Biological Role of HGF/Met Pathway in Renal Cell Carcinoma

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

doi:10.1016/s0022-5347(01)61834-2

Cited by 35 publications

(12 citation statements)

References 32 publications

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“…High HGF levels and intracellular MET pathway activation were also correlated with poor prognosis in patients with RCC (30). We directly assessed the effect of MET and AXL ligands on downstream signaling pathways.…”

Section: Resultsmentioning

confidence: 99%

Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma

et al. 2015

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Antiangiogenic therapy resistance occurs frequently in patients with metastatic renal cell carcinoma (RCC). The purpose of this study was to understand the mechanism of resistance to sunitinib, an antiangiogenic small molecule, and to exploit this mechanism therapeutically. We hypothesized that sunitinib-induced upregulation of the prometastatic MET and AXL receptors is associated with resistance to sunitinib and with more aggressive tumor behavior. In the present study, tissue microarrays containing sunitinib treated and untreated RCC tissues were stained with MET and AXL antibodies. The low malignant RCC cell line, 786-O, was chronically treated with sunitinib, and assayed for AXL, MET, epithelial mesenchymal transition (EMT) protein expression and activation. Co-culture experiments were used to examine the effect of sunitinib pretreatment on endothelial cell growth. The effects of AXL and MET were evaluated in various cell-based models by shRNA or inhibition by cabozantinib, the multi-tyrosine kinases inhibitor that targets VEGFR, MET and AXL. Xenograft mouse models tested the ability of cabozantinib to rescue sunitinib resistance. We demonstrated that increased AXL and MET expression was associated with inferior clinical outcome in patients. Chronic sunitinib treatment of RCC cell lines activated both AXL and MET, induced EMT associated gene expression changes including upregulation of Snail and β-catenin, and increased cell migration and invasion. Pretreatment with sunitinib enhanced angiogenesis in 786-0/HUVEC co-culture models. The suppression of AXL or MET expression, and the inhibition of AXL and MET activation using cabozantinib both impaired chronic sunitinib treatment-induced prometastatic behavior in cell culture, and rescued acquired resistance to sunitinib in xenograft models. In summary, chronic sunitinib treatment induces the activation of AXL and MET signaling and promotes pro-metastatic behavior and angiogenesis. The inhibition of AXL and MET activity may overcome resistance induced by prolonged sunitinib therapy in metastatic RCC.

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Section: Resultsmentioning

confidence: 99%

Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma

et al. 2015

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“…In PC12 cells, nerve growth factor (NGF) was found to increase shedding of the NILE glycoprotein (39), which was later identified as the rat homologue of L1 (31). We found that in renal carcinoma cells, basal shedding of L1 is stimulated by HGF, a growth factor important for proper kidney development (17), which is strongly expressed in 90% of renal cell carcinomas (10,11,12) and increases invasiveness in renal carcinoma cells in vitro and in vivo (13,14). HGF stimulated basal shedding of L1 at physiological concentrations with a maximum reached at 5 ng/ml HGF.…”

Section: Discussionmentioning

confidence: 95%

Hepatocyte Growth Factor-induced Ectodomain Shedding of Cell Adhesion Molecule L1

