Identification of the source of elevated hepatocyte growth factor levels in multiple myeloma patients

Rampa, Christoph; Tian, Erming; Våtsveen, Thea Kristin; Buene, Glenn; Slørdahl, Tobias S.; Børset, Magne; Waage, Anders; Sundan, Anders

doi:10.1186/2050-7771-2-8

Cited by 13 publications

(12 citation statements)

References 39 publications

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“…MM cells directly stimulate OC formation by releasing a variety of proinflammatory OCactivating factors (OAFs), including receptor activator of nuclear factor κB (NF-κB) ligand (RANKL), macrophage inflammatory protein 1α (MIP-1α), tumor necrosis factor α (TNFα), interleukin (IL)-3, IL-6, parathyroid hormone-related protein (PTHrP), and hepatocyte growth factor (HGF) (Choi et al 2000;Frassanito et al 2001;Giuliani et al 2004;Lee et al 2004;Cafforio et al 2014;Rampa et al 2014). Moreover, MM cells indirectly increase osteoclastogenesis via interactions with BMSCs, osteocytes, and resident T cells.…”

Section: Mechanisms Of Bone Destruction In Mmbdmentioning

confidence: 99%

Multiple Myeloma and Bone: The Fatal Interaction

Marino

Roodman

2017

Cold Spring Harb Perspect Med

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Multiple myeloma (MM) is the second-most-common hematologic malignancy and the most frequent cancer to involve bone. MM bone disease (MMBD) has devastating consequences for patients, including dramatic bone loss, severe bone pain, and pathological fractures that markedly decrease the quality of life and impact survival of MM patients. MMBD results from excessive osteoclastic bone resorption and persistent suppressed osteoblastic bone formation, causing lytic lesions that do not heal, even when patients are in complete and prolonged remission. This review discusses the cellular and molecular mechanisms that regulate the uncoupling of bone remodeling in MM, the effects of MMBD on tumor growth, and potential therapeutic approaches that may prevent severe bone loss and repair damaged bone in MM patients.

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Section: Mechanisms Of Bone Destruction In Mmbdmentioning

confidence: 99%

Multiple Myeloma and Bone: The Fatal Interaction

Marino

Roodman

2017

Cold Spring Harb Perspect Med

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“…Activation of the HGF/c-MET pathway has been evaluated using serum or plasma HGF, because HGF is expelled from tumor cells to the extracellular matrix and blood plasma by a paracrine mechanism [ 12 ]. Increased serum HGF (sHGF) has been reported to be a negative prognostic marker in various malignancies including colorectal cancer, gastric cancer [ 13 – 15 ], prostate cancer [ 16 ], ovarian cancer [ 17 ], breast cancer [ 18 , 19 ], glioma[ 20 ], melanoma [ 21 ], and multiple myeloma [ 22 , 23 ]. Recently, a Spanish group reported that high sHGF in patients with SCLC predicts poor outcome and epithelial-mesenchymal transition (EMT) change in the tumor [ 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

Clinical impact of high serum hepatocyte growth factor in advanced non-small cell lung cancer

et al. 2017

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Activation of c-MET through hepatocyte growth factor (HGF) increases tumorigenesis, induces resistance, and is associated with poor prognosis in various solid tumors. However, the clinical value of serum HGF (sHGF) in patients with advanced non-small cell lung cancer (NSCLC), especially those receiving cytotoxic chemotherapy, remains unknown. Here, we show that sHGF may be useful to predict tumor response and progression-free survival (PFS) in patients with advanced NSCLC. A total of 81 patients with NSCLC were investigated. sHGF levels were evaluated using ELISA at 4 time-points: at pre-treatment, at response-evaluation (1–2 months after treatment initiation), at the best tumor response, and at disease progression. As a control biomarker, CEA was also evaluated in lung adenocarcinoma. Positive-sHGF at response-evaluation predicted poor PFS compared with Negative-sHGF in both first-line (median, 153.5 vs. 288.0; P < 0.05) and second-line treatment (87.0 vs. 219.5; P = 0.01). In 55 patients that received cytotoxic chemotherapy, multiple Cox proportional hazards models showed significant independent associations between poor PFS and Positive-sHGF at response-evaluation (hazard ratio, 4.24; 95% CI, 2.05 to 9.46; P < 0.01). Lung adenocarcinoma subgroup analysis showed that in patients receiving second cytotoxic chemotherapy, there were no significant differences in PFS between patients with low-CEA compared with those with high-CEA, but Positive-sHGF at pre-treatment or at response-evaluation predicted poor PFS (35.0 vs. 132.0; P < 0.01, 50.0 vs. 215.0; P < 0.01, respectively). These findings give a rationale for future research investigating the merit of sHGF as a potential clinical biomarker to evaluate HGF/c-MET activity, which would be useful to indicate administration of c-MET inhibitors.

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“…In association with basic fibroblast growth factor, vascular endothelial growth factor, and soluble syndecan‐1, HGF significantly increases angiogenic activity within myeloma bone marrow, supporting the survival and regeneration of malignant PCs (Gherardi, ; Sezer et al, ; Andersen et al, ). High concentrations of HGF in MM sera are produced by myeloma cells and associated with short‐term responses to therapies and early relapses of MM (Seidel et al, ; Rampa et al, ).…”

Section: Introductionmentioning

confidence: 99%

Allelic mutations in noncoding genomic sequences construct novel transcription factor binding sites that promote gene overexpression

Tian

Børset

Sawyer

et al. 2015

Genes Chromosomes & Cancer

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The growth and survival factor hepatocyte growth factor (HGF) is expressed at high levels in multiple myeloma (MM) cells. We report here that elevated HGF transcription in MM was traced to DNA mutations in the promoter alleles of HGF. Sequence analysis revealed a previously undiscovered single-nucleotide polymorphism (SNP) and crucial single-nucleotide variants (SNVs) in the promoters of myeloma cells that produce large amounts of HGF. The allele-specific mutations functionally reassembled wild-type sequences into the motifs that affiliate with endogenous transcription factors NFKB (nuclear factor kappa-B), MZF1 (myeloid zinc finger 1), and NRF-2 (nuclear factor erythroid 2-related factor 2). In vitro, a mutant allele that gained novel NFKB–binding sites directly responded to transcriptional signaling induced by tumor necrosis factor alpha (TNFα) to promote high levels of luciferase reporter. Given the recent discovery by genome-wide sequencing (GWS) of numerous non-coding mutations in myeloma genomes, our data provide evidence that heterogeneous SNVs in the gene regulatory regions may frequently transform wild-type alleles into novel transcription factor binding properties to aberrantly interact with dysregulated transcriptional signals in MM and other cancer cells.

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Identification of the source of elevated hepatocyte growth factor levels in multiple myeloma patients

Cited by 13 publications

References 39 publications

Multiple Myeloma and Bone: The Fatal Interaction

Multiple Myeloma and Bone: The Fatal Interaction

Clinical impact of high serum hepatocyte growth factor in advanced non-small cell lung cancer

Allelic mutations in noncoding genomic sequences construct novel transcription factor binding sites that promote gene overexpression

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