Downregulation of discoidin domain receptor 2 decreases tumor growth of hepatocellular carcinoma

Park, Joong-Won; Lee, Yeon-Su; Kim, Jin Sook; Lee, Sook-Kyung; Kim, Bo Hyun; Lee, Jung Ahn; Lee, Nam Oak; Kim, Seong Hoon; Hong, Eun Kyung

doi:10.1007/s00432-015-1967-5

Cited by 19 publications

(19 citation statements)

References 24 publications

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“…Taking into account the IHC data, where no further increase between primary tumors and lymph node metastases was evident, one could suggest that DDR2 mainly supports the metastatic spread of the primary tumor but plays only a minor role after formation of metastases. The importance of DDR2 for metastatic spread has already been proven in several tumor entities such as melanoma, liver‐ and breast cancer . A crucial step in the formation of metastases is adhesion when evading lymphatic‐ and blood vessels.…”

Section: Discussionmentioning

confidence: 99%

“…The importance of DDR2 for metastatic spread has already been proven in several tumor entities such as melanoma, liver-and breast cancer. 18,21,44 A crucial step in the formation of metastases is adhesion when evading lymphatic-and blood vessels. Our data demonstrates that DDR2 increases adhesion on cell-culture coated plates but not on collagen I coated plates for both analyzed cell lines.…”

Section: Discussionmentioning

confidence: 99%

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Targeting DDR2 in head and neck squamous cell carcinoma with dasatinib

Mäßenhausen¹,

Sanders²,

Brägelmann³

et al. 2016

Intl Journal of Cancer

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Squamous cell carcinoma of the head and neck (HNSCC) is the tenth most common tumor entity in men worldwide. Nevertheless therapeutic options are mostly limited to surgery and radio-chemotherapy resulting in 5-year survival rates of around 50%. Therefore new therapeutic options are urgently needed. During the last years, targeting of receptor tyrosine kinases has emerged as a promising strategy that can complement standard therapeutical approaches. Here, we aimed at investigating if the receptor tyrosine kinase DDR2 is a targetable structure in HNSCC. DDR2 expression was assessed on a large HNSCC cohort (554 patients) including primary tumors, lymph node metastases and recurrences and normal mucosa as control. Subsequently, DDR2 was stably overexpressed in two different cell lines (FaDu and HSC-3) using lentiviral technology. Different tumorigenic properties such as proliferation, migration, invasion, adhesion and anchorage independent growth were assessed with and without dasatinib treatment using in-vitro cell models and in-vivo zebrafish xenografts. DDR2 was overexpressed in all tumor tissues when compared to normal mucosa. DDR2 overexpression led to increased migration, invasion, adhesion and anchorage independent growth whereas proliferation remained unaltered. Upon dasatinib treatment migration, invasion and adhesion could be inhibited in-vitro and in-vivo whereas proliferation was unchanged. Our data suggest treatment with dasatinib as a promising new therapeutic option for patients suffering from DDR2 overexpressing HNSCC. Since dasatinib is already FDA-approved we propose to test this drug in clinical trials so that patients could directly benefit from this new treatment option.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Targeting DDR2 in head and neck squamous cell carcinoma with dasatinib

Mäßenhausen¹,

Sanders²,

Brägelmann³

et al. 2016

Intl Journal of Cancer

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“…Hammerman and colleagues showed that a subset of DDR2 mutations, including L63V, I638F, and S768R, mediated an oncogenic effect (25). A recent study demonstrated that the inhibition of DDR2 suppressed the in vivo and in vitro growth of human hepatocellular carcinoma cell lines (26). In contrast, the activation of DDR2 by collagen has been shown to inhibit the proliferation of human melanoma and fibrosarcoma cell lines (27,28).…”

Section: Discussionmentioning

confidence: 99%

Functional Analyses of Mutations in Receptor Tyrosine Kinase Genes in Non–Small Cell Lung Cancer: Double-Edged Sword of DDR2

