Metastasis is a highly selective process during which cancer cells colonize secondary organs in distinct patterns. Organ colonization is initiated by the arrest of blood-borne tumor cells in selected blood vessels of the secondary target organ. This event appears to be regulated by organ-specific adhesion molecules expressed on the lumenal surface of vascular endothelial cells (ECAMs). To study the regulatory role of ECAMs in metastasis, we rely in our experiments on an essay system that circumvents the cumbersome isolation and culture of phenotypically stable, microvascular endothelial cells and, instead, use large vessel endothelial cells [e.g., bovine aortic endothelial cells (BAEC)] modulated with organ-specific extracellular matrix to assume phenotypic traits of the organ from which the matrix has been derived. This system has been successfully used in generating monoclonal antibodies (mAbs) that crossreact with a lung-specific B16 melanoma cell-binding mouse ECAM (Lu-ECAM-1) and, thus, constitute the foundation for our studies on the vascular arrest of blood-borne cancer cells. The goal of our studies is to purify receptor-ligand pairs from lung (or liver)-specific endothelium and lung (or liver)-metastatic tumor cells and to clone their respective genes. Tissue distribution as well as translational and transcriptional regulation of these molecules on the endothelial and tumor cell surfaces are analyzed under various microenvironmental conditions (e.g., various organ-specific extracellular matrices). Further studies are directed to determine ECAM tumor ligand distribution in primary tumors and to compare such distributions with eventual metastatic spread and, finally, to assess adhesion of tumor cells to endothelial cell monolayers or various densities of purified, immobilized ECAM (or combinations of different ECAMs) under conditions of fluid flow and shear stress. The ultimate goal of these studies is to exploit our understanding of the molecular mechanisms of tumor cell/endothelial cell interactions for the development of new anti-metastatic treatment strategies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA047668-06
Application #
2092685
Study Section
Pathology B Study Section (PTHB)
Project Start
1988-04-01
Project End
1994-11-30
Budget Start
1993-12-01
Budget End
1994-11-30
Support Year
6
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Cornell University
Department
Pathology
Type
Schools of Veterinary Medicine
DUNS #
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Beckley, Janel R; Pauli, Bendicht U; Elble, Randolph C (2004) Re-expression of detachment-inducible chloride channel mCLCA5 suppresses growth of metastatic breast cancer cells. J Biol Chem 279:41634-41
Cheng, Hung-Chi; Abdel-Ghany, Mossaad; Pauli, Bendicht U (2003) A novel consensus motif in fibronectin mediates dipeptidyl peptidase IV adhesion and metastasis. J Biol Chem 278:24600-7
Abdel-Ghany, Mossaad; Cheng, Hung-Chi; Elble, Randolph C et al. (2003) The interacting binding domains of the beta(4) integrin and calcium-activated chloride channels (CLCAs) in metastasis. J Biol Chem 278:49406-16
Elble, Randolph C; Ji, Guangju; Nehrke, Keith et al. (2002) Molecular and functional characterization of a murine calcium-activated chloride channel expressed in smooth muscle. J Biol Chem 277:18586-91
Abdel-Ghany, Mossaad; Cheng, Hung-Chi; Elble, Randolph C et al. (2002) Focal adhesion kinase activated by beta(4) integrin ligation to mCLCA1 mediates early metastatic growth. J Biol Chem 277:34391-400
Abdel-Ghany, M; Cheng, H C; Elble, R C et al. (2001) The breast cancer beta 4 integrin and endothelial human CLCA2 mediate lung metastasis. J Biol Chem 276:25438-46
Fuller, C M; Ji, H L; Tousson, A et al. (2001) Ca(2+)-activated Cl(-) channels: a newly emerging anion transport family. Pflugers Arch 443 Suppl 1:S107-10
Elble, R C; Pauli, B U (2001) Tumor suppression by a proapoptotic calcium-activated chloride channel in mammary epithelium. J Biol Chem 276:40510-7
Pauli, B U; Abdel-Ghany, M; Cheng, H C et al. (2000) Molecular characteristics and functional diversity of CLCA family members. Clin Exp Pharmacol Physiol 27:901-5
Gruber, A D; Pauli, B U (1999) Clustering of the human CLCA gene family on the short arm of chromosome 1 (1p22-31). Genome 42:1030-2

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