Biological Role of HGF/Met Pathway in Renal Cell Carcinoma

Horie, Shigeo; Aruga, Seiji; Kawamata, Hitoshi; Okui, Nobuo; Kakizoe, Tadao; Kitamura, Tadaichi

doi:10.1097/00005392-199903000-00076

Cited by 14 publications

(20 citation statements)

References 30 publications

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“…64 Furthermore, HGF/SF and its receptor c-MET are frequently overexpressed in CC-RCC. [65][66][67][68] Therefore, it would be of interest to determine whether the overexpression of MMP2, MMP9 or HGF/SF is responsible for the cleavage of E-cadherin in CC-RCC.…”

Section: Discussionmentioning

confidence: 99%

Nuclear E-cadherin and VHL immunoreactivity are prognostic indicators of clear-cell renal cell carcinoma

Gervais

Henry

Saravanan

et al. 2007

Laboratory Investigation

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The loss of functional von Hippel-Lindau (VHL) tumor suppressor gene is associated with the development of clear-cell renal cell carcinoma (CC-RCC). Recently, VHL was shown to promote the transcription of E-cadherin, an adhesion molecule whose expression is inversely correlated with the aggressive phenotype of numerous epithelial cancers. Here, we performed immunohistochemistry on CC-RCC tissue microarrays to determine the prognostic value of E-cadherin and VHL with respect to Fuhrman grade and clinical prognosis. Low Fuhrman grade and good prognosis associated with positive VHL and E-cadherin immunoreactivity, whereas poor prognosis and high-grade tumors associated with a lack of E-cadherin and lower frequency of VHL staining. A significant portion of CC-RCC with positive VHL immunostaining correlated with nuclear localization of C-terminally cleaved E-cadherin. DNA sequencing revealed in a majority of nuclear E-cadherin-positive CC-RCC, subtle point mutations, deletions and insertions in VHL. Furthermore, nuclear E-cadherin was not observed in chromophobe or papillary RCC, as well as matched normal kidney tissue. In addition, nuclear E-cadherin localization was recapitulated in CC-RCC xenografts devoid of functional VHL or reconstituted with synthetic mutant VHL grown in SCID mice. These findings provide the first evidence of aberrant nuclear localization of E-cadherin in CC-RCC harboring VHL mutations, and suggest potential prognostic value of VHL and E-cadherin in CC-RCC. [4][5][6][7] Currently, a prediction of patient survival is based on traditional clinical parameters, including tumor size and Fuhrman nuclear grade. 8 However, the emerging understanding of the molecular pathways implicated in CC-RCC genesis and progression is providing previously unappreciated markers, which may serve as additional or better prognostic indicators of CC-RCC.The principal cause of sporadic CC-RCC and familial von Hippel-Lindau (VHL) disease-associated CC-RCC is the inactivating mutations of VHL. Although VHL patients also develop tumors in other organs including the central nervous system, retina and the adrenal gland, CC-RCC remains to be the leading cause of morbidity and death for VHL patients. 9 The most well-established function of VHL is its role in the oxygen-dependent negative regulation of hypoxia-inducible factor (HIF). VHL is a substrate-conferring component of an E3 ubiquitin ligase ECV (elongins/Cul2/VHL) that polyubiquitylates the catalytic a-subunit of HIF that has undergone hydroxylation on conserved prolyl residues within the oxygen-dependent degradation (ODD) domain. Prolyl hydroxylation is mediated by a class of prolyl hydroxylases (PHD1-3) in an oxygen-dependent manner. Thus, under hypoxia or in the absence of a functional VHL, HIFa becomes stabilized and binds to its common and constitutively expressed b-subunit, forming an active HIF transcription factor capable of transactivating numerous hypoxia-inducible genes such as vascular endothelial growth factor (VEGF),

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Section: Discussionmentioning

confidence: 99%

Nuclear E-cadherin and VHL immunoreactivity are prognostic indicators of clear-cell renal cell carcinoma

