Stromal Derived Factor-1 (SDF-1/CXCL12) and CXCR4 in renal cell carcinoma metastasis

Judong Pan, Javier Mestas, Marie D. Burdick, Roderick J. Phillips, George Thomas, Karen Reckamp, John A. Belperio, Robert M. Strieter

Research output: Contribution to journalArticle

137 Citations (Scopus)

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-1 α (HIF-1α) 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.

Original languageEnglish (US)
Article number56
JournalMolecular Cancer
Volume5
DOIs
StatePublished - Nov 3 2006
Externally publishedYes

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Renal Cell Carcinoma
Cells
Neoplasm Metastasis
CXCR4 Receptors
Tumors
Von Hippel-Lindau Tumor Suppressor Protein
SCID Mice
Hypoxia-Inducible Factor 1
Cell proliferation
Keratins
Chemokines
Genetic Promoter Regions
Genes
Neoplasms
Apoptosis
Messenger RNA
Up-Regulation
Cell Proliferation
Proteins
Cell Line

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)
  • Cancer Research
  • Molecular Medicine

Cite this

Pan, J., Mestas, J., Burdick, M. D., Phillips, R. J., Thomas, G., Reckamp, K., ... Strieter, R. M. (2006). Stromal Derived Factor-1 (SDF-1/CXCL12) and CXCR4 in renal cell carcinoma metastasis. Molecular Cancer, 5, [56]. https://doi.org/10.1186/1476-4598-5-56

Stromal Derived Factor-1 (SDF-1/CXCL12) and CXCR4 in renal cell carcinoma metastasis. / Pan, Judong; Mestas, Javier; Burdick, Marie D.; Phillips, Roderick J.; Thomas, George; Reckamp, Karen; Belperio, John A.; Strieter, Robert M.

In: Molecular Cancer, Vol. 5, 56, 03.11.2006.

Research output: Contribution to journalArticle

Pan, J, Mestas, J, Burdick, MD, Phillips, RJ, Thomas, G, Reckamp, K, Belperio, JA & Strieter, RM 2006, 'Stromal Derived Factor-1 (SDF-1/CXCL12) and CXCR4 in renal cell carcinoma metastasis', Molecular Cancer, vol. 5, 56. https://doi.org/10.1186/1476-4598-5-56
Pan, Judong ; Mestas, Javier ; Burdick, Marie D. ; Phillips, Roderick J. ; Thomas, George ; Reckamp, Karen ; Belperio, John A. ; Strieter, Robert M. / Stromal Derived Factor-1 (SDF-1/CXCL12) and CXCR4 in renal cell carcinoma metastasis. In: Molecular Cancer. 2006 ; Vol. 5.
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