Biologie

Aberrations chromosomiques

Menée sur 594 patients atteints d'un sarcome, cette étude française identifie la présence d'une fusion des gènes BCOR et CCNB3 dans un sous-groupe de 24 patients

A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion
• Nature Genetics, sous presse, 2012 (résumé)

Détails

Fermer
Menée sur 594 patients atteints d'un sarcome, cette étude française identifie la présence d'une fusion des gènes BCOR et CCNB3 dans un sous-groupe de 24 patients

“A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion”

• Pierron, Gaelle;Tirode, Franck;Lucchesi, Carlo;Reynaud, Stephanie;Ballet, Stelly;Cohen-Gogo, Sarah;Perrin, Virginie;Coindre, Jean-Michel;Delattre, Olivier

The identification of subtype-specific translocations has revolutionized the diagnostics of sarcoma and has provided new insight into oncogenesis. We used RNA-seq to investigate samples from individuals diagnosed with small round cell tumors of bone, possibly Ewing sarcoma, but which lacked the canonical EWSR1-ETS translocation. A new fusion was observed between BCOR (encoding the BCL6 co-repressor) and CCNB3 (encoding the testis-specific cyclin B3) on the X chromosome. RNA-seq results were confirmed by RT-PCR and through cloning of the tumor-specific genomic translocation breakpoints. In total, 24 BCOR-CCNB3–positive tumors were identified among a series of 594 sarcoma cases. Gene profiling experiments indicated that BCOR-CCNB3–positive cases are biologically distinct from other sarcomas, particularly Ewing sarcoma. Finally, we show that CCNB3 immunohistochemistry is a powerful diagnostic marker for this subgroup of sarcoma and that overexpression of BCOR-CCNB3 or of truncated ...

Mots clés : Sarcome; Biologie (Aberrations chromosomiques)

Menée sur un échantillon tumoral et un échantillon de tissu sain adjacent prélevés sur un patient atteint d'un carcinome rénal à cellules claires, cette étude de séquençage des exons à l'échelle d'une seule cellule met en évidence l'hétérogénéité de la population cellulaire de la tumeur

Single-Cell Exome Sequencing Reveals Single-Nucleotide Mutation Characteristics of a Kidney Tumor
• Cell, Vol. 148 (5), pp. 886-895, 2012 (résumé)

Détails

Fermer
Menée sur un échantillon tumoral et un échantillon de tissu sain adjacent prélevés sur un patient atteint d'un carcinome rénal à cellules claires, cette étude de séquençage des exons à l'échelle d'une seule cellule met en évidence l'hétérogénéité de la population cellulaire de la tumeur

“Single-Cell Exome Sequencing Reveals Single-Nucleotide Mutation Characteristics of a Kidney Tumor”

• Xu, Xun;Hou, Yong;Yin, Xuyang;Bao, Li;Tang, Aifa;Song, Luting;Li, Fuqiang;Tsang, Shirley;Wu, Kui;Wu, Hanjie;He, Weiming;Zeng, Liang;Xing, Manjie;Wu, Renhua;Jiang, Hui;Liu, Xiao;Cao, Dandan;Guo, Guangwu;Hu, Xueda;Gui, Yaoting;Li, Zesong;Xie, Wenyue;Sun, Xiaojuan;Shi, Min;Cai, Zhiming;Wang, Bin;Zhong, Meiming;Li, Jingxiang;Lu, Zuhong;Gu, Ning;Zhang, Xiuqing;Goodman, Laurie;Bolund, Lars;Wang, Jian;Yang, Huanming;Kristiansen, Karsten;Dean, Michael;Li, Yingrui;Wang, Jun

Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer and has very few mutations that are shared between different patients. To better understand the intratumoral genetics underlying mutations of ccRCC, we carried out single-cell exome sequencing on a ccRCC tumor and its adjacent kidney tissue. Our data indicate that this tumor was unlikely to have resulted from mutations in VHL and PBRM1. Quantitative population genetic analysis indicates that the tumor did not contain any significant clonal subpopulations and also showed that mutations that had different allele frequencies within the population also had different mutation spectrums. Analyses of these data allowed us to delineate a detailed intratumoral genetic landscape at a single-cell level. Our pilot study demonstrates that ccRCC may be more genetically complex than previously thought and provides information that can lead to new ways to investigate individual tumors, with the aim of developing more effective ...