Gervais

Henry

Saravanan

et al. 2007

Laboratory Investigation

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“…[31][32][33][34] We also reported that the augmentation of HGF/c-met signal upregulated proMMP9, proMMP1, and uPA in a renal cell carcinoma cell line, Caki-1. 18 In this oral SCC cell system, we also examined the effect of HGF on the activity of the gelatinase produced by BHY and HN cells. We could not detect the upregulation of gelatinase, however, and uPA or the downregulation of their inhibitors, such as TIMPs or plasminogen activator inhibitors by treatment of BHY and HN cells with HGF (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…Taq DNA polymerase (Takara Biomedicals, Kusatsu, Japan) was added to the mixture at a final concentration of 0.05 U/ l, and the reaction was carried out in a Takara Thermal Cycler MP (Takara Biomedicals) under the following conditions: 94°C for 3 min and then 94°C for 1 min, 55°C for 1.5 min, 72°C for 2.5 min for 30 cycles, and extension at 72°C for 4 min. To determine whether conditions were adequate for semi-quantitative RT-PCR, we reverse-transcribed 0.05, 0.5, 5, and 10 g of total RNA and amplified the fragments under the same PCR conditions with different numbers of cycles (18,22,26,30,34 cycles). We used 5 g of cytoplasmic or total RNA as a template for reverse transcription and 30 cycles of PCR amplification for c-met and 22 cycles for GAPDH.…”

Section: Rt-pcrmentioning

confidence: 99%

“…17 We recently reported that ectopic expression of HGF cDNA in a renal cell carcinoma cell line, Caki, which originally expressed functional c-met protein, enhanced the invasiveness in vitro and increased the activity of proMMP1, proMMP9, and uPA. 18 It was reported that HGF induced tyrosine phosphorylation of focal adhesion kinase, p125FAK, 19 and promoted the migration and invasion of oral SCC cells. 20 Moreover, in several clinical studies, a relationship between the concentration of HGF in serum or in cancer tissue and the progression of disease has been noted in patients with gastric cancer, 21 breast cancer 22 and lung cancer, 23 but has not been reported in patients with oral cancer.…”

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confidence: 97%

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Role of HGF/c-met system in invasion and metastasis of oral squamous cell carcinoma cellsin vitro and its clinical significance

et al. 2001

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We examined the role of the hepatocyte growth factor (HGF)/c-met system on invasion and metastasis of oral squamous cell carcinoma (SCC) cells. In monolayer culture, exogenous HGF marginally affected the growth of oral SCC cells (BHY, HN, IH) and human gingival epithelial cells (GE). In type I collagen matrix, however, HGF significantly enhanced the invasive growth of the cancer cells (p < 0.05). We detected the expression of c-met (HGF receptor) mRNA in all of the cancer cells, but not in human gingival fibroblasts (GF). Oral SCC cells did not secret HGF protein into the medium, but GF secreted a large amount of HGF protein (15 ng/ml). Furthermore, HGF markedly enhanced the migration of cancer cells in a Transwell invasion chamber. Then, we examined the serum levels of HGF in oral SCC patients, or HGF concentrations in oral cancer tissues. Serum levels of HGF in the patients were significantly higher than those in healthy volunteers (p < 0.05). After initial treatment, all of the tumor-free survivors showed a marked decline in the serum HGF levels. Furthermore, HGF concentrations in metastatic cancer tissues were significantly higher than those of nonmetastatic cancer tissues and normal gingiva (p < 0.01). These results suggest that HGF plays an important role in invasion and metastasis of oral SCC cells as a paracrine factor, and an elevated HGF level in the cancer tissue can be a predictive marker for metastasis formation in patients with oral SCC. © 2001 Wiley-Liss, Inc. Key words: oral SCC; HGF; c-met; metastasisOral SCCs are characterized by a high degree of local invasion and a high rate of metastases to cervical lymph nodes, but a low rate of metastases to distant organs. Moreover, oral SCC frequently show local recurrence after initial treatment, probably due to micro-invasion or micro-metastasis of the tumor cells at the primary site. We recently reported that oral SCC cells produced a large amount of matrix-degrading enzymes and that the net activity of MMP2 (active-MMP2/TIMP2) produced by cancer cells contributes to lymph-node metastasis in a nude-mouse orthotopic inoculation model. 1 We also noted that cancer cells in the peripheral blood of patients with oral SCC were frequently detected by RT-PCR for cytokeratin 20 mRNA, and that there was no clear relationship between the hematogenous cancer cells and the metastasis. 2 Furthermore, by microdissection zymography, we demonstrated that active MMP2 in cancer cell nests could be a predictive marker for metastasis formation in patients with oral SCC. 3 The precise molecular mechanisms of invasion and metastasis of oral cancer, however, especially the interaction between cancer cells and host cells, are still unknown.