Heiz

Grünberg

Schubiger

et al. 2004

Journal of Biological Chemistry

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The L1 cell adhesion molecule and its soluble form are tumor-associated proteins and potential markers for tumor staging as well as targets for therapeutic intervention. Soluble L1 is produced by metalloprotease-mediated ectodomain shedding of L1. We investigated effects of hepatocyte growth factor (HGF), a growth factor shown to increase invasiveness of renal carcinoma cells, on ectodomain shedding of L1 from these cells. All of the tested L1-positive renal carcinoma cell lines released a 180-kDa form of L1 into the medium. In the presence of serum, addition of HGF led to a dose-dependent increase in L1 shedding with a maximum reached at 5 ng/ml. In contrast, L1 shedding was inhibited by glial cell linederived neurotrophic factor (GDNF). The tyrosine kinase inhibitor Genistein reduced basal and HGFstimulated L1 shedding, indicating that protein phosphorylation is involved. To investigate the role of the L1 intracellular domain, two mutants of the L1 cytoplasmic part were constructed. L1trun lacking the complete intracellular domain showed enhanced basal shedding. In a L1YH mutant, containing the mutation tyrosine 1229 to histidine that deletes the ankyrin binding motif of L1, basal shedding was reduced. Disruption of actin assembly by cytochalasin D also reduced shedding of L1. These results indicate that the cytoplasmic domain regulates basal shedding of L1, and association with the cytoskeleton through the L1 ankyrin binding site is involved. HGF stimulated L1 shedding in both mutants, indicating that receptor-mediated phosphorylation in the L1 cytoplasmic domain is not required for HGF-stimulated shedding.The L1 cell adhesion molecule (L1) 1 was originally described as a protein of the nervous system, and mutated forms of L1 are linked to severe neurological pathologies referred to as MASA syndrome (1). A non-neuronal isoform of L1 lacking exons 2 and 27 is expressed at low levels in the normal adult human kidney (2) as well as during renal development (3). In contrast, high expression of L1 was found in 8 of 12 renal tumor cell lines and in some renal tumors (2). 2 It was shown that the cell-bound form of L1 can serve as a target for radioimmunodiagnosis of metastatic neuroblastoma (4), and L1 may also be a marker and therapeutic target for certain renal cancers.In cultured cell lines originating from a number of different tumors the L1 ectodomain was found to be cleaved proximal to the cell membrane by metalloproteases, followed by release of soluble L1 into the medium (5-7). Ectodomain shedding of L1 could be stimulated by phorbol esters and vanadate, indicating that phosphorylation events regulate L1 release (6). In cell culture soluble L1 substrate was found to stimulate cellular motility and migration (8). Release of soluble L1 is not restricted to cells in culture as soluble L1 was recently detected in serum samples of patients with ovarian and uterine tumors and is believed to lead to increased cell migration and metastatic spread in these malignancies (9).Here we investigated whether hepatocyte grow...

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“…These results are comparable to those of a few studies demonstrating strong expression of MET in more than 80% of RCC with higher grades (18,19). HGF/SF-MET pathway was reported to enhance the invasive properties in the chemoinvasion assay and inhibit Fas-induced apoptosis in vitro (7). In present study, MET expression was more frequently found in the tumors of advanced stage (stage 3 or 4) than in localized stage (stage 1 or 2), and all three clear cell RCC with distant metastasis expressed MET, although it was not statistically significant.…”

Section: Discussionmentioning

confidence: 99%

“…The ligand of MET is a hepatocyte growth factor/scatter factor (HGF/SF), which has diverse biologic functions including mitogenic (2), motogenic (3) and morphogenetic (4) activities on a variety of epithelial cells, including renal tubular cells (5,6). HGF/SF has been also reported to promote the invasive properties of cultured renal cell carcinoma (RCC) cells in vitro (7), suggesting a possible role of MET in the progression of RCC. The evidences implicating the mutation of met in the development of hereditary papillary renal carcinoma have been obtained (8-10).…”

Section: Introductionmentioning

confidence: 99%

MET Expression in Sporadic Renal Cell Carcinomas

Choi¹,

Kim

Seo

et al. 2006

J Korean Med Sci

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Although germline mutations of met proto-oncogene on human chromosome 7q31-34 have been known as useful molecular markers of hereditary papillary renal cell carcinoma (RCC), the expression of MET, a product of met proto-oncogene, has not been fully studied in sporadic RCC, along with its clinical significance. We investigated the expression of MET by immunohistochemistry in 182 cases of renal neoplasm encompassing 145 RCC, 25 urothelial carcinomas of renal pelvis, and 12 oncocytomas. MET was diffusely and strongly expressed in 90% of papillary RCC, all collecting duct carcinomas, and 92% of urothelial carcinomas of renal pelvis. On the contrary, clear cell RCC, chromophobe RCC, and oncocytomas were negative or focally positive for MET expression. In clear cell RCC, MET expression was positively correlated with high nuclear grade, presence of infiltrative growth, tumoral necrosis, papillary architecture, sarcomatoid component, tumoral involvement of the renal pelvis or ureter, involvement of the calyx, and lymphatic invasion. In conclusion, diffuse and strong expression of MET in papillary RCC and collecting duct carcinoma might be helpful in discriminating from the other subtypes of RCC with tubular or papillary growth. In case of MET expression observed in clear cell RCC, it might correlate with those clinicopathological parameters implying aggressive behavior.

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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 35 publications

References 32 publications

Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma

Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma

Hepatocyte Growth Factor-induced Ectodomain Shedding of Cell Adhesion Molecule L1

MET Expression in Sporadic Renal Cell Carcinomas

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