Pretreatment hepatocyte growth factor and thrombospondin-1 levels predict response to high-dose chemotherapy for multiple myeloma

Neoplasma ◽  
2010 ◽  
Vol 57 (1) ◽  
pp. 29-34 ◽  
Author(s):  
L. POUR ◽  
H. SVACHOVA ◽  
Z. ADAM ◽  
Z. MIKULKOVA ◽  
L. BURESOVA ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Thrombospondin 1 ◽  
Hepatocyte Growth

Hepatocyte growth factor in myeloma patients treated with high-dose chemotherapy

2002 ◽  
Vol 119 (3) ◽  
pp. 672-676 ◽  
Author(s):  
Carina Seidel ◽  
Stig Lenhoff ◽  
Sigmund Brabrand ◽  
Gøran Anderson ◽  
Therese Standal ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Hepatocyte Growth

Abstract 621: High-dose gefitinib overcomes the resistance to gefitinib related to hepatocyte growth factor

2010 ◽  
Author(s):  
Hiromi Kashihara ◽  
Eiki Ichihara ◽  
Saburo Takata ◽  
Kadoaki Ohashi ◽  
Toshio Kubo ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
High Dose ◽  
Hepatocyte Growth

Multiple Myeloma Plasma Cell Expression of Hepatocyte Growth Factor mRNA Isoforms Correlates with Overall Survival In Myeloma Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4983-4983
Author(s):  
Ida Bruun Kristensen ◽  
Jacob Haaber Christensen ◽  
Maria Lyng ◽  
Tobias W Klausen ◽  
Lene Meldgaard Knudsen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Growth Factor ◽  
Prognostic Factor ◽  
Hepatocyte Growth Factor ◽  
Full Length ◽  
Transcript Variant ◽  
Kringle Domain ◽  
Adverse Prognostic Factor ◽  
Hepatocyte Growth

Abstract Abstract 4983 Background: Full length Hepatocyte growth Factor (HGF) (consisting of four “kringle”-domains) is known to be produced by multiple myeloma plasma cells (MM PC) in vivo and HGF is among the 70 most up regulated genes in MM. Elevated serum levels of HGF are known to be an adverse prognostic factor and recently, MM PC expression of the HGF receptor cMET has been shown to be an adverse prognostic factor. Functionally, HGF inhibits osteoblastogenesis in vitro and promotes migration of MM PC. So far, studies on HGF and its impact in MM have focused on measuring full-length or all isoforms of HGF expression. However, naturally occurring shorter isoforms of HGF (known as NK1 and NK2) are known to work as partial inhibitors of full-length HGF (Otsuka et al, Mol and Cell Biol, 2000). We examined the HGF isoforms and cMET expression at the mRNA level in isolated MM PC of >150 newly diagnosed patients with MM, 18 MGUS patients and 8 healthy volunteers (HV) and associated it to overall survival (OS) and degree of osteolytic bone disease (OBD). Methods: Aberrant MM PCs (CD38++/CD19-/CD45-/i/CD56-/+/++) were sorted directly into PCR tubes by fluorescence activated cell sorting (FACS) using a FACS Aria (BDIS). In all cases a PC-purity above 98% was obtained. A cDNA archive was generated by global reverse transcription. By using a polyadenylating step 5x-oligo(dT)-transcript-poly(A)-3xcDNA were generated and finally amplified by PCR using a sequence independent X-(dT)24 primer. The conditions of the reverse transcriptase reaction is designed to limit the size of the first strand cDNA to 300–700 bases, which leads to a more uniform and unbiased amplification. Isoform specific primers were designed using the Primer Express program and experimentally tested. The HGF version covered full-length HGF (transcript variant 1 and 3), HGF2 covered the 2 kringle domain versions (transcript variant 2 and 4) and HGF5 covered the 1 kringle domain version (transcript variant 5). cMET only exists in one isoform. Quantitative PCR was performed using β-actin as internal reference gene, using the δCt method. Determination of positivity or negativity was made from a cut-off-value at 10E-05. OBD was evaluated by standard radiographic methods. The MM patients were treated with either high-dose melphalan with ASCT or melphalan-prednisone according to age recommendations. Results: At least one of the HGF isoforms were found to be expressed in PCxs from 43% of MM patients compared to 32% of MGUS patients, and 0% of HV. Full length HGF was expressed in 17 %, HGF2 in 29%, and HGF5 in 26% of the MM patients. Expression of any HGF variant was associated to an adverse OS (p=0.04) (Fig. 1). The quantitative expression of the transcript variant 5 associated negatively to OS (p=0.02), while expression of the other specific isoforms showed no association to OS. Thus, somehow surprisingly, MM PC expression of the shorter isoform of HGF (HGF5) was more predictive of poor prognosis. A tendency towards elevated expression of full-length HGF in patients with no OBD compared to limited or advanced was observed but did not reach statistically significance (p=0.13). Pre-liminary analysis of cMET expression data showed no correlation between MM PC cMet expression and degree of OBD. Further data on cMet will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Serine Protease Matriptase Acts As a Tumour Suppressor in Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 14-14
Author(s):  
Ida Steiro ◽  
Pegah Abdollahi ◽  
Magne Børset ◽  
Tobias S. Slørdahl
Keyword(s):  
Multiple Myeloma ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Serine Protease ◽  
Cell Lines ◽  
Myeloma Cell ◽  
Tumour Suppressor ◽  
Hepatocyte Growth

