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Pokhrel A, Wu R, Wang JC. Review of Merkel cell carcinoma with solitary pancreatic metastases mimicking primary neuroendocrine tumor of the pancreas. Clin J Gastroenterol 2023; 16:641-662. [PMID: 37421584 DOI: 10.1007/s12328-023-01821-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 06/05/2023] [Indexed: 07/10/2023]
Abstract
OBJECTIVE/BACKGROUND Merkel cell carcinoma (MCC) but metastases to the pancreas are very rare. There are only a few cases of isolated metastases of MCC to the pancreas. Because of this rarity, it can be wrongly diagnosed as a neuroendocrine tumor of the pancreas(pNET), especially the poorly differentiated neuroendocrine carcinoma (PNEC) subtype, in which the treatment is vastly different than that of MCC with isolated metastases of the pancreas. METHODS An electronic search of the PubMed and google scholar databases was performed to obtain the literature on MCC with pancreatic metastases, using the following search terms: Merkel cell carcinoma, pancreas, and metastases. Results are limited to the following available article types: case reports and case series. We identified 45 cases of MCC with pancreatic metastases from the PubMed and Google Scholar database search and examined their potential relevance. Only 22 cases with isolated pancreatic metastases were taken for review including one case that we encountered. RESULTS The results from our review of cases of isolated pancreatic metastases of MCC were compared to the characteristics of the poorly differentiated pancreatic neuroendocrine tumor (PNEC). We found the following: (a) MCC with isolated pancreatic metastases occurred at an older age than PNEC and with male gender predominance (b) Most of the metastases occurred within 2 years of initial diagnosis of MCC (c) Resection of pancreatic mass was the first line treatment in case of resectable PNECs whereas resection of metastases was infrequently performed in MCC with pancreatic metastases.
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Affiliation(s)
- Akriti Pokhrel
- Department of Internal Medicine, Brookdale University Hospital Medical Center, Brooklyn, NY, USA
- Department of Hematology and Oncology, Brookdale University Hospital Medical Center, Brooklyn, NY, USA
| | - Richard Wu
- Department of Pathology, Division of Hematology/Oncology, Brookdale University Hospital Medical Center, Brooklyn, NY, USA
- Department of Hematology and Oncology, Brookdale University Hospital Medical Center, Brooklyn, NY, USA
| | - Jen Chin Wang
- Department of Pathology, Division of Hematology/Oncology, Brookdale University Hospital Medical Center, Brooklyn, NY, USA.
- Department of Hematology and Oncology, Brookdale University Hospital Medical Center, Brooklyn, NY, USA.
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Zhang MY, He D, Zhang S. Pancreatic neuroendocrine tumors G3 and pancreatic neuroendocrine carcinomas: Differences in basic biology and treatment. World J Gastrointest Oncol 2020; 12:705-718. [PMID: 32864039 PMCID: PMC7428799 DOI: 10.4251/wjgo.v12.i7.705] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 05/17/2020] [Accepted: 06/17/2020] [Indexed: 02/05/2023] Open
Abstract
In 2017 the World Health Organization revised the criteria for classification of pancreatic neuroendocrine neoplasms (pNENs) after a consensus conference at the International Agency for Research on Cancer. The major change in the new classification was to subclassify the original G3 group into well-differentiated pancreatic neuroendocrine tumors G3 (pNETs G3) and poorly differentiated pancreatic neuroendocrine carcinomas (pNECs), which have been gradually proven to be completely different in biological behavior and clinical manifestations in recent years. In 2019 this major change subsequently extended to NENs involving the entire digestive tract. The updated version of the pNENs grading system marks a growing awareness of these heterogeneous tumors. This review discusses the clinicopathological, genetic and therapeutic features of poorly differentiated pNECs and compare them to those of well-differentiated pNETs G3. For pNETs G3 and pNECs (due to their lower incidence), there are still many problems to be investigated. Previous studies under the new grading classification also need to be reinterpreted. This review summarizes the relevant literature from the perspective of the differences between pNETs G3 and pNECs in order to deepen understanding of these diseases and discuss future research directions.
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Affiliation(s)
- Ming-Yi Zhang
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Du He
- Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Shuang Zhang
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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3
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Cave DD, Di Guida M, Costa V, Sevillano M, Ferrante L, Heeschen C, Corona M, Cucciardi A, Lonardo E. TGF-β1 secreted by pancreatic stellate cells promotes stemness and tumourigenicity in pancreatic cancer cells through L1CAM downregulation. Oncogene 2020; 39:4271-4285. [PMID: 32291413 PMCID: PMC7239770 DOI: 10.1038/s41388-020-1289-1] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 03/23/2020] [Accepted: 03/27/2020] [Indexed: 02/08/2023]
Abstract
Pancreatic stellate cells (PSCs) secrete high levels of transforming growth factor-β1 (TGF-β1) that contributes to the development of pancreatic ductal adenocarcinoma (PDAC). TGF-β1 modulates the expression of L1 cell adhesion molecule (L1CAM), but its role in tumour progression still remains controversial. To clarify L1 function in PDAC and cellular phenotypes, we performed L1CAM cell sorting, silencing and overexpression in several primary pancreatic cancer cells. PSCs silenced for TGF-β1 were used for crosstalk experiments. We found that TGF-β1 secreted by PSCs negatively regulates L1CAM expression, through canonical TGF-β-Smad2/3 signalling, leading to a more aggressive PDAC phenotype. Cells with reduced expression of L1CAM harboured enhanced stemness potential and tumourigenicity. Inactivation of TGF-β1 signalling in PSCs strongly reduced the aggressiveness of PDAC cells. Our data provide functional proof and mechanistic insights for the tumour-suppressive function of L1CAM via reducing stemness. Rescuing L1CAM expression in cancer cells through targeting of TGF-β1 reverses stemness and bears the potential to improve the still miserable prognosis of PDAC patients.
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Affiliation(s)
- Donatella Delle Cave
- Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso' (IGB), CNR, Via Pietro Castellino 111, 80131, Naples, Italy
| | - Martina Di Guida
- Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso' (IGB), CNR, Via Pietro Castellino 111, 80131, Naples, Italy
| | - Valerio Costa
- Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso' (IGB), CNR, Via Pietro Castellino 111, 80131, Naples, Italy
| | - Marta Sevillano
- Institute for Research in Biomedicine (IRB), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Luigi Ferrante
- Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso' (IGB), CNR, Via Pietro Castellino 111, 80131, Naples, Italy
| | | | - Marco Corona
- Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso' (IGB), CNR, Via Pietro Castellino 111, 80131, Naples, Italy
| | - Antonio Cucciardi
- Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso' (IGB), CNR, Via Pietro Castellino 111, 80131, Naples, Italy
| | - Enza Lonardo
- Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso' (IGB), CNR, Via Pietro Castellino 111, 80131, Naples, Italy. .,Spanish National Cancer Research Centre, CNIO, Madrid, Spain.
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4
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L1CAM induces perineural invasion of pancreas cancer cells by upregulation of metalloproteinase expression. Oncogene 2018; 38:596-608. [PMID: 30171263 DOI: 10.1038/s41388-018-0458-y] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2018] [Revised: 07/11/2018] [Accepted: 07/14/2018] [Indexed: 11/08/2022]
Abstract
Pancreas cancer cells have a tendency to invade along nerves. Such cancerous nerve invasion (CNI) is associated with poor outcome; however, the exact mechanism that drives cancer cells to disseminate along nerves is unknown. Immunohistochemical analysis of human pancreatic ductal adenocarcinoma (PDAC) specimens showed overexpression of the L1 cell adhesion molecule (L1CAM) in cancer cells and in adjacent Schwann cells (SC) in invaded nerves. By modeling the neural microenvironment, we found that L1CAM secreted from SCs acts as a strong chemoattractant to cancer cells, through activation of MAP kinase signaling. L1CAM also upregulated expression of metalloproteinase-2 (MMP-2) and MMP-9 by PDAC cells, through STAT3 activation. Using a transgenic Pdx-1-Cre/KrasG12D /p53R172H (KPC) mouse model, we show that treatment with anti-L1CAM Ab significantly reduces CNI in vivo. We provide evidence of a paracrine response between SCs and cancer cells in the neural niche, which promotes cancer invasion via L1CAM secretion.
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5
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Jo DH, Lee K, Kim JH, Jun HO, Kim Y, Cho YL, Yu YS, Min JK, Kim JH. L1 increases adhesion-mediated proliferation and chemoresistance of retinoblastoma. Oncotarget 2017; 8:15441-15452. [PMID: 28061460 PMCID: PMC5362498 DOI: 10.18632/oncotarget.14487] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 12/13/2016] [Indexed: 01/07/2023] Open
Abstract
Retinoblastoma is the most common intraocular cancer in children, affecting 1/20,000 live births. Currently, children with retinoblastoma were treated with chemotherapy using drugs such as carboplatin, vincristine, and etoposide. Unfortunately, if conventional treatment fails, the affected eyes should be removed to prevent extension into adjacent tissues and metastasis. This study is to investigate the roles of L1 in adhesion-mediated proliferation and chemoresistance of retinoblastoma. L1 was differentially expressed in 30 retinoblastoma tissues and 2 retinoblastoma cell lines. Furthermore, the proportions of L1-positive cells in retinoblastoma tumors were negatively linked with the number of Flexner-Wintersteiner rosettes, a characteristic of differentiated retinoblastoma tumors, in each tumor sample. Following in vitro experiments using L1-deleted and -overexpressing cells showed that L1 increased adhesion-mediated proliferation of retinoblastoma cells via regulation of cell cycle-associated proteins with modulation of Akt, extracellular signal-regulated kinase, and p38 pathways. In addition, L1 increased resistance against carboplatin, vincristine, and esoposide through up-regulation of apoptosis- and multidrug resistance-related genes. In vivo tumor formation and chemoresistance were also positively linked with the levels of L1 in an orthotopic transplantation model in mice. In this manner, L1 increases adhesion-mediated proliferation and chemoresistance of retinoblastoma. Targeted therapy to L1 might be effective in the treatment of retinoblastoma tumors, especially which rapidly proliferate and demonstrate resistance to conventional chemotherapeutic drugs.
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Affiliation(s)
- Dong Hyun Jo
- Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.,Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.,Tumor Microenvironment Research Center, Global Core Research Center, Seoul National University, Seoul, Republic of Korea
| | - Kyungmin Lee
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.,Department of Biomolecular Science, University of Science & Technology, Daejeon, Republic of Korea
| | - Jin Hyoung Kim
- Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.,Tumor Microenvironment Research Center, Global Core Research Center, Seoul National University, Seoul, Republic of Korea
| | - Hyoung Oh Jun
- Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.,Tumor Microenvironment Research Center, Global Core Research Center, Seoul National University, Seoul, Republic of Korea
| | - Younghoon Kim
- Department of Pathology, College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Young-Lai Cho
- Department of Chemistry, Dongguk University, Seoul, Republic of Korea
| | - Young Suk Yu
- Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.,Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jeong-Ki Min
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.,Department of Biomolecular Science, University of Science & Technology, Daejeon, Republic of Korea
| | - Jeong Hun Kim
- Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.,Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.,Tumor Microenvironment Research Center, Global Core Research Center, Seoul National University, Seoul, Republic of Korea.,Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Republic of Korea
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6
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Girardi DM, Silva ACB, Rêgo JFM, Coudry RA, Riechelmann RP. Unraveling molecular pathways of poorly differentiated neuroendocrine carcinomas of the gastroenteropancreatic system: A systematic review. Cancer Treat Rev 2017; 56:28-35. [PMID: 28456055 DOI: 10.1016/j.ctrv.2017.04.002] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 04/04/2017] [Accepted: 04/05/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Poorly differentiated neuroendocrine carcinomas (NECs) are rare and aggressive tumors. Their molecular pathogenesis is still largely unknown, and consequently, the best therapeutic management also remains to be determined. We conducted a systematic review on molecular alterations found in gastroenteropancreatic NECs (GEP-NECs) and discuss potential applications of targeted therapies in setting. MATERIALS AND METHODS Systematic review of studies about molecular features in tumor tissues of patients with GEP-NECs. The Medline, Lilacs, Embase, Cochrane, Scopus and Opengrey databases were sought, without time, study design or language restrictions. RESULTS Of the 1.564 studies retrieved, 41 were eligible: 33 were retrospective studies and eight were case reports. The studies spanned the years 1997-2017 and involved mostly colorectal, stomach and pancreas primary tumors. Molecular alterations in the TP53 gene and the p53 protein expression were the most commonly observed, regardless of the primary site. Other consistently found molecular alterations were microsatellite instability (MSI) in approximately 10% of gastric and colorectal NEC, and altered signaling cascades of p16/Rb/cyclin D1, Hedgehog and Notch pathways, and somatic mutations in KRAS, BRAF, RB1 and Bcl2. In studies of mixed adeno-neuroendocrine carcinomas (MANECs) the molecular features of GEP-NEC largely resemble their carcinoma/adenocarcinomas tumor counterparts. CONCLUSIONS Despite the paucity of data about the molecular drivers associated with GEP-NEC, some alterations may be potentially targeted with new cancer-directed therapies. Collaborative clinical trials for patients with advanced GEP-NEC are urgently needed.
