L1 Cell Adhesion Molecule Is a Novel Therapeutic Target in Intrahepatic Cholangiocarcinoma

Kim, Jung Min; Kim, Jin Man; Li, Shengjin; Lee, Jung Whoi; Yoon, Hyunho; Ryu, Chun Jeih; Jeon, Soung Hoo; Lee, Jae-Hyek; Kim, Jin Young; Yoon, Hee Kwan; Lee, Youngkwan; Kim, Bong-Hui; Son, Yeon Sung; Choi, Hong Seo; Lim, Nam-Kyu; Kim, Dae-Ghon; Hong, Hyo Jeong

doi:10.1158/1078-0432.ccr-09-3075

Cited by 40 publications

(59 citation statements)

References 45 publications

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“…In addition, biweekly intraperitoneal injection of a monoclonal L1CAM antibody (chCE7) in ovarian carcinoma-bearing mice led to significant reduction of tumor burden (45). Similar effects were recently reported using anti-L1CAM treatment in intrahepatic cholangiocarcinoma-bearing mice (46).…”

Section: Discussionsupporting

confidence: 70%

L1 Cell Adhesion Molecule Promotes Tumorigenicity and Metastatic Potential in Non–Small Cell Lung Cancer

Hai

Zhu

Bandarchi

et al. 2012

Clinical Cancer Research

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Purpose: Non-small cell lung cancer (NSCLC) is a highly metastatic cancer with limited treatment options, thus requiring development of novel targeted therapies. Our group previously identified L1 cell adhesion molecule (L1CAM) expression as a member of a prognostic multigene expression signature for NSCLC patients. However, there is little information on the biologic function of L1CAM in lung cancer cells. This study investigates the functional and prognostic role of L1CAM in NSCLC.Experimental Design: Cox proportional hazards regression analysis was done on four independent published mRNA expression datasets of primary NSCLCs. L1CAM expression was suppressed by shorthairpin RNA (shRNA)-mediated silencing in human NSCLC cell lines. Effects were assessed by examining in vitro migration and invasion, in vivo tumorigenicity in mice, and metastatic potential using an orthotopic xenograft rat model of lung cancer.Results: L1CAM is an independent prognostic marker in resected NSCLC patients, with overexpression strongly associated with worse prognosis. L1CAM downregulation significantly decreased cell motility and invasiveness in lung cancer cells and reduced tumor formation and growth in mice. Cells with L1CAM downregulation were deficient in constitutive extracellular signal-regulated kinase (Erk) activation. Orthotopic studies showed that L1CAM suppression in highly metastatic lung cancer cells significantly decreases spread to distant organs, including bone and kidney.Conclusion: L1CAM is a novel prometastatic gene in NSCLC, and its downregulation may effectively suppress NSCLC tumor growth and metastasis. Targeted inhibition of L1CAM may be a novel therapy for NSCLC.

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Section: Discussionsupporting

confidence: 70%

L1 Cell Adhesion Molecule Promotes Tumorigenicity and Metastatic Potential in Non–Small Cell Lung Cancer

Hai

Zhu

Bandarchi

et al. 2012

Clinical Cancer Research

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“…Min et al demonstrated in a nude mouse model with subcutaneously inoculated cholangiocarcinoma Choi-CK cells that treatment with an anti-L1CAM antibody three times per week resulted in reduced tumor outgrowth compared to therapy with a control antibody. Similar results were obtained with the cholangiocarcinoma cell line SCK in which L1CAM expression was suppressed by short hairpin RNA (shRNA) (Min et al 2010). Targeting of L1CAM using lentiviral-mediated shRNA interference in glioma tumor stem cells before injection into nude mice reduced tumor formation and prolonged survival of tumor bearing mice as well (Bao et al, 2008).…”

Section: L1cam As Target Structure In Cancer Treatment -Preclinical Rsupporting

confidence: 73%

“…Again elevated L1CAM expression conferred an apoptosis resistant phenotype even in non-tumorigenic pancreatic epithelial cells. Recent data by Min et al similarly showed that L1CAM diminished the apoptotic response of cholangiocarcinoma cells towards drug treatment with gemcitabine (Min et al, 2010). In glioblastoma stem cells, a role for L1CAM in the control of DNA damage checkpoint responses and resistance to radiotherapy has been described .…”

Section: L1cam and Apoptosis Resistancementioning

confidence: 97%

“…Accordingly, inhibition of L1CAM expression or function suppresses proliferation of tumor cells, e.g. in cholangiocarcinoma (Min et al 2010) Zecchini et al, 2008). Cotreatment of SKOV3ip ovarian carcinoma cells with anti-L1CAM antibodies and the soy-derived isoflavone Genistein potentiated the antiproliferative effects of the anti-L1CAM antibody along with reduced activation of Erk1/2, Akt and Src kinase (Novak-Hofer et al, 2008).…”

Section: L1cam and Cell Growthmentioning

confidence: 99%

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The Adhesion Molecule L1CAM as a Novel Therapeutic Target for Treatment of Pancreatic Cancer Patients?