Both in newly diagnosed multiple myeloma (MM) and during progression of the disease, malignant plasma cells are found circulating in peripheral blood as well as in the bone marrow (BM). The disseminated nature of MM is strongly dependent on the interplay between the cancer cells and the BM microenvironment, promoting myeloma cell migration in the BM. Matriptase (ST14), a type-II transmembrane serine protease primarily found in epithelial tissues, is overexpressed in a variety of human malignancies and is sufficient to induce tumour formation in mice. Frequently, a concomitant reduction in the levels of its cognate inhibitor hepatocyte growth factor activator inhibitor (HAI)-1 (SPINT1) is observed in carcinomas, while expression and function of the related inhibitor HAI-2 (SPINT2) is yet to be clarified. Dysregulated expression causing increased matriptase proteolytic activity has been associated with cancer growth, survival and metastasis. Here, we show for the first time a role of matriptase as a possible tumour suppressor in myeloma pathogenesis. Gene expression analysis of primary cells from MM patients (n=24) and human myeloma cell lines (n=8) revealed highly variable levels of matriptase, HAI-1 and HAI-2. This observation prompted us to investigate the functional role of matriptase in vitro. We showed that stable overexpression of matriptase in INA-6, a MM cell line with no endogenous ST14 expression, reduced migration by more than 50% in response to the combination of the pro-migratory cytokines stromal cell-derived factor-1 alpha (SDF-1α) and hepatocyte growth factor (HGF, Fig. 1A). Conversely, stable knockdown of matriptase in two MM cell lines with high endogenous matriptase expression (RPMI-8226 and JJN-3) significantly enhanced migration in vitro. Mechanistically, matriptase overexpression blocked activation of Src kinase (Fig. 1B), well-known as a critical player in metastasis formation promoting cancer cell motility, invasiveness and angiogenesis. In agreement with our result, previous studies have demonstrated the activation of Src family kinases (SFK) downstream SDF-1/CXCR4-signaling. Finally, we performed survival analyses in the public available MMRF CoMMpass trial database (release version IA14). Low ST14 expression was associated with significant worse overall survival (P=0.05, Fig. 1C) and progression-free survival (P=0.02, Fig. 1D). Altogether, our data are in marked contrast to the role ascribed to matriptase in epithelial and certain non-epithelial tumours as an oncogenic protein and an unfavourable prognostic marker. In conclusion, these findings suggest a novel role of matriptase as a tumour suppressor in MM pathogenesis. Disclosures Slørdahl: Celgene: Consultancy; Janssen and Celgene: Honoraria.

scholarly journals Hepatocyte growth factor and its receptor c-met in multiple myeloma

Blood ◽  
1996 ◽  
Vol 88 (10) ◽  
pp. 3998-4004 ◽  
Author(s):  
M Borset ◽  
H Hjorth-Hansen ◽  
C Seidel ◽  
A Sundan ◽  
A Waage
Keyword(s):  
Multiple Myeloma ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Mononuclear Cells ◽  
Primary Cultures ◽  
Enzyme Linked Immunosorbent Assay ◽  
Myeloma Cells ◽  
The Mean ◽  
Hepatocyte Growth ◽  
Normal Controls

We have examined whether the hepatocyte growth factor (HGF)/c-met receptor-ligand pair is expressed in freshly isolated and highly purified myeloma cells and whether HGF can be found in the sera of myeloma patients. Myeloma cells were purified with an immunomagnetic method using the syndecan 1-specific antibody B-B4. HGF and c-met mRNA in these cells were examined by reverse transcriptase-polymerase chain reaction (RT-PCR). HGF and c-met proteins were detected by enzyme- linked immunosorbent assay (ELISA) and Western blot, respectively. Serum from 13 myeloma patients was obtained at diagnosis and the levels of HGF were determined by ELISA. HGF and c-met mRNA were expressed in all examined samples (n = 7). HGF was detected in the supernatants of 17 of 20 primary cultures of myeloma cells, whereas bone marrow mononuclear cells from normal controls did not produce detectable amounts of HGF (n = 3). The mean HGF level in serum of myeloma patients at diagnosis was more than fourfold higher than the mean level in normal controls. Possible implications of HGF/c-met expression for the pathophysiology of multiple myeloma are discussed.

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

2014 ◽  
Vol 2 (1) ◽  
Author(s):  
Christoph Rampa ◽  
Erming Tian ◽  
Thea Kristin Våtsveen ◽  
Glenn Buene ◽  
Tobias Schmidt Slørdahl ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Hepatocyte Growth
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