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Affiliation(s)
- Daniel M Girardi
- Discipline of Radiology and Oncology, Instituto do Câncer do Estado de São Paulo, Universidade de São Paulo, São Paulo, Brazil.
| | - Andrea C B Silva
- Discipline of Radiology and Oncology, Instituto do Câncer do Estado de São Paulo, Universidade de São Paulo, São Paulo, Brazil.
| | - Juliana Florinda M Rêgo
- Unit of Oncology and Hematology, Hospital Universitário Onofre Lopes, Universidade Federal do Rio Grande do Norte, Rio Grande do Norte, Brazil.
| | | | - Rachel P Riechelmann
- Discipline of Radiology and Oncology, Instituto do Câncer do Estado de São Paulo, Universidade de São Paulo, São Paulo, Brazil; Oncology Center, Hospital Sírio Libanês, São Paulo, Brazil.
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7
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Pechriggl EJ, Concin N, Blumer MJ, Bitsche M, Zwierzina M, Dudas J, Koziel K, Altevogt P, Zeimet AG, Fritsch H. L1CAM in the Early Enteric and Urogenital System. J Histochem Cytochem 2016; 65:21-32. [PMID: 28026654 DOI: 10.1369/0022155416677241] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
L1 cell adhesion molecule (L1CAM) is a transmembrane molecule belonging to the L1 protein family. It has shown to be a key player in axonal guidance in the course of neuronal development. Furthermore, L1CAM is also crucial for the establishment of the enteric and urogenital organs and is aberrantly expressed in cancer originating in these organs. Carcinogenesis and embryogenesis follow a lot of similar molecular pathways, but unfortunately, comprehensive data on L1CAM expression and localization in human developing organs are lacking so far. In the present study we, therefore, examined the spatiotemporal distribution of L1CAM in the early human fetal period (weeks 8-12 of gestation) by means of immunohistochemistry and in situ hybridization (ISH). In the epithelia of the gastrointestinal organs, L1CAM localization cannot be observed in the examined stages most likely due to their advanced polarization and differentiation. Despite these results, our ISH data indicate weak L1CAM expression, but only in few epithelial cells. The genital tracts, however, are distinctly L1CAM positive throughout the entire fetal period. We, therefore, conclude that in embryogenesis L1CAM is crucial for further differentiation of epithelia.
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Affiliation(s)
- Elisabeth Judith Pechriggl
- Division of Clinical and Functional Anatomy, Department of Anatomy, Histology and Embryology (EJP, MJB, MB, MZ, HF), Medical University of Innsbruck, Innsbruck, Austria
| | - Nicole Concin
- Department of Gynaecology and Obstetrics (NC, KK, A-GZ), Medical University of Innsbruck, Innsbruck, Austria
| | - Michael J Blumer
- Division of Clinical and Functional Anatomy, Department of Anatomy, Histology and Embryology (EJP, MJB, MB, MZ, HF), Medical University of Innsbruck, Innsbruck, Austria
| | - Mario Bitsche
- Division of Clinical and Functional Anatomy, Department of Anatomy, Histology and Embryology (EJP, MJB, MB, MZ, HF), Medical University of Innsbruck, Innsbruck, Austria
| | - Marit Zwierzina
- Division of Clinical and Functional Anatomy, Department of Anatomy, Histology and Embryology (EJP, MJB, MB, MZ, HF), Medical University of Innsbruck, Innsbruck, Austria
| | - Jozsef Dudas
- Department of Otolaryngology (JD), Medical University of Innsbruck, Innsbruck, Austria
| | - Katarzyna Koziel
- Department of Gynaecology and Obstetrics (NC, KK, A-GZ), Medical University of Innsbruck, Innsbruck, Austria
| | - Peter Altevogt
- Skin Cancer Unit, German Cancer Research Center, Heidelberg, Germany (PA).,Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Heidelberg, Germany (PA)
| | - Alain-Gustave Zeimet
- Department of Gynaecology and Obstetrics (NC, KK, A-GZ), Medical University of Innsbruck, Innsbruck, Austria
| | - Helga Fritsch
- Division of Clinical and Functional Anatomy, Department of Anatomy, Histology and Embryology (EJP, MJB, MB, MZ, HF), Medical University of Innsbruck, Innsbruck, Austria
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8
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L1 Cell Adhesion Molecule-Specific Chimeric Antigen Receptor-Redirected Human T Cells Exhibit Specific and Efficient Antitumor Activity against Human Ovarian Cancer in Mice. PLoS One 2016; 11:e0146885. [PMID: 26761817 PMCID: PMC4711972 DOI: 10.1371/journal.pone.0146885] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 12/24/2015] [Indexed: 01/01/2023] Open
Abstract
New therapeutic modalities are needed for ovarian cancer, the most lethal gynecologic malignancy. Recent clinical trials have demonstrated the impressive therapeutic potential of adoptive therapy using chimeric antigen receptor (CAR)-redirected T cells to target hematological cancers, and emerging studies suggest a similar impact may be achieved for solid cancers. We sought determine whether genetically-modified T cells targeting the CE7-epitope of L1-CAM, a cell adhesion molecule aberrantly expressed in several cancers, have promise as an immunotherapy for ovarian cancer, first demonstrating that L1-CAM was highly over-expressed on a panel of ovarian cancer cell lines, primary ovarian tumor tissue specimens, and ascites-derived primary cancer cells. Human central memory derived T cells (TCM) were then genetically modified to express an anti-L1-CAM CAR (CE7R), which directed effector function upon tumor antigen stimulation as assessed by in vitro cytokine secretion and cytotoxicity assays. We also found that CE7R+ T cells were able to target primary ovarian cancer cells. Intraperitoneal (i.p.) administration of CE7R+ TCM induced a significant regression of i.p. established SK-OV-3 xenograft tumors in mice, inhibited ascites formation, and conferred a significant survival advantage compared with control-treated animals. Taken together, these studies indicate that adoptive transfer of L1-CAM-specific CE7R+ T cells may offer a novel and effective immunotherapy strategy for advanced ovarian cancer.