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“…HGF/ SF and its receptor, c-Met, are frequently overexpressed in RCCs [12][13][14] AMG 102 is an investigational, fully human monoclonal antibody to HGF/SF that prevents HGF/SF from binding to c-Met and blocks signalling pathways that drive tumour-cell proliferation, migration, invasion and survival. The initial dose-finding study of AMG 102 in adult patients with advanced solid tumours showed good tolerability at the maximal dose of 20 mg/kg administered once every 2 weeks [21].…”

Section: Introductionmentioning

confidence: 99%

A phase II study of the efficacy and safety of AMG 102 in patients with metastatic renal cell carcinoma

et al. 2010

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Study Type – Therapy (case series)Level of Evidence 4What’s known on the subject? and What does the study add?It is now recognized that all patients with mRCC will eventually become resistant to VEGF inhibition. Although existing level 1 evidence supports the use of second‐line therapy, the oral mTOR inhibitor Everolimus, recent data also indicates that sequential VEGF inhibition is an appropriate therapeutic manoeuver in this cohort of patients. Targeting the alternative signaling pathway of Hepatocyte growth factor/c‐met can lead to anti‐tumour activity in RCC. AMG‐102 is a fully human monoclonal antibody to HGF/SF that prevents HGF/SF from binding to c‐Met and blocks signaling pathways that drive tumour‐cell proliferation, migration, invasion and survival.It emphasizes the need to continue exploring new therapeutic targets in RCC.OBJECTIVE• To evaluate the efficacy and safety of single‐agent AMG 102, an investigational, fully human monoclonal antibody to hepatocyte growth factor/scatter factor (HGF/SF), in renal cell carcinoma (RCC).PATIENTS AND METHODS• This open‐label phase II study included patients ≥18 years old with histologically confirmed, advanced or metastatic RCC (mRCC) and Eastern Cooperative Oncology Group performance status 0 to 2. AMG 102 was administered i.v. at 10 or 20 mg/kg once every 2 weeks.• A two‐stage design was used at each dose level and the primary endpoint was objective best confirmed response (by Response Evaluation Criteria in Solid Tumours) at any time.RESULTS• Sixty‐one patients with mRCC enrolled and received AMG 102 (40 at 10 mg/kg; 21 at 20 mg/kg). Overall, 70.5% were men, median age was 59 years (range, 39 to 84 years), and 92% had received previous anti‐vascular endothelial growth factor therapy. RCC histologies were: clear cell (75.4%), papillary (11.5%), chromophobe (4.9%) and unclassified (8.2%).• One confirmed partial response occurred at 10 mg/kg, maintained for over 2.5 years; 26 patients (43%) had stable disease, 10 (16%) for ≥32 weeks. The median profression‐free survival was 3.7 months at 10 mg/kg and 2.0 months at 20 mg/kg. The commonest adverse events were oedema (45.9%), fatigue (37.7%) and nausea (27.9%). Grade 3 or 4 adverse events occurred in 33% of patients, the most common being oedema (9.8%).• Baseline levels of plasma HGF/SF and soluble c‐Met as well as archival‐tumour c‐Met did not correlate with measures of efficacy.CONCLUSION• Single‐agent AMG 102 was tolerable, but it is unclear if AMG 102 was growth inhibitory in this population of patients with mRCC.

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Biological Role of HGF/Met Pathway in Renal Cell Carcinoma

Abstract: HGF enhanced the invasive properties of cultured RCC cells and inhibited Fas-induced apoptosis in vitro. Both HGF and MET mRNA were expressed in RCC tissues tested. Our results indicate that HGF/MET pathway may have a significant role in the progression of RCC.

Cited by 14 publications

References 30 publications

Nuclear E-cadherin and VHL immunoreactivity are prognostic indicators of clear-cell renal cell carcinoma

Nuclear E-cadherin and VHL immunoreactivity are prognostic indicators of clear-cell renal cell carcinoma

Role of HGF/c-met system in invasion and metastasis of oral squamous cell carcinoma cellsin vitro and its clinical significance

A phase II study of the efficacy and safety of AMG 102 in patients with metastatic renal cell carcinoma

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