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PMID: 17083723 Published · epublish English Journal Article Research Support, N.I.H., Extramural

Stromal derived factor-1 (SDF-1/CXCL12) and CXCR4 in renal cell carcinoma metastasis.

Molecular cancer ·Vol. 5 ·2006-11-03 ·Pages 56

Pan J, Mestas J, Burdick MD, Phillips RJ, Thomas GV, Reckamp K, Belperio JA, Strieter RM

Abstract

Renal cell carcinoma (RCC) is characterized by organ-specific metastases. The chemokine stromal derived factor-1 (SDF-1/CXCL12) and its receptor CXCR4 have been suggested to regulate organ-specific metastasis in various other cancers. On this basis, we hypothesized that the biological axis of CXCL12 via interaction with its receptor, CXCR4, is a major mechanism for RCC metastasis. We demonstrated that CXCR4 was significantly expressed on circulating cytokeratin+ RCC cells from patients with known metastatic RCC. We detected up-regulation of CXCR4 mRNA and protein levels on a human RCC cell line by either knockdown of the von Hippel-Lindau (VHL) tumor suppressor protein, or incubating the cells under hypoxic conditions. The enhanced CXCR4 expression was mediated through the interaction of the Hypoxia Inducible Factor-1alpha (HIF-1alpha) with the promoter region of the CXCR4 gene. Furthermore, the expression of CXCR4 on human RCC directly correlated with their metastatic ability in vivo in both heterotopic and orthotopic SCID mouse models of human RCC. Neutralization of CXCL12 in SCID mice abrogated metastasis of RCC to target organs expressing high levels of CXCL12; without altering tumor cell proliferation, apoptosis, or tumor-associated angiogenesis. Therefore, our data suggest that the CXCL12/CXCR4 biological axis plays an important role in regulating the organ-specific metastasis of RCC.

MeSH Terms
Animals Biomarkers, Tumor/genetics,metabolism Carcinoma, Renal Cell/genetics,metabolism,secondary Cell Hypoxia Cell Line, Tumor Chemokine CXCL12 Chemokines, CXC/antagonists & inhibitors,pharmacology,physiology Chemotaxis/drug effects Gene Expression Regulation, Neoplastic Humans Hypoxia-Inducible Factor 1, alpha Subunit/metabolism Keratins/analysis Kidney Neoplasms/genetics,metabolism,pathology Mice Mice, SCID Promoter Regions, Genetic RNA Interference Receptors, CXCR4/genetics,metabolism Transcriptional Activation Von Hippel-Lindau Tumor Suppressor Protein/antagonists & inhibitors,genetics
Chemicals
Biomarkers, Tumor CXCL12 protein, human Chemokine CXCL12 Chemokines, CXC Cxcl12 protein, mouse HIF1A protein, human Hypoxia-Inducible Factor 1, alpha Subunit Receptors, CXCR4 Keratins Von Hippel-Lindau Tumor Suppressor Protein
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Pan Judong
Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA. jpan@mednet.ucla.edu
Mestas Javier
Burdick Marie D
Phillips Roderick J
Thomas George V
Reckamp Karen
Belperio John A
Strieter Robert M
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Article Info
Journal
Molecular cancer
Abbr.
Mol Cancer
ISSN
1476-4598
DOI
10.1186/1476-4598-5-56
Email
jpan@mednet.ucla.edu
Published
2006-11-03
Epub
2006-00-03
Pages
56
Language
English
Region
England
NLM ID
101147698
PMCID
PMC1636662
Subset
IM
Grants
NCI NIH HHS · P50 CA090388 · United States
NCI NIH HHS · R01 CA087879 · United States
NCI NIH HHS · CA87879 · United States
NCI NIH HHS · P50CA90388 · United States
External Links
PubMed source DOI: 10.1186/1476-4598-5-56 PMC Full Text View journal details
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