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9
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Altevogt P, Doberstein K, Fogel M. L1CAM in human cancer. Int J Cancer 2015; 138:1565-76. [DOI: 10.1002/ijc.29658] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Accepted: 06/19/2015] [Indexed: 12/18/2022]
Affiliation(s)
- Peter Altevogt
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany and Department of Dermatology, Venereology and Allergology; University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg; Mannheim Germany
| | - Kai Doberstein
- Ovarian Cancer Research Center, Perelman School of Medicine; University of Pennsylvania; Philadelphia, PA
| | - Mina Fogel
- Central Laboratories; Kaplan Medical Center; Rehovot Israel
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10
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Neuroendocrine Carcinomas of the Gastroenteropancreatic System: A Comprehensive Review. Diagnostics (Basel) 2015; 5:119-76. [PMID: 26854147 PMCID: PMC4665594 DOI: 10.3390/diagnostics5020119] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Revised: 03/24/2015] [Accepted: 03/26/2015] [Indexed: 02/07/2023] Open
Abstract
To date, empirical literature has generally been considered lacking in relation to neuroendocrine carcinomas (NECs), the highly malignant subgroup of neuroendocrine neoplasms. NECs are often found in the lungs or the gastroenteropancreatic (GEP) system and can be of small or large cell type. Concentrating on GEP-NECs, we can conclude that survival times are poor, with a median of only 4–16 months depending on disease stage and primary site. Further, this aggressive disease appears to be on the rise, with incidence numbers increasing while survival times are stagnant. Treatment strategies concerning surgery are often undecided and second-line chemotherapy is not yet established. After an analysis of over 2600 articles, we can conclude that there is indeed more empirical literature concerning GEP-NECs available than previously assumed. This unique review is based on 333 selected articles and contains detailed information concerning all aspects of GEP-NECs. Namely, the classification, histology, genetic abnormalities, epidemiology, origin, biochemistry, imaging, treatment and survival of GEP-NECs are described. Also, organ-specific summaries with more detail in relation to disease presentation, diagnosis, treatment and survival are presented. Finally, key points are discussed with directions for future research priorities.
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11
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Bergmann F, Aulmann S, Sipos B, Kloor M, von Heydebreck A, Schweipert J, Harjung A, Mayer P, Hartwig W, Moldenhauer G, Capper D, Dyckhoff G, Freier K, Herpel E, Schleider A, Schirmacher P, Mechtersheimer G, Klöppel G, Bläker H. Acinar cell carcinomas of the pancreas: a molecular analysis in a series of 57 cases. Virchows Arch 2014; 465:661-72. [PMID: 25298229 DOI: 10.1007/s00428-014-1657-8] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Revised: 08/15/2014] [Accepted: 09/12/2014] [Indexed: 12/14/2022]
Abstract
Pancreatic acinar cell carcinomas (PACs) are rare but are distinct aggressive neoplasms that phenotypically differ from pancreatic ductal adenocarcinomas (PDACs) and pancreatic neuroendocrine neoplasms (PNENs). Despite recent work on the genetic changes of PACs, their molecular pathogenesis is still poorly understood. In this study, we focus on a comparative genomic hybridization analysis. Based on frequent chromosomal imbalances, the involvement of DCC and c-MYC in the pathogenesis of PACs is further investigated. Moreover, we examine markers harboring potential therapeutic relevance (K-RAS, BRAF, EGFR, MGMT, HSP90, L1CAM, Her2). PACs revealed a microsatellite stable, chromosomal unstable genotype, defined by recurrent chromosomal losses of 1p, 3p, 4q, 5q, 6q, 8p, 9p, 11q, 13q, 16q, and 18, as well as gains of 1q, 7, 8q, 12, 17q, and 20q. Subsets of PAC displayed reduction/loss of DCC (79 %) and c-MYC-amplification (17 %). Significant EGFR expression occurred in 42 %, HSP90 expression in 98 %, L1CAM expression in 72 %, and loss of MGMT in 26 %. Two cases carried a K-RAS mutation. Mutations of EGFR or BRAF were not detected. All cases were Her2/neu-negative. PACs display characteristic chromosomal imbalances which are distinctly different from those in pancreatic ductal adenocarcinomas and pancreatic neuroendocrine neoplasms. Our findings suggest that DCC and c-MYC alterations may play an important role in the pathogenesis of PACs. Furthermore, EGFR, MGMT, HSP90, and L1CAM may be useful as therapeutic markers and predictors of response to therapy in a subset of PACs.
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Affiliation(s)
- Frank Bergmann
- Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 224, D-69120, Heidelberg, Germany,
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12
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Nagaraj K, Mualla R, Hortsch M. The L1 Family of Cell Adhesion Molecules: A Sickening Number of Mutations and Protein Functions. ADVANCES IN NEUROBIOLOGY 2014; 8:195-229. [DOI: 10.1007/978-1-4614-8090-7_9] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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13
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Zhao WJ, Schachner M. Neuregulin 1 enhances cell adhesion molecule l1 expression in human glioma cells and promotes their migration as a function of malignancy. J Neuropathol Exp Neurol 2013; 72:244-55. [PMID: 23399902 DOI: 10.1097/nen.0b013e3182863dc5] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Similar functions of L1, a cell adhesion molecule, and the cytokine neuregulin 1 (Nrg1) have been suggested in tumorigenesis and the promotion of metastasis. We studied the relationships of Nrg1 and L1 expression in human gliomas. Using immunofluorescence staining on a human glioma tissue microarray, we found a positive correlation between levels of L1 and Nrg1α or Nrg1β expression; expression tended to increase with increasing WHO (World Health Organization) tumor grade. L1 was also found to colocalize with either Nrg1 isoform. In cultures of U87-MG human glioblastoma and human U251 and SHG-44 glioma cells, the base levels of full-length L1 expression were increased by the 2 Nrg1 molecules in the nanomolar range, and Nrg1 siRNA downregulated full-length L1 expression in these tumor cell lines. U87-MG cells treated with either Nrg1 isoform also showed enhanced migration when compared with that treated with vehicle control. In addition, administration of either lapatinib (a dual inhibitor of both the epidermal growth factor receptor and ErbB-2) or erlotinib (an inhibitor of the epidermal growth factor receptor) in combination with either Nrg1α or Nrg1β inhibited the L1 expression elicited by these cytokines in U87-MG cells. Together, our data suggest that Nrg1 regulates L1 expression in gliomas, and that Nrg1 may contribute to malignancy by upregulating the L1 expression in glioblastoma cells, thereby enhancing their migration.
