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The Stromal Derived Factor‐1/CXCL12‐CXC Chemokine Receptor 4 Biological Axis in Renal Cell Carcinoma Metastasis
Author(s) -
Pan Judong,
Burdick Marie D,
Phillips Roderick J,
Thomas George V,
Reckamp Karen,
Figlin Robert A,
Mestