple targets have been recently developed to overcome tumors resistant against a single-targeting agent.

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Section: Met-targeted Therapymentioning

confidence: 99%

Receptor Tyrosine Kinases and Targeted Cancer Therapeutics

Takeuchi

Ito

2011

Biological & Pharmaceutical Bulletin

144

113

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“…Moreover, it may account for the increased microvessel density observed in the BM [5][6][7] . Hepatocyte growth factor (HGF) produced by myeloma cells is a pleiotropic cytokine which promotes tumor cell growth, bone marrow dissemination, inhibits osteoblast function and contributes to myeloma bone disease and BM angio- 8 . Migration and invasion of myeloma cells require the secretion of metaloproteinase-2 (MMP-2) and MMP-9 which are possibly modulated, in part, by syndecan-1 (CD 138 ), expressed in plasma cells and which can be shed from the surface of myeloma cells and circulate as soluble factor 9,10 .…”

Section: Introductionmentioning

confidence: 99%

The Relationship Between Some Soluble Osteogenic Markers, Angiogenic Cytokines/Other Biological Parameters and the Stages of Multiple Myeloma Evaluated According to the Durie-Salmon and International Prognostic Index Stratification Systems

Scudla¹,

Pika²,

Budíková³

et al. 2009

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Background:The aim of the present paper was to examine the correlation between serum concentrations of 12 soluble biological markers and stages of myeloma evaluated according to the Durie-Salmon (D-S) and International Prognostic Index (IPI) stratification systems.Methods: We analyzed a non-pretreated group of 179 patients with MM stratified according to D-S and IPI. Serum levels of soluble biological markers were evaluated using ELISA, REA and quantitative sandwich enzymatic immunoassays. The data were analyzed using the Kruskal-Wallis and Mann-Whitney U tests.Results: The staging system according to D-S revealed a highly significant relationship between all stages (I-III) in case of β 2 -m (p<0.0001) and sTK (p<0.001), in sICTP a significant difference was found only in stages II vs III (p<0.001) and I vs III (p<0.001), in case of sCD 138 (syndecan-1) in stages I vs II (p = 0.006) and I vs III (p<0.001), in sVEGF only in stages I vs III (p = 0.006). In substages A vs B we found a significant difference in case of β 2 -m (p<0.0001), sTK (p = 0.041), sICTP (p 0.0001), sOSP (p = 0.008), sHGF (p<0.001), sCD138 (p = 0.001) and sFas (p= 0.001). The relationship between other factors and stages and substages according to D-S appeared nonsignificant. The IPI system showed a highly significant relationship between all 3 categories (1-3) in case of β 2 -m (p<0.001), sTK (p<0.0001) and sICTP (p<0.0001), while in sHGF only in stages 2 vs 3 (p<0.0001) and 1 vs 3 (p<0.0001). In 4 parameters there were only discrete differences in 1 vs 3: sPINP (p= 0.036), sOSP (p= 0.002), sCD 138 (p = 0.03) and sFas (p=0.012), in the remaining markers the analysis was negative.Conclusions: A highly convincing relationship between myeloma stages and serum levels was found only in β 2 -m, sTK, sICTP and partly also in sCD 138 (syndecan-1) and sHGF. More favourable was the IPI stratification system.

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“…Interestingly, cytoskeletal activation downstream from mTORC2 has been suggested via Rho and other related proteins (16), which are consistent with our observation at a later time point of RAPA induced GBM motility. Alternatively, a study using a transwell two-chamber migration assay indicated that cytokine-induced cell migration did not involve mTOR in cancer cells (43).…”

Section: Discussionmentioning

confidence: 99%

Involvement of mTORC1 and mTORC2 in regulation of glioblastoma multiforme growth and motility

Gulati

Karsy²,

Albert³

et al. 2009

Int J Oncol

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Abstract. The AKT/mammalian target of Rapamycin (mTOR) signaling pathway plays a critical role in glioblastoma multiforme (GBM) oncogenesis due to activation of AKT. We studied two distinct complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), through which mTOR controls cell survival, growth and motility. Inhibition of mTOR by Rapamycin (RAPA) resulted in time-dependent suppression of S6 ribosomal protein (pS6K Ser235/236 ; mTORC1 substrate) and caused transient suppression of pAKT Ser473 (mTORC2 substrate) at 1 to 3 h followed by a consistent increase from 6 to 24 h. Inhibition of mTOR or phosphoinositide 3-kinase (PI3K) suppressed platelet-derived growth factor (PDGF)-or fibronectin (FN)-induced activation of p70S6K Thr389 . Combined inhibition of mTOR and PI3K abolished PDGF-or FN-induced activation of STAT3 Ser727 . Expression of pAKT was suppressed by siRNA silencing of mTORC2 co-protein Rictor, but not by mTORC1 co-protein Raptor. GBM cell proliferation and motility paralleled the activation of mTORC2. Combined inhibition of mTOR and PI3K had an additive effect on suppressing cell growth and motility. PDGF-induced nuclear localization of mTOR was blocked by pre-treatment with RAPA. The results demonstrated that an activation of mTORC2 occurs when mTORC1 is inhibited by RAPA. Therefore, simultaneous suppression of mTORC1 and mTORC2 may provide novel therapy for GBM.

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Hepatocyte growth factor promotes migration of human myeloma cells

Cited by 42 publications

References 21 publications

Receptor Tyrosine Kinases and Targeted Cancer Therapeutics

Receptor Tyrosine Kinases and Targeted Cancer Therapeutics

The Relationship Between Some Soluble Osteogenic Markers, Angiogenic Cytokines/Other Biological Parameters and the Stages of Multiple Myeloma Evaluated According to the Durie-Salmon and International Prognostic Index Stratification Systems

Involvement of mTORC1 and mTORC2 in regulation of glioblastoma multiforme growth and motility

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