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Integrin alpha2 mediates selective metastasis to the liver.

ABSTRACT: Cancers display distinct patterns of organ-specific metastasis. Comparative analysis of a broad array of cell membrane molecules on a liver-metastasizing subline of B16 melanoma versus the parental B16-F0 revealed unique up-regulation of integrin alpha2. The direct role of integrin alpha2 in hepatic metastasis was shown by comparison of high versus low-expressing populations, antibody blockade, and ectopic expression. Integrin alpha2-mediated binding to collagen type IV (highly exposed in the liver sinusoids) and collagen type IV-dependent activation of focal adhesion kinase are both known to be important in the metastatic process. Analysis of primary colorectal cancers as well as coexisting liver and lung metastases from individual patients suggests that integrin alpha2 expression contributes to liver metastasis in human colorectal cancer. These findings define integrin alpha2 as a molecule conferring selective potential for formation of hepatic metastasis, as well as a possible target to prevent their formation.

SUBMITTER: Yoshimura K

PROVIDER: S-EPMC4857201 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Integrin alpha2 mediates selective metastasis to the liver.

Yoshimura Kiyoshi K Meckel Kristen F KF Laird Lindsay S LS Chia Christina Y CY Park Jang-June JJ Olino Kelly L KL Tsunedomi Ryouichi R Harada Toshio T Iizuka Norio N Hazama Shoichi S Kato Yukihiko Y Keller Jesse W JW Thompson John M JM Chang Fumin F Romer Lewis H LH Jain Ajay A Iacobuzio-Donahue Christine C Oka Masaaki M Pardoll Drew M DM Schulick Richard D RD

Cancer research 20090908 18

Cancers display distinct patterns of organ-specific metastasis. Comparative analysis of a broad array of cell membrane molecules on a liver-metastasizing subline of B16 melanoma versus the parental B16-F0 revealed unique up-regulation of integrin alpha2. The direct role of integrin alpha2 in hepatic metastasis was shown by comparison of high versus low-expressing populations, antibody blockade, and ectopic expression. Integrin alpha2-mediated binding to collagen type IV (highly exposed in the li ...[more]

PMID: 19738067

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Project description:Previous reports demonstrate that the Î±2-integrin (Î±2) mediates pancreatic ductal adenocarcinoma (PDAC) cell interaction with collagens. We found that untransformed pancreatic ductal epithelial cells and well-differentiated PDAC cells use Î±2 exclusively to adhere and migrate on collagenI. In contrast, poorly-differentiated PT45P1 and MIAPaCa2 cells demonstrate reduced reliance on, or complete loss of Î±2, respectively. Further, well-differentiated PDAC lines exhibit reduced in vitro invasion compared to poorly-differentiated lines, and Î±2-blockade suppressed invasion of well-differentiated lines exclusively. Based on these data and the demonstrated role of Î±2 in maintaining tissue architecture in other organs, we hypothesized that Î±2 may actually suppress the malignant phenotype in PDAC. Accordingly, stable ectopic expression of Î±2 in MIAPaCa2 cells (MP2-Î±2) retarded in vitro invasion. MP2-Î±2 cells maintained on collagenI were more invasion-retarded than MP2-Î±2 cells maintained in standard tissue culture, and demonstrated higher Î±2Î²1 expression that was reflected in faster and more complete adhesion/migration on collagenI. Affymetrix gene expression profiling of Î±2-expressing and mock-transfected cells revealed that kallikrein-related peptidases (KLK)-5, 6 and 7 were specifically upregulated by Î±2. Accordingly, well-differentiated PDAC lines express KLK-5, 6 and 7 and KLK blockade increased invasion as well as collagenI-migration in KLK-positive lines. Importantly, an Î±2 cytoplasmic deletion mutant promoted KLK expression and retarded invasion, while an Î±9Î±2 chimera retarded invasion less efficiently, and did not impact KLK expression. These data demonstrate for the first time that the Î±2-ectodomain and KLKâ??s coordinately regulate a less invasive phenotype in PDAC cells. Experiment Overall Design: Affymetrix global gene arrays were used to analyse differences in gene expression patterns in MIAPaCa2 cells stably reexpressing the alpha2 integrin, a cytoplasmic deletion of the alpha2 integrin (dCYTO) or an alpha9 ectodomain and transmembrane domain/alpha2 cytoplasmic domain chimera, versus vector-only mock controls. RNA was harvested from cells passaged identically and maitained under standard tissue culture conditions or on collagenI- or tenascin FNIII-coated plates.. Experiment Overall Design: Genetic manipulation (stable transgene expression)

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Integrin alpha2 mediates selective metastasis to the liver.

Publications

Integrin alpha2 mediates selective metastasis to the liver.

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