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Affiliation(s)
- Wei-Jiang Zhao
- Center for Neuroscience, Shantou University Medical College, Shantou, Guandong Province, People's Republic of China
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Blessmann M, Gröbe A, Quaas A, Kaifi JT, Mistakidis G, Bernreuther C, Sauter G, Gros S, Rawnaq T, Friedrich R, Mautner VF, Smeets R, Heiland M, Schachner M, Izbicki JR. Adhesion molecule L1 is down-regulated in malignant peripheral nerve sheath tumors versus benign neurofibromatosis type 1–associated tumors. Oral Surg Oral Med Oral Pathol Oral Radiol 2012; 113:239-44. [DOI: 10.1016/j.tripleo.2011.04.019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2011] [Revised: 04/14/2011] [Accepted: 04/15/2011] [Indexed: 01/27/2023]
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L1 cell adhesion molecule as a novel independent poor prognostic factor in gallbladder carcinoma. Hum Pathol 2011; 42:1476-83. [PMID: 21496863 DOI: 10.1016/j.humpath.2011.01.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2010] [Revised: 12/30/2010] [Accepted: 01/13/2011] [Indexed: 12/16/2022]
Abstract
Gallbladder carcinoma is a lethal malignancy and is hard to cure by current treatment. Thus, identification of molecular prognostic markers to predict gallbladder carcinoma as therapeutic targets is urgently needed. Recent studies have demonstrated that L1 cell adhesion molecule is associated with the prognosis of variable malignancy. Here, we investigated L1 cell adhesion molecule expression in gallbladder carcinoma and its prognostic significance. In this study, we examined L1 cell adhesion molecule expression in tumor specimens from 69 patients with gallbladder carcinoma by immunohistochemistry and analyzed the correlation between L1 cell adhesion molecule expression and clinicopathologic factors or survival. L1 cell adhesion molecule was not expressed in the normal epithelium of the gallbladder but in 63.8% of gallbladder carcinomas, remarkably at the invasive front of the tumors. In addition, L1 cell adhesion molecule expression was significantly associated with high histologic grade, advanced pathologic T stage and clinical stage, and positive venous/lymphatic invasion. Multivariate analyses showed that L1 cell adhesion molecule expression (hazard ratio, 3.503; P = .028) and clinical stage (hazard ratio, 3.091; P = .042) were independent risk factor for disease-free survival. L1 cell adhesion molecule expression in gallbladder carcinoma was significantly correlated with tumor progression and unfavorable clinicopathologic features. L1 cell adhesion molecule expression was an independent poor prognostic factor for disease-free survival in patients with gallbladder carcinoma. Taken together, our findings suggest that L1 cell adhesion molecule expression could be used as a novel prognostic factor for patient survival and might be a potential therapeutic target in gallbladder carcinomas.
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Tsutsumi S, Morohashi S, Kudo Y, Akasaka H, Ogasawara H, Ono M, Takasugi K, Ishido K, Hakamada K, Kijima H. L1 Cell adhesion molecule (L1CAM) expression at the cancer invasive front is a novel prognostic marker of pancreatic ductal adenocarcinoma. J Surg Oncol 2011; 103:669-73. [PMID: 21360711 DOI: 10.1002/jso.21880] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2010] [Accepted: 01/06/2011] [Indexed: 11/10/2022]
Abstract
BACKGROUND AND OBJECTIVES Pancreatic ductal adenocarcinoma (PDAC) is one of the most extremely aggressive cancers with a poor prognosis after curative resection. L1 cell adhesion molecule (L1CAM) is a 200-220 kDa type I transmembrane glycoprotein of the immunoglobulin superfamily, which has been shown to affect the prognosis of several cancers. No clinicopathological significance of L1CAM expression has been examined at the invasive front of PDAC. In this study, we examined the relationship between L1CAM expression and clinicopathological features in PDAC by immunohistochemistry. METHODS One hundred seven surgically resected specimens of PDAC were immunohistochemically examined using a monoclonal antibody against L1CAM. RESULTS Positive expression of L1CAM was found in 23 of 107 cases with PDAC. In most cases (21/23), L1CAM expression was localized at the invasive front of the tumor tissue. Positive expression of L1CAM was significantly correlated with the histological grade, lymph node involvement, and distant metastasis. In univariate analysis, a positive expression of L1CAM was associated with short overall survival (P = 0.0002), and this was significant in multivariate analysis (P = 0.009). CONCLUSIONS L1CAM could play an important role in the invasive process in vivo, and is thought to be a good indicator of prognosis in PDAC.
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Affiliation(s)
- Shinji Tsutsumi
- Department of Pathology Hirosaki University School of Medicine, Hirosaki, Aomori, Japan
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Satahoo-Dawes S, Palmer J, III EWM, Levi J. Breast and lung metastasis from pancreatic neuroendocrine carcinoma. World J Radiol 2011; 3:32-7. [PMID: 21286493 PMCID: PMC3030725 DOI: 10.4329/wjr.v3.i1.32] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2010] [Revised: 12/07/2010] [Accepted: 12/14/2010] [Indexed: 02/06/2023] Open
Abstract
Pancreatic neuroendocrine tumors (PNETs) are an uncommon malignancy, accounting for a small percentage of all pancreatic malignancies. Due to their insidious course, most PNETs present with metastatic disease. Although reports in the literature describe PNET metastasis to the liver, lung and brain, to date there are no reports of stage IV disease involving the breast. Moreover, the lack of consensus regarding classification and treatment of this entity leaves practitioners without standards of practice or a firm base from which to formulate prognosis. In this report, the case of a previously healthy 51-year-old woman with stage IV PNET is examined. After combined neoadjuvant therapy with 5-fluorouracil, carboplatin, etoposide and radiation, surgical resection revealed metastatic PNET to the breast and lung, with no microscopic evidence of residual disease within the pancreas. An extensive analysis of the presentation, diagnosis, imaging modalities, treatment options, and prognosis is included in the discussion. As demonstrated by our review, there is a need for further studies to delineate inconclusive evidence with respect to subtype classification, treatment and prognosis of PNETs.