Mots clés : Rein; Biologie (Aberrations chromosomiques)

Menée sur des cellules tumorales prélevées sur un patient atteint d'une néoplasie myéloproliférative JAK2-, cette étude montre la faisabilité d'une méthode de séquençage des exons à l'échelle d'une seule cellule

Single-Cell Exome Sequencing and Monoclonal Evolution of a JAK2-Negative Myeloproliferative Neoplasm
• Cell, Vol. 148 (5), pp. 873-885, 2012 (résumé)

Détails

Fermer
Menée sur des cellules tumorales prélevées sur un patient atteint d'une néoplasie myéloproliférative JAK2-, cette étude montre la faisabilité d'une méthode de séquençage des exons à l'échelle d'une seule cellule

“Single-Cell Exome Sequencing and Monoclonal Evolution of a JAK2-Negative Myeloproliferative Neoplasm”

• Hou, Yong;Song, Luting;Zhu, Ping;Zhang, Bo;Tao, Ye;Xu, Xun;Li, Fuqiang;Wu, Kui;Liang, Jie;Shao, Di;Wu, Hanjie;Ye, Xiaofei;Ye, Chen;Wu, Renhua;Jian, Min;Chen, Yan;Xie, Wei;Zhang, Ruren;Chen, Lei;Liu, Xin;Yao, Xiaotian;Zheng, Hancheng;Yu, Chang;Li, Qibin;Gong, Zhuolin;Mao, Mao;Yang, Xu;Yang, Lin;Li, Jingxiang;Wang, Wen;Lu, Zuhong;Gu, Ning;Laurie, Goodman;Bolund, Lars;Kristiansen, Karsten;Wang, Jian;Yang, Huanming;Li, Yingrui;Zhang, Xiuqing;Wang, Jun

Tumor heterogeneity presents a challenge for inferring clonal evolution and driver gene identification. Here, we describe a method for analyzing the cancer genome at a single-cell nucleotide level. To perform our analyses, we first devised and validated a high-throughput whole-genome single-cell sequencing method using two lymphoblastoid cell line single cells. We then carried out whole-exome single-cell sequencing of 90 cells from a JAK2-negative myeloproliferative neoplasm patient. The sequencing data from 58 cells passed our quality control criteria, and these data indicated that this neoplasm represented a monoclonal evolution. We further identified essential thrombocythemia (ET)-related candidate mutations such as SESN2 and NTRK1, which may be involved in neoplasm progression. This pilot study allowed the initial characterization of the disease-related genetic architecture at the single-cell nucleotide level. Further, we established a single-cell sequencing method that opens the ...

Mots clés : Myélome multiple et maladies immunoprolifératives; Biologie (Aberrations chromosomiques)

Menée sur des échantillons tumoraux prélevés sur des patients atteints d'un lymphome de Burkitt ou d'un lymphome diffus à grandes cellules B, cette étude identifie des anomalies génomiques différentes chez les patients pédiatriques et les patients adultes

Molecular distinctions between pediatric and adult mature B-cell non-Hodgkin lymphomas identified through genomic profiling
• Blood, sous presse, 2012 (résumé)

Détails

Fermer
Menée sur des échantillons tumoraux prélevés sur des patients atteints d'un lymphome de Burkitt ou d'un lymphome diffus à grandes cellules B, cette étude identifie des anomalies génomiques différentes chez les patients pédiatriques et les patients adultes

“Molecular distinctions between pediatric and adult mature B-cell non-Hodgkin lymphomas identified through genomic profiling”

• Deffenbacher, Karen E.;Iqbal, Javeed;Sanger, Warren;Shen, Yulei;Lachel, Cynthia;Liu, Zhongfeng;Liu, Yanyan;Lim, Megan S.;Perkins, Sherrie L.;Fu, Kai;Smith, Lynette;Lynch, James;Staudt, Louis M.;Rimsza, Lisa M.;Jaffe, Elaine;Rosenwald, Andreas;Ott, German K.;Delabie, Jan;Campo, Elias;Gascoyne, Randy D.;Cairo, Mitchell S.;Weisenburger, Dennis D.;Greiner, Timothy C.;Gross, Thomas G.;Chan, Wing C.

