ADAM15 supports prostate cancer metastasis by modulating tumor cell-endothelial cell interaction.

Using human tumor and cDNA microarray technology, we have recently shown that the ADAM15 disintegrin is significantly overexpressed during the metastatic progression of human prostate cancer. In the current study, we used lentiviral-based short hairpin RNA (shRNA) technology to down-regulate ADAM15 in the metastatic prostate cancer cell line, PC-3. ADAM15 down-regulation dramatically attenuated many of the malignant characteristics of PC-3 cells in vitro and prevented the s.c. growth of PC-3 cells in severe combined immunodeficient (SCID) mice. By inhibiting the expression of ADAM15 in PC-3 cells, we showed decreased cell migration and adhesion to specific extracellular matrix proteins. This was accompanied by a reduction in the cleavage of N-cadherin by ADAM15 at the cell surface. Fluorescence-activated cell sorting analysis revealed reduced cell surface expression of the metastasis-associated proteins alpha(v) integrin and CD44. Furthermore, matrix metalloproteinase 9 secretion and activity were abrogated in response to ADAM15 reduction. In an in vitro model of vascular invasion, loss of ADAM15 reduced PC-3 adhesion to, and migration through, vascular endothelial cell monolayers. Using an SCID mouse model of human prostate cancer metastasis, we found that the loss of ADAM15 significantly attenuated the metastatic spread of PC-3 cells to bone. Taken together, these data strongly support a functional role for ADAM15 in prostate tumor cell interaction with vascular endothelium and the metastatic progression of human prostate cancer.

[1]  M. Rogers,et al.  Mechanisms of osteopontin and CD44 as metastatic principles in prostate cancer cells , 2007, Molecular Cancer.

[2]  O. De Wever,et al.  Soluble N‐cadherin in human biological fluids , 2006, International journal of cancer.

[3]  P. Saftig,et al.  Breaking up the tie: disintegrin-like metalloproteinases as regulators of cell migration in inflammation and invasion. , 2006, Pharmacology & therapeutics.

[4]  C. Blobel,et al.  ADAM12 is highly expressed in carcinoma-associated stroma and is required for mouse prostate tumor progression , 2006, Oncogene.

[5]  S. Varambally,et al.  ADAM15 disintegrin is associated with aggressive prostate and breast cancer disease. , 2006, Neoplasia.

[6]  L. Coussens,et al.  Inflammation, proteases and cancer. , 2006, European journal of cancer.

[7]  H. Li,et al.  Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells , 2006, Oncogene.

[8]  A. Abdel‐Mageed,et al.  Up-regulation of CXCR4 expression in PC-3 cells by stromal-derived factor-1alpha (CXCL12) increases endothelial adhesion and transendothelial migration: role of MEK/ERK signaling pathway-dependent NF-kappaB activation. , 2005, Cancer research.

[9]  C. Blobel,et al.  Critical function for ADAM9 in mouse prostate cancer. , 2005, Cancer research.

[10]  B. de Strooper,et al.  ADAM10 cleavage of N‐cadherin and regulation of cell–cell adhesion and β‐catenin nuclear signalling , 2005, The EMBO journal.

[11]  D. Ghosh,et al.  Androgen-Independent Prostate Cancer Is a Heterogeneous Group of Diseases , 2004, Cancer Research.

[12]  D. Zurakowski,et al.  ADAM 12 Cleaves Extracellular Matrix Proteins and Correlates with Cancer Status and Stage* , 2004, Journal of Biological Chemistry.

[13]  P. Johnston,et al.  CD44 Potentiates the Adherence of Metastatic Prostate and Breast Cancer Cells to Bone Marrow Endothelial Cells , 2004, Cancer Research.

[14]  L. Mir,et al.  Evidence of Antiangiogenic and Antimetastatic Activities of the Recombinant Disintegrin Domain of Metargidin , 2004, Cancer Research.

[15]  K. Pienta,et al.  Dynamic process of prostate cancer metastasis to bone , 2004, Journal of cellular biochemistry.

[16]  A. Ullrich,et al.  EGFR signal transactivation in cancer cells. , 2003, Biochemical Society transactions.

[17]  R. Shah,et al.  In Vivo Visualization of Metastatic Prostate Cancer and Quantitation of Disease Progression in Immunocompromised Mice , 2003, Cancer biology & therapy.

[18]  J. White.  ADAMs: modulators of cell-cell and cell-matrix interactions. , 2003, Current opinion in cell biology.

[19]  Meenhard Herlyn,et al.  Axis of evil: molecular mechanisms of cancer metastasis , 2003, Oncogene.