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Bergmann F, Moldenhauer G, Herpel E, Gaida MM, Strobel O, Werner J, Esposito I, Müerköster SS, Schirmacher P, Kern MA. Expression of L1CAM, COX-2, EGFR, c-KIT and Her2/neu in anaplastic pancreatic cancer: putative therapeutic targets? Histopathology 2011; 56:440-8. [PMID: 20459551 DOI: 10.1111/j.1365-2559.2010.03499.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
AIMS Undifferentiated (anaplastic) pancreatic cancer and undifferentiated pancreatic carcinoma with osteoclast-like giant cells (giant cell tumour) are rare variants of pancreatic ductal adenocarcinoma. Representing biologically highly aggressive neoplasms, they are frequently diagnosed at an advanced stage. The response to established chemo- or radiochemotherapeutic treatment regimens is poor, and undifferentiated pancreatic cancer generally has a dismal prognosis. As additional therapeutic options have not yet been investigated in undifferentiated pancreatic cancer, the aim was to analyse the expression of putative therapeutic targets that have shown promising results in various other neoplasms. METHODS AND RESULTS Fifteen cases of undifferentiated pancreatic cancer (seven containing osteoclast-like giant cells) were investigated clinicopathologically and immunohistochemically for putative therapeutic targets. Whereas L1CAM, cyclooxygenase (COX)-2 and epidermal growth factor receptor (EGFR) were found to be significantly expressed in 80%, 93% and 87% of the investigated tumours, respectively, there was no substantial expression of c-kit (CD117) and there was no detectable expression of Her2/neu. CONCLUSIONS The expression of L1CAM, COX-2 and EGFR in the majority of undifferentiated pancreatic carcinomas suggests that they might represent targets for adjuvant therapy in anaplastic pancreatic cancer. On the other hand, c-kit and Her2/neu seem to have no relevance for the therapy of these tumours.
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Affiliation(s)
- Frank Bergmann
- Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220, D-69120 Heidelberg, Germany.
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Rawnaq T, Quaas A, Zander H, Gros SJ, Reichelt U, Blessmann M, Wilzcak W, Schachner M, Sauter G, Izbicki JR, Kaifi JT. L1 is highly expressed in tumors of the nervous system: a study of over 8000 human tissues. J Surg Res 2010; 173:314-9. [PMID: 21195422 DOI: 10.1016/j.jss.2010.10.029] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2010] [Revised: 10/17/2010] [Accepted: 10/25/2010] [Indexed: 11/20/2022]
Abstract
BACKGROUND L1 cell adhesion molecule (CD171) has been detected in different malignant tumors and is associated with unfavorable outcome. It thus represents a target for tumor diagnosis and therapy. In this study, we assessed L1 expression in more than 8000 normal human tissues and different types of tumors, both malignant and non-malignant, and neural and non-neural. MATERIALS AND METHODS Tissue micro-arrays, including a multi-tumor-array of 128 different tumor types, up to 50 samples of each type (approximately 5500 different samples), arrays with approximately 3000 different prostate and 600 mesenchymal tumor samples, and a normal human tissue-array were analyzed by immunohistochemistry with a monoclonal antibody using immunoperoxidase staining. RESULTS L1 expression was detected in tumors of neural and neural crest origin and other types of non-neural tumors, but not in those of epithelial origin. In normal human tissues, L1 was detected in skin basal cells and small blood vessels, most notably in the mature placenta and peripheral nerves. CONCLUSION This first comprehensive study of the importance of L1 expression in human demonstrates strong L1 overexpression in tumors of neuroectodermal and neural crest origin and an expression in only very few normal human tissues. L1 thus is a potentially important therapeutic target, particularly with respect to malignant melanoma, gastrointestinal stromal tumor, neuroblastoma, and certain subtypes of non-neural tumors.
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Affiliation(s)
- Tamina Rawnaq
- Department of General, Visceral and Thoracic Surgery, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany.
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Li S, Jo YS, Lee JH, Min JK, Lee ES, Park T, Kim JM, Hong HJ. L1 cell adhesion molecule is a novel independent poor prognostic factor of extrahepatic cholangiocarcinoma. Clin Cancer Res 2009; 15:7345-51. [PMID: 19920102 DOI: 10.1158/1078-0432.ccr-09-0959] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Cholangiocarcinomas (CC) are associated with poor survival, but diagnostic markers and therapeutic targets have not yet been elucidated. We previously found aberrant expression of L1 cell adhesion molecule in intrahepatic CC and a role for L1 in the progression of intrahepatic CC. Here, we analyzed L1 expression in extrahepatic CC (ECC) and evaluated its prognostic significance. EXPERIMENTAL DESIGN We examined L1 expression in tumors from 75 ECC patients by immunohistochemistry. We analyzed the correlations between L1 expression and clinicopathologic factors as well as patient survival. RESULTS L1 was not expressed in normal extrahepatic bile duct epithelium but was aberrantly expressed in 42.7% of ECC tumors. High expression of L1 was detected at the invasive front of tumors and was significantly associated with perineural invasion (P < 0.01). Univariate analysis indicated that various prognostic factors such as histologic grade 3, advanced pathologic T stage and clinical stage, perineural invasion, nodal metastasis, and high expression of L1 were risk factors predicting patient survival. Multivariate analyses done by Cox's proportional hazards model showed that high expression of L1 (hazard ratio, 2.171; 95% confidence interval, 1.162-4.055; P = 0.015) and nodal metastasis (hazard ratio, 2.088; 95% confidence interval, 1.159-3.764; P = 0.014) were independent risk factors for patient death. CONCLUSIONS L1 was highly expressed in 42.7% of ECC and its expression was significantly associated with perineural invasion. High expression of L1 and nodal metastasis were independent poor prognostic factors predicting overall survival in patients with ECC.
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Affiliation(s)
- Shengjin Li
- Department of Pathology and Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon, Korea
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KIM HYOSONG, YI SEONGYOON, JUN HYUNJUNG, AHN JINSEOK, AHN MYUNGJU, LEE JEEYUN, KIM YOUNGWOOK, CUI ZHENGYUN, HONG HYOJEONG, KIM JINMAN, LI SHENGJIN, HWANG INGYU, PARK KEUNCHIL. L1 cell adhesion molecule as a predictor for recurrence in pulmonary carcinoids and large-cell neuroendocrine tumors. APMIS 2009; 117:140-6. [DOI: 10.1111/j.1600-0463.2009.02433.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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Abstract
BACKGROUND L1-cell adhesion molecule (L1-CAM) is a cell adhesion receptor of the immunoglobulin superfamily, known for its roles in nerve cell function. While originally believed to be present only in brain cells, in recent years L1-CAM has been detected in other tissues, and in a variety of cancer cells, including some common types of human cancer. OBJECTIVE/METHODS We review the prevalence of L1-CAM in human cancer, the possible mechanisms involved in L1-CAM-mediated tumorigenesis, and cancer therapies based upon L1-CAM antibody treatment. RESULTS/CONCLUSIONS In colon cancer cells, the L1-CAM gene was identified as a target of the Wnt/beta-catenin-TCF signaling pathway, and L1-CAM was exclusively detected at the invasive front of colon and ovarian cancer tissue. The expression of L1-CAM in normal and cancer cells enhanced tumorigenesis and conferred metastasis in colon cancer cells. Antibodies against the L1-CAM ectodomain severely inhibited the proliferation of a variety of cancer cells in culture and reduced tumor burden when injected into mice harboring cancer cells expressing L1-CAM. These results, in addition to the presence of L1-CAM on the cell surface and its restricted distribution in normal tissues, make it an ideal target for tumor therapy.
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Affiliation(s)
- Nancy Gavert
- Weizmann Institute of Science, Department of Molecular Cell Biology, Rehovot, Israel
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Raveh S, Gavert N, Ben-Ze'ev A. L1 cell adhesion molecule (L1CAM) in invasive tumors. Cancer Lett 2009; 282:137-45. [PMID: 19144458 DOI: 10.1016/j.canlet.2008.12.021] [Citation(s) in RCA: 104] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2008] [Revised: 12/08/2008] [Accepted: 12/11/2008] [Indexed: 01/11/2023]
Abstract
The L1 cell adhesion molecule (L1CAM) belongs to the immunoglobulin superfamily and was originally identified in the nervous system. Recent studies demonstrated L1CAM expression in various types of cancer, predominantly at the invasive front of tumors and in metastases, suggesting its involvement in advanced stages of tumor progression. Overexpression of L1CAM in normal and cancer cells increased motility, enhanced growth rate and promoted cell transformation and tumorigenicity. Moreover, the expression of L1CAM in tumor cells conferred the capacity to form metastases. These properties of L1CAM, in addition to its cell surface localization, make it a potentially useful diagnostic marker for cancer progression and a candidate for anti-cancer therapy. We review the role of L1CAM in cancer progression with particular emphasis on colon cancer, and the potential of anti-L1CAM antibodies as a therapeutic tool for cancer.
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Affiliation(s)
- Shani Raveh
- Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, 76100, Israel
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Kaifi JT, Reichelt U, Quaas A, Schurr PG, Wachowiak R, Yekebas EF, Strate T, Schneider C, Pantel K, Schachner M, Sauter G, Izbicki JR. L1 is associated with micrometastatic spread and poor outcome in colorectal cancer. Mod Pathol 2007; 20:1183-90. [PMID: 17873897 DOI: 10.1038/modpathol.3800955] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
L1 is a cell adhesion molecule expressed at the invasive front of colorectal tumors with an important role in metastasis. The aim of the present study was to determine L1 protein expression in a large cohort of colorectal cancer patients and its impact on early metastatic spread and survival. A total of 375 patients that underwent surgical treatment for colorectal cancer were chosen retrospectively. A tissue microarray was constructed of 576 tissue samples from these patients and analyzed by immunohistochemistry with a monoclonal antibody against human L1 (UJ127). Lymph node and bone marrow micrometastasis were assessed with monoclonal antibodies Ber-EP4 and pancytokeratin A45-B/B3, respectively. Associations between L1 expression and lymph node, bone marrow micrometastasis and survival were investigated with Fisher's, log-rank test and Cox multivariate analysis. All statistical tests were two-sided. L1 was detected in a subset of 48 (13%) of 375 patients examined. Analysis of L1 expression and survival revealed a significantly worse outcome for L1-positive patients by log-rank test (P<0.05). Multivariate Cox regression analysis showed the strongest independent prognostic impact of L1 expression (P<0.05). Fisher's test revealed a significant association of L1 expression and presence of disseminated tumor cells in lymph nodes and bone marrow (P<0.05). L1 is a powerful prognostic marker for patients that undergo complete surgical resection. It may have a role in early metastatic spread, as L1 is associated with micrometastases to both the lymph nodes and bone marrow. Thus, L1 should be explored further as a target for adjuvant therapy for micrometastatic disease.
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Affiliation(s)
- Jussuf T Kaifi
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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25
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Wachowiak R, Fiegel HC, Kaifi JT, Quaas A, Krickhahn A, Schurr PG, Erttmann R, Schachner M, Kluth D, Sauter G, Izbicki JR. L1 is associated with favorable outcome in neuroblastomas in contrast to adult tumors. Ann Surg Oncol 2007; 14:3575-80. [PMID: 17917782 DOI: 10.1245/s10434-007-9608-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2007] [Revised: 08/12/2007] [Accepted: 08/13/2007] [Indexed: 12/14/2022]
Abstract
BACKGROUND Neuroblastoma is the most common solid tumor in childhood with unconventional clinical behavior. L1, a neuronal cell adhesion molecule, is associated with poor survival in malignant adult tumors. The aim of the current study was to determine expression of L1 in pediatric neuroblastoma. METHODS L1 expression was assessed on a tissue microarray with 66 surgically resected neuroblastoma samples by immunohistochemistry with a monoclonal antibody and peroxidase method. Additionally, mRNA expression was analyzed by reverse transcriptase-polymerase chain reaction with L1-specific primers. Data were correlated survival data by log rank test and Cox regression multivariate analysis. RESULTS L1 was detected in 57 (86%) of 66 neuroblastomas, whereas 9 (14%) were L1 negative. Median survival of all children was 72 months. Analysis with Kaplan-Meier method revealed a surprising and contrary finding to adult tumor entities: an association of L1 positivity with better event-free and overall survival (P < .001 and P < .01 by log rank test). Multivariate Cox regression analysis showed an independent prognostic impact of L1 negativity for event-free and overall survival of the children (P < .05). CONCLUSIONS In contrast to adult tumor entities, where L1 is associated with aggressive clinical behavior, our data show that L1 predicts good outcome in children with neuroblastoma. This novel finding suggests an inverse role of L1 in neuroblastoma. Future studies might focus on the molecular basis of the varying effect of L1 in different tumors.