Burkitt lymphoma (BL) predominates in pediatric patients while diffuse large B-cell lymphoma (DLBCL) is uncommon. In contrast to adults, BL and DLBCL are treated similarly in children and both entities have superior outcomes in children compared to adults. Gene expression profiling (GEP) and miRNA expression profiling clearly differentiated pediatric DLBCL from BL, forming distinct clusters regardless of patient age. However, pathway analysis of GEP data identified minor differences between corresponding pediatric and adult tumors. Predominance (6:1) of the germinal center B-cell (GCB) subtype to activated B-cell (ABC) subtype was found among pediatric DLBCL. Two cases were molecularly classified as primary mediastinal B-cell lymphoma. We observed frequent abnormalities in 8q24 in pediatric DLBCL including MYC rearrangement in 31% (5/16) and gain or amplification in 50% (6/12) non-rearranged cases. MYC rearrangement was present in 96% (23/24) BL cases. Array-based CGH analysis ...

Mots clés : Lymphome; Biologie (Aberrations chromosomiques)

Oncogènes et suppresseurs de tumeurs

Menée sur 6 911 participants inclus dans 4 cohortes cas-témoins, cette étude met en évidence le rôle de voies de signalisation spécifiquement associées à la réparation de l'ADN dans le cancer du poumon

Lung Cancer and DNA Repair Genes: Multilevel Association Analysis from the International Lung Cancer Consortium
• Carcinogenesis, sous presse, 2012 (résumé)

Détails

Fermer
Menée sur 6 911 participants inclus dans 4 cohortes cas-témoins, cette étude met en évidence le rôle de voies de signalisation spécifiquement associées à la réparation de l'ADN dans le cancer du poumon

“Lung Cancer and DNA Repair Genes: Multilevel Association Analysis from the International Lung Cancer Consortium”

• Kazma, Rémi;Babron, Marie-Claude;Gaborieau, Valérie;Génin, Emmanuelle;Brennan, Paul;Hung, Rayjean J.;McLaughlin, John R.;Krokan, Hans E.;Elvestad, Maiken B.;Skorpen, Frank;Anderssen, Endre;Vooder, Tõnu;Välk, Kristjan;Metspalu, Andres;Field, John K.;Lathrop, Mark;Sarasin, Alain;Benhamou, Simone

Lung cancer is the leading cause of cancer-related death worldwide and tobacco smoking is the major associated risk factor. DNA repair is an important process, maintaining genome integrity, and polymorphisms in DNA repair genes may contribute to susceptibility to lung cancer. To explore the role of DNA repair genes in lung cancer, we conducted a multilevel association study with 1,655 Single Nucleotide Polymorphisms (SNPs) in 211 DNA repair genes using 6,911 individuals pooled from four genome-wide case-control studies. Single SNP association corroborates previous reports of association with rs3131379, located on the gene MSH5 (P = 3.57 × 10-5), and returns a similar risk estimate. The effect of this SNP is modulated by histological subtype. On the log-additive scale, the odds ratio per allele is 1.04 [0.84 – 1.30] for adenocarcinomas, 1.52 [1.28 – 1.80] for squamous cell carcinomas and 1.31 [1.09 – 1.57] for other histologies (Heterogeneity test: P = 9.1 × 10-3). Gene-based ...

Mots clés : Poumon; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée à l'aide de lignées cellulaires et de modèles murins, cette étude suggère que le gène CLIC4 joue un rôle de suppresseur de tumeurs dans les carcinomes épidermoïdes cutanés

CLIC4 is a tumor suppressor for cutaneous squamous cell cancer
• Carcinogenesis, sous presse, 2012 (résumé)

Détails

Fermer
Menée à l'aide de lignées cellulaires et de modèles murins, cette étude suggère que le gène CLIC4 joue un rôle de suppresseur de tumeurs dans les carcinomes épidermoïdes cutanés

“CLIC4 is a tumor suppressor for cutaneous squamous cell cancer”

• Suh, K. Stephen;Malik, Mariam;Shukla, Anjali;Ryscavage, Andrew;Wright, Lisa;Jividen, Kasey;Crutchley, John M.;Dumont, Rebecca A.;Fernandez-Salas, Ester;Webster, Joshua D.;Simpson, R. Mark;Yuspa, Stuart H.

CLIC4 is a member of a redox-regulated metamorphic multifunctional protein family, first characterized as intracellular chloride channels. Current knowledge indicates that CLICs participate in signaling, cytoskeleton integrity and differentiation functions of multiple tissues. In metabolically stressed skin keratinocytes, cytoplasmic CLIC4 is S-nitrosylated and translocates to the nucleus where it enhances TGF-β signaling by protecting phospho-Smad 2 and 3 from dephosphorylation. CLIC4 expression is diminished in multiple human epithelial cancers, and the protein is excluded from the nucleus. We now show that CLIC4 expression is reduced in chemically-induced mouse skin papillomas, mouse and human squamous carcinomas and squamous cancer cell lines, and the protein is excluded from the nucleus. The extent of reduction in CLIC4 coincides with progression of squamous tumors from benign to malignant. Inhibiting anti-oxidant defense in tumor cells increases S-nitrosylation and nuclear ...

Mots clés : Peau (hors mélanome); Biologie (Oncogènes et suppresseurs de tumeurs)

Menée sur des échantillons tumoraux prélevés sur des patients atteints d'un adénocarcinome de l'œsophage, cette étude met en évidence un mécanisme par lequel l'amplification du facteur de transcription GATA6 favorise la survie des cellules tumorales

Activation of GATA binding protein 6 (GATA6) sustains oncogenic lineage-survival in esophageal adenocarcinoma
• Proceedings of the National Academy of Sciences, sous presse, 2012 (résumé)

Détails

Fermer
Menée sur des échantillons tumoraux prélevés sur des patients atteints d'un adénocarcinome de l'œsophage, cette étude met en évidence un mécanisme par lequel l'amplification du facteur de transcription GATA6 favorise la survie des cellules tumorales

“Activation of GATA binding protein 6 (GATA6) sustains oncogenic lineage-survival in esophageal adenocarcinoma”

• Lin, Lin;Bass, Adam J.;Lockwood, William W.;Wang, Zhuwen;Silvers, Amy L.;Thomas, Dafydd G.;Chang, Andrew C.;Lin, Jules;Orringer, Mark B.;Li, Weiquan;Glover, Thomas W.;Giordano, Thomas J.;Lam, Wan L.;Meyerson, Matthew;Beer, David G.

Gene amplification is a tumor-specific event during malignant transformation. Recent studies have proposed a lineage-dependency (addiction) model of human cancer whereby amplification of certain lineage transcription factors predisposes a survival mechanism in tumor cells. These tumor cells are derived from tissues where the lineage factors play essential developmental and maintenance roles. Here, we show that recurrent amplification at 18q11.2 occurs in 21% of esophageal adenocarcinomas (EAC). Utilization of an integrative genomic strategy reveals a single gene, the embryonic endoderm transcription factor GATA6, as the selected target of the amplification. Overexpression of GATA6 is found in EACs that contain gene amplification. We find that EAC patients whose tumors carry GATA6 amplification have a poorer survival. We show that ectopic expression of GATA6, together with FGFR2 isoform IIIb, increases anchorage-independent growth in immortalized Barrett's esophageal cells. Conversely, ...

Mots clés : Oesophage; Biologie (Oncogènes et suppresseurs de tumeurs)

Progression et métastases

Menée sur des lignées cellulaires de cancers du sein, cette étude met en évidence le rôle joué par le gène GRHL2 pour supprimer la transition épithélio-mésenchymateuse

Suppression of the Epithelial-Mesenchymal Transition by Grainyhead-Like-2
• Cancer Research, sous presse, 2012 (résumé)

Détails

Fermer
Menée sur des lignées cellulaires de cancers du sein, cette étude met en évidence le rôle joué par le gène GRHL2 pour supprimer la transition épithélio-mésenchymateuse

“Suppression of the Epithelial-Mesenchymal Transition by Grainyhead-Like-2”

• Frisch, Steven M.;Cieply, Benjamin;Riley, Philip;Pifer, Phillip M;Widmeyer, Joseph;Addison, Joseph B.;Ivanov, Alexey V.;Denvir, James

Grainyhead genes are involved in wound healing and developmental neural tube closure. In light of the high degree of similarity between the epithelial-mesenchymal transitions (EMT) occurring in wound healing processes and the cancer stem cell-like compartment of tumors, including TGF-β-dependence, we investigated the role of the Grainyhead gene, Grainyhead-Like-2 (GRHL2) in oncogenic EMT. GRHL2 was down-regulated specifically in the claudin-low subclass breast tumors and in basal-B subclass breast cancer cell lines. GRHL2 suppressed TGF-β-induced, Twist-induced or spontaneous EMT, enhanced anoikis-sensitivity, and suppressed mammosphere generation in mammary epithelial cells. These effects were mediated in part by suppression of ZEB1 expression via direct repression of the ZEB1 promoter. GRHL2 also inhibited Smad-mediated transcription and it upregulated mir200b/c as well as the TGF-β receptor antagonist, BMP2. Lastly, ectopic expression of GRHL2 in MDA-MB-231 breast cancer cells ...