[20]  K. Horiuchi,et al.  Potential Role for ADAM15 in Pathological Neovascularization in Mice , 2003, Molecular and Cellular Biology.

[21]  J. Wilhelm,et al.  Increased expression of disintegrin‐metalloproteinases ADAM‐15 and ADAM‐9 following upregulation of integrins α5β1 and αvβ3 in atherosclerosis , 2003 .

[22]  G. Glinsky,et al.  Malignancy-associated regions of transcriptional activation: gene expression profiling identifies common chromosomal regions of a recurrent transcriptional activation in human prostate, breast, ovarian, and colon cancers. , 2003, Neoplasia.

[23]  D. Baltimore,et al.  Inhibiting HIV-1 infection in human T cells by lentiviral-mediated delivery of small interfering RNA against CCR5 , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[24]  John D. Williams,et al.  The Role of ADAM 15 in Glomerular Mesangial Cell Migration* , 2002, The Journal of Biological Chemistry.

[25]  J. Brugge,et al.  Sensing the environment: a historical perspective on integrin signal transduction , 2002, Nature Cell Biology.

[26]  R. Ross,et al.  ADAM15 overexpression in NIH3T3 cells enhances cell-cell interactions. , 2001, Experimental cell research.

[27]  R. Ádány,et al.  Chromosomal imbalances in primary and metastatic melanomas revealed by comparative genomic hybridization. , 2001, Cytometry.

[28]  G. Laurie,et al.  Integrin expression and usage by prostate cancer cell lines on laminin substrata. , 2001, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[29]  D. McCulloch,et al.  The expression of the ADAMs proteases in prostate cancer cell lines and their regulation by dihydrotestosterone , 2000, Molecular and Cellular Endocrinology.

[30]  H. Tanke,et al.  Identification of Genetic Markers for Prostatic Cancer Progression , 2000, Laboratory Investigation.

[31]  D. Nance,et al.  Interactions between cancer cells and the endothelium in metastasis , 2000, The Journal of pathology.

[32]  P. Primakoff,et al.  The ADAM gene family: surface proteins with adhesion and protease activity. , 2000, Trends in genetics : TIG.

[33]  R. Nagle,et al.  N-Cadherin expression in human prostate carcinoma cell lines. An epithelial-mesenchymal transformation mediating adhesion withStromal cells. , 1999, The American journal of pathology.

[34]  F. Loechel,et al.  Cysteine-rich domain of human ADAM 12 (meltrin alpha) supports tumor cell adhesion. , 1999, The American journal of pathology.

[35]  P. Slocombe,et al.  Interaction of metargidin (ADAM-15) with alphavbeta3 and alpha5beta1 integrins on different haemopoietic cells. , 1999, Journal of cell science.

[36]  David C. Lee,et al.  An essential role for ectodomain shedding in mammalian development. , 1998, Science.

[37]  Y. Takada,et al.  Specific Interaction of the Recombinant Disintegrin-like Domain of MDC-15 (Metargidin, ADAM-15) with Integrin αvβ3* , 1998, The Journal of Biological Chemistry.

[38]  P. Croucher,et al.  Expression of members of the novel membrane linked metalloproteinase family ADAM in cells derived from a range of haematological malignancies. , 1997, Biochemical and biophysical research communications.

[39]  T. Carey,et al.  Expression of N-cadherin by human squamous carcinoma cells induces a scattered fibroblastic phenotype with disrupted cell-cell adhesion , 1996, The Journal of cell biology.

[40]  M. Corada,et al.  Functional properties of human vascular endothelial cadherin (7B4/cadherin-5), an endothelium-specific cadherin. , 1995, Arteriosclerosis, thrombosis, and vascular biology.

[41]  Stephanie Daignault,et al.  Inhibition of DNA methyltransferase activity prevents tumorigenesis in a mouse model of prostate cancer. , 2006, Cancer research.

[42]  Hong Li,et al.  Endothelial metalloprotease-disintegrin protein (ADAM) is implicated in angiogenesis in vitro , 2004, Angiogenesis.

[43]  P. Herrlich,et al.  CD44: From adhesion molecules to signalling regulators , 2003, Nature Reviews Molecular Cell Biology.

[44]  D. Seals,et al.  The ADAMs family of metalloproteases: multidomain proteins with multiple functions. , 2003, Genes & development.

[45]  I. Macdonald,et al.  Metastasis: Dissemination and growth of cancer cells in metastatic sites , 2002, Nature Reviews Cancer.

[46]  Kenneth M. Yamada,et al.  Interaction of metargidin (ADAM-15) with αvβ3 and α5β1 integrins on different haemopoietic cells , 1999 .