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Affiliation(s)
- Robin Wachowiak
- Department of Pediatric Surgery, University Medical Center, 04103, Leipzig, Germany.
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Shtutman M, Levina E, Ohouo P, Baig M, Roninson IB. Cell adhesion molecule L1 disrupts E-cadherin-containing adherens junctions and increases scattering and motility of MCF7 breast carcinoma cells. Cancer Res 2007; 66:11370-80. [PMID: 17145883 DOI: 10.1158/0008-5472.can-06-2106] [Citation(s) in RCA: 108] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The first steps of invasion and metastasis include the dissociation of adherens junctions and the induction of migratory phenotype, through a program that resembles epithelial-mesenchymal transition (EMT). The L1 cell adhesion molecule, which is normally found primarily in the brain, was recently shown to be expressed in different types of cancer and to have tumor-promoting activity. We now find that L1 mediates EMT-like events in MCF7 breast carcinoma cells. MCF7 predominantly expresses the nonneuronal isoform of L1, as do 16 of 17 other cell lines derived from different types of cancer. L1 protein expression in MCF7 cells, which form E-cadherin-containing adherens junctions, is inversely related to cell density. Analysis of MCF7 cells with overexpression or knockdown of nonneuronal L1 isoform revealed that L1 expression leads to the disruption of adherens junctions and increases beta-catenin transcriptional activity. As a result, L1 expression promotes the scattering of epithelial cells from compact colonies. Expression of the full-length L1 protein, but not of its soluble extracellular moiety, increases the motility of the MCF7 epithelial monolayer in a wound-healing assay, in which L1 expression is preferentially observed and required in cells leading the movement of the monolayer. Based on these results, we propose a model for the role of L1 as a trigger of EMT-like events in transformed epithelial cells.
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Affiliation(s)
- Michael Shtutman
- Cancer Center, Ordway Research Institute, Albany, New York 12208, USA.
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Sebens Müerköster S, Werbing V, Sipos B, Debus MA, Witt M, Grossmann M, Leisner D, Kötteritzsch J, Kappes H, Klöppel G, Altevogt P, Fölsch UR, Schäfer H. Drug-induced expression of the cellular adhesion molecule L1CAM confers anti-apoptotic protection and chemoresistance in pancreatic ductal adenocarcinoma cells. Oncogene 2006; 26:2759-68. [PMID: 17086212 DOI: 10.1038/sj.onc.1210076] [Citation(s) in RCA: 97] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by rapid tumor progression, high metastatic potential and profound chemoresistance. We recently reported that induction of a chemoresistant phenotype in the PDAC cell line PT45-P1 by long-term chemotherapy involves an increased interleukin 1 beta (IL1beta)-dependent secretion of nitric oxide (NO) accounting for efficient caspase inhibition. In the present study, we elucidated the involvement of L1CAM, an adhesion molecule previously found in other malignancies, in this NO-dependent chemoresistance. Chemoresistant PT45-P1res cells, but not chemosensitive parental PT45-P1 cells, express high levels of L1CAM in an ILbeta-dependent fashion. PT45-P1res cells subjected to short interfering RNA (siRNA)-mediated L1CAM knock-down exhibited reduced inducible nitric oxide synthase expression and NO secretion, as well as a significant increase of anti-cancer drug-induced caspase activation, an effect reversed by the NO donor S-nitroso-N-acetyl-D,L-penicillamine. Conversely, overexpression of L1CAM in PT45-P1 cells conferred anti-apoptotic protection to anti-cancer drug treatment. Interestingly, L1CAM ectodomain shedding, in example, by ADAM10, as reported for other L1CAM-related activities, seemed to be dispensable for anti-apoptotic protection by L1CAM. Neither the shedded L1CAM ectodomain was detected in chemoresistant L1CAM-expressing PT45-P1 cells nor did the administration of various metalloproteinase inhibitors affect L1CAM-dependent chemoresistance. Immunohistochemical analysis revealed L1CAM expression in 80% of pancreatic cancer specimens, supporting a potential role of L1CAM in the malignancy of this tumor. These findings substantiate our understanding of the molecular mechanisms leading to chemoresistance in PDAC cells and indicate the importance of L1CAM in this scenario.
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Affiliation(s)
- S Sebens Müerköster
- Clinic of Internal Medicine, Laboratory of Molecular Gastroenterology and Hepatology, UKSH-Campus Kiel, Kiel, Germany
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Kaifi JT, Strelow A, Schurr PG, Reichelt U, Yekebas EF, Wachowiak R, Quaas A, Strate T, Schaefer H, Sauter G, Schachner M, Izbicki JR. L1 (CD171) is highly expressed in gastrointestinal stromal tumors. Mod Pathol 2006; 19:399-406. [PMID: 16400320 DOI: 10.1038/modpathol.3800547] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The treatment strategy for mesenchymal tumors of the gastrointestinal tract is based upon typing of the tumor. Especially differential diagnosis of gastrointestinal stromal tumors (GISTs) to leiomyomas is crucial for determining radicality of surgery. L1 cell adhesion molecule (CD171) plays an essential role in tumor progression. The aim of this study was to determine expression of L1 in GISTs, smooth muscle tumors, desmoid-type fibromatosis and peripheral nerve sheath tumors (PNSTs). We retrospectively analyzed a total of 129 surgically resected primary tumors or metastases of 72 GISTs, 29 smooth muscle tumors, seven PNSTs and 21 desmoid-type fibromatosis by immunohistochemistry for c-kit, CD34, smooth muscle actin, desmin, vimentin, S-100 and L1 expression. L1 expression was detected in 53 (74%) of 72 GISTs but in none of 29 smooth muscle tumors or 21 desmoid-type fibromatosis (P<0.01 by Fisher's test). In all, four (57%) of seven peripheral nerve sheath tumors were L1-positive. Survival analysis of 55 surgically completely resected GISTs presenting without metastasis at initial diagnosis revealed no tumor-specific death among L1-negative patients (P=0.13 by log-rank test; median follow-up time 41 months) and one recurrence was observed (P=0.12). Interestingly high levels of L1 were seen in tumor vascular endothelial cells of smooth muscle tumors and PNSTs, but not in GISTs. Our data show that L1 is highly expressed in GISTs but not in smooth muscle tumors and desmoid-type fibromatosis being important differential diagnoses. The trend towards a reduced survival of L1-positive patients in this study has to be further evaluated in future trials with higher patient numbers.
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Affiliation(s)
- Jussuf T Kaifi
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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