Mots clés : Sein; Biologie (Progression et métastases)

Menée à l'aide de xénogreffes, cette étude met en évidence le rôle joué par la tyrosine phosphatase SHP2 dans la progression d'un cancer du sein

Tyrosine phosphatase SHP2 promotes breast cancer progression and maintains tumor-initiating cells via activation of key transcription factors and a positive feedback signaling loop
• Nature Medicine, sous presse, 2012 (résumé)

Détails

Fermer
Menée à l'aide de xénogreffes, cette étude met en évidence le rôle joué par la tyrosine phosphatase SHP2 dans la progression d'un cancer du sein

“Tyrosine phosphatase SHP2 promotes breast cancer progression and maintains tumor-initiating cells via activation of key transcription factors and a positive feedback signaling loop”

• Aceto, Nicola;Sausgruber, Nina;Brinkhaus, Heike;Gaidatzis, Dimos;Martiny-Baron, Georg;Mazzarol, Giovanni;Confalonieri, Stefano;Quarto, Micaela;Hu, Guang;Balwierz, Piotr J.;Pachkov, Mikhail;Elledge, Stephen J.;van Nimwegen, Erik;Stadler, Michael B.;Bentires-Alj, Mohamed

New cancer therapies are likely to arise from an in-depth understanding of the signaling networks influencing tumor initiation, progression and metastasis. We show a fundamental role for Src-homology 2 domain-containing phosphatase 2 (SHP2) in these processes in human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancers. Knockdown of SHP2 eradicated breast tumor-initiating cells in xenograft models, and SHP2 depletion also prevented invasion in three-dimensional cultures and in a transductal invasion assay in vivo. Notably, SHP2 knockdown in established breast tumors blocked their growth and reduced metastasis. Mechanistically, SHP2 activated stemness-associated transcription factors, including v-myc myelocytomatosis viral oncogene homolog (c-Myc) and zinc finger E-box binding homeobox 1 (ZEB1), which resulted in the repression of let-7 microRNA and the expression of a set of 'SHP2 signature' genes. We found these genes to be simultaneously activated ...

Mots clés : Sein; Biologie (Progression et métastases)

Menée sur un modèle murin, cette étude met en évidence le rôle joué par l'expression stromale de Dkk1, un inhibiteur de la signalisation Wnt, pour favoriser le développement d'un myélome multiple

Bone marrow stromal cells create a permissive microenvironment for myeloma development: a new stromal role for Wnt inhibitor Dkk1
• Cancer Research, sous presse, 2012 (résumé)

Détails

Fermer
Menée sur un modèle murin, cette étude met en évidence le rôle joué par l'expression stromale de Dkk1, un inhibiteur de la signalisation Wnt, pour favoriser le développement d'un myélome multiple

“Bone marrow stromal cells create a permissive microenvironment for myeloma development: a new stromal role for Wnt inhibitor Dkk1”

• Fowler, Jessica A;Mundy, Gregory R;Lwin, Seint T;Edwards, Claire M

The rapid progression of multiple myeloma is dependent upon cellular interactions within the bone marrow microenvironment. In vitro studies suggest that bone marrow stromal cells (BMSCs) can promote myeloma growth and survival and osteolytic bone disease. However, it is not possible to recreate all cellular aspects of the bone marrow microenvironment in an in vitro system, and the contributions of BMSCs to myeloma pathogenesis in an intact, immune competent, in vivo system are unknown. To investigate this, we utilized a murine myeloma model that replicates many features of the human disease. Co-inoculation of myeloma cells and a BMSC line isolated from myeloma-permissive mice in otherwise non-permissive mice resulted in myeloma development, associated with tumor growth within bone marrow and osteolytic bone disease. In contrast, inoculation of myeloma cells alone did not result in myeloma. BMSCs inoculated alone induced osteoblast suppression, associated with an increase in serum ...

Mots clés : Myélome multiple et maladies immunoprolifératives; Biologie (Progression et métastases)

Menée à l'aide d'un modèle murin et d'échantillons prélevés sur des patients atteints d'un mésothéliome pleural malin, cette étude met en évidence le rôle joué par la mésothéline dans le processus invasif

Mesothelin overexpression promotes mesothelioma cell invasion and MMP-9 secretion in an orthotopic mouse model and in epithelioid pleural mesothelioma patients
• Clinical Cancer Research, sous presse, 2012 (résumé)

Détails

Fermer
Menée à l'aide d'un modèle murin et d'échantillons prélevés sur des patients atteints d'un mésothéliome pleural malin, cette étude met en évidence le rôle joué par la mésothéline dans le processus invasif

“Mesothelin overexpression promotes mesothelioma cell invasion and MMP-9 secretion in an orthotopic mouse model and in epithelioid pleural mesothelioma patients”

• Servais, Elliot L.;Colovos, Christos;Rodriguez, Luis A.;Bograd, Adam J.;Nitadori, Jun-ichi;Sima, Camelia S.;Rusch, Valerie W.;Sadelain, Michel;Adusumilli, Prasad S.

Purpose: Mesothelin (MSLN) is a tumor-associated antigen, being investigated as a biomarker and therapeutic target in malignant pleural mesothelioma (MPM). The biological function of MSLN overexpression in MPM is unknown. We hypothesized that MSLN may promote tumor invasion in MPM, a tumor characterized primarily by regional aggressiveness and rare distant metastases. Experimental Design: Human and murine MPM cells with MSLN forced expression and shRNA knockdown were examined for proliferation, invasion, and matrix metalloproteinase (MMP) secretion. The influence of MSLN overexpression on MPM cell invasion was assessed in an orthotopic mouse model and in patient samples. Results: MSLN expression promotes MPM cell invasion and MMP secretion in both human and murine MPM cells. In an orthotopic MPM mouse model characterized by our laboratory, MPM cells with MSLN overexpression preferentially localized to the tumor invading edge, co-localized with MMP-9 expression, and promoted decreased ...

Mots clés : Mésothéliome; Biologie (Progression et métastases)

Menée sur des souris génétiquement modifiées, cette étude met en évidence le rôle joué par le récepteur Stab2 dans la régulation du niveau sanguin d'acide hyaluronique et dans le processus métastatique

Inhibition of Stabilin-2 elevates circulating hyaluronic acid levels and prevents tumor metastasis
• Proceedings of the National Academy of Sciences, sous presse, 2012 (résumé)

Détails

Fermer
Menée sur des souris génétiquement modifiées, cette étude met en évidence le rôle joué par le récepteur Stab2 dans la régulation du niveau sanguin d'acide hyaluronique et dans le processus métastatique

“Inhibition of Stabilin-2 elevates circulating hyaluronic acid levels and prevents tumor metastasis”

• Hirose, Yoshikazu;Saijou, Eiko;Sugano, Yasuyoshi;Takeshita, Fumitaka;Nishimura, Satoshi;Nonaka, Hidenori;Chen, Yen-Rong;Sekine, Keisuke;Kido, Taketomo;Nakamura, Takashi;Kato, Shigeaki;Kanke, Toru;Nakamura, Koji;Nagai, Ryozo;Ochiya, Takahiro;Miyajima, Atsushi

Hyaluronic acid (HA) has been implicated in the proliferation and metastasis of tumor cells. However, most previous studies were conducted on extracellular matrix or pericellular HA, and the role of circulating HA in vivo has not been studied. HA is rapidly cleared from the bloodstream. The scavenger receptor Stabilin-2 (Stab2) is considered a major clearance receptor for HA. Here we report a dramatic elevation in circulating HA levels in Stab2-deficient mice without any overt phenotype. Surprisingly, the metastasis of B16F10 melanoma cells to the lungs was markedly suppressed in the Stab2-deficient mice, whereas cell proliferation was not affected. Furthermore, administration of an anti-Stab2 antibody in Stab2+ mice elevated serum HA levels and prevented the metastasis of melanoma to the lung, and also suppressed spontaneous metastasis of mammary tumor and human breast tumor cells inoculated in the mammary gland. Administration of the antibody or high-dose HA in mice blocked the ...