Terashima

Togashi

Sato

et al. 2016

Clinical Cancer Research

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Purpose: This study investigated whether mutations of receptor tyrosine kinase (RTK) genes detected using next-generation sequencing (NGS) are suitable therapeutic targets.Experimental design: Fifty surgically resected non-small cell lung cancer (NSCLC) samples were target resequenced using NGS. We then investigated the functions of the identified RTK gene mutations, including their oncogenic potential, in vitro.Results: Mutations in RTK genes were found in 20 samples (EGFR, 15; ERBB4, 1; ALK, 1; DDR2, 2; FGFR1, 1), mutations in MAPK pathway genes were found in nine samples (KRAS, 7; NRAS, 1; BRAF, 2), and mutations in PI3K pathway genes were found in three samples (PIK3CA, 1; PTEN, 3). Among the mutations in RTKs, the functions of four mutations were unclear (ERBB4 D245G; DDR2 H246R and E655K; FGFR1 A263V). These mutations did not exhibit any transformational activities. Neither the phosphorylation nor the protein expressions of RTKs were changed by the DDR2 H246R, ERBB4 D245G, and FGFR1 A263V mutations, although the expression level of the DDR2 protein harboring the E655K mutation was particularly low. Collagen stimulation decreased cellular proliferation through p38 activation in the DDR2 wild-type-overexpressed cell lines, whereas the growthsuppressive effect was weakened in DDR2 E655K-overexpressed cell lines. Furthermore, the DDR2 E655K protein strongly bound to ubiquitin ligase E3 (Cbl-b), and the mutant protein expression was increased after treatment with a proteasome inhibitor.Conclusions: Our experimental findings suggest that RTK mutations are not always suitable as therapeutic targets. The DDR2 E655K mutation can play a role in cancer progression by reducing the growth-inhibitory effect of collagen.

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“…High DDR2 expression is correlated with poor prognosis (122). DDR2 overexpression facilitates migration, invasion, and the EMT of HCC by activating ERK2 and stabilizing Snail1, whereas DDR2 silencing in HCC decreases the EMT, Snail1 half-life, and invasion but increases cell death (122, 123). …”

Section: Hepatocellular Carcinomamentioning

confidence: 99%

The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer

Affò

Schwabe

2017

Annu. Rev. Pathol. Mech. Dis.

478

425

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Liver cancer is the second leading cause of cancer mortality worldwide, causing more than 700,000 deaths annually. Because of the wide landscape of genomic alterations and limited therapeutic success of targeting tumor cells, a recent focus has been on better understanding and possibly targeting the microenvironment in which liver tumors develop. A unique feature of liver cancer is its close association with liver fibrosis. More than 80% of hepatocellular carcinomas (HCCs) develop in fibrotic or cirrhotic livers, suggesting an important role of liver fibrosis in the premalignant environment (PME) of the liver. Cholangiocarcinoma (CCA), in contrast, is characterized by a strong desmoplasia that typically occurs in response to the tumor, suggesting a key role of cancer-associated fibroblasts (CAFs) and fibrosis in its tumor microenvironment (TME). Here, we discuss the functional contributions of myofibroblasts, CAFs, and fibrosis to the development of HCC and CCA in the hepatic PME and TME, focusing on myofibroblast- and extracellular matrix—associated growth factors, fibrosis-associated immunosuppressive pathways, as well as mechanosensitive signaling cascades that are activated by increased tissue stiffness. Better understanding of the role of myofibroblasts in HCC and CCA development and progression may provide the basis to target these cells for tumor prevention or therapy.

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Downregulation of discoidin domain receptor 2 decreases tumor growth of hepatocellular carcinoma

Abstract: The inhibition of DDR2 by RNA interference suppressed in vivo and in vitro growth of human HCC cells. Our results may support that the use of DDR2 as a novel target of HCC treatment through control of tumor apoptosis, migration, and invasion.

Cited by 19 publications

References 24 publications

Targeting DDR2 in head and neck squamous cell carcinoma with dasatinib

Targeting DDR2 in head and neck squamous cell carcinoma with dasatinib

Functional Analyses of Mutations in Receptor Tyrosine Kinase Genes in Non–Small Cell Lung Cancer: Double-Edged Sword of DDR2

The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer

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