Sebens¹,

Schäfer²

2012

Pancreatic Cancer - Molecular Mechanism and Targets

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“…In particular, numerous studies have shown that forced expression of L1 in normal and cancer cell lines increases cell motility and invasiveness in vitro and in animal models in vivo. Interestingly, L1 was also shown to be aberrantly expressed in malignant tumors of the biliary tract (13,31), implying that L1 is closely associated with develop- ment and progression of biliary tract tumors. However, the exact role of L1 in GBC cells has not been previously elucidated.…”

Section: Discussionmentioning

confidence: 99%

The cell adhesion molecule L1 promotes gallbladder carcinoma progression in vitro and in vivo

et al. 2011

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Abstract. Recent studies have demonstrated that the cell adhesion molecule, L1, is expressed in several malignant tumor types and its expression correlates with tumor progression and metastasis. However, the role of L1 in gallbladder carcinoma (GBC) remains unclear. Here, we demonstrate that L1 is expressed in GBC cells and plays an important role in the growth, motility, invasiveness, and adhesiveness of GBC cells. Specific depletion or overexpression of L1 in the GBC cell lines JCRB1033 and SNU-308, respectively, was achieved by lentivirus-mediated transduction and expression of an L1 mRNA-specific short hairpin RNA or full-length human L1. Stable depletion of L1 led to a significant decrease in GBC cell proliferation, migration and invasion, as well as decreased intracellular signaling through AKT and FAK. Overexpression of L1 in GBC cells enhanced these cellular activities. In a GBC xenograft nude mouse model, suppression of L1 markedly reduced tumor growth and increased the survival of tumorbearing mice whereas L1 overexpression stimulated tumorigenicity. Taken together, these results suggest that L1 plays a crucial role in GBC progression and may be a novel therapeutic target in GBC treatment. IntroductionGallbladder carcinoma (GBC) is the most common malignancy of the biliary tract. Although occurrence is rare compared to other gastrointestinal tract neoplasms such as gastric and colorectal cancers, GBC has a distinctly higher incidence in certain demographic groups and geographic areas (1,2). The prevalence of GBC in China, Thailand and Northern India is much higher than in the United States and Europe (3). Surgical resection is currently the most effective and potentially curative treatment for GBC. However, many patients present late in the course of the disease when surgical intervention is no longer effective; most patients with advanced GBC experience frequent recurrence after surgery. Therefore, the overall survival rate remains quite poor (4). Although the most important risk factor for the development of GBC is cholelithiasis (up to 95% of GBCs are associated with gallstones) (5), the molecular mechanisms involved in early carcinogenesis and the factors affecting disease progression remain unclear. Therefore, the identification of factors crucial for GBC progression is necessary for development of new therapeutic strategies.L1 is a transmembrane glycoprotein of 200-220 kDa that belongs to the immunoglobulin superfamily of cell adhesion molecules. It consists of six immunoglobulin-like domains and five fibronectin type III repeats in the extracellular region, a single-pass transmembrane domain and a cytoplasmic tail (6). L1 was originally described as a neural cell adhesion molecule and has been shown to initiate a variety of dynamic motile processes, including cerebellar cell migration and neurite extension in the central nervous system (7,8). L1 is also expressed in other cell types such as endothelial cells, certain epithelial cells, reticular fibroblasts, and cells of lymphoid and myelomonocyt...

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L1 Cell Adhesion Molecule Is a Novel Therapeutic Target in Intrahepatic Cholangiocarcinoma

Cited by 40 publications

References 45 publications

L1 Cell Adhesion Molecule Promotes Tumorigenicity and Metastatic Potential in Non–Small Cell Lung Cancer

L1 Cell Adhesion Molecule Promotes Tumorigenicity and Metastatic Potential in Non–Small Cell Lung Cancer

The Adhesion Molecule L1CAM as a Novel Therapeutic Target for Treatment of Pancreatic Cancer Patients?

The cell adhesion molecule L1 promotes gallbladder carcinoma progression in vitro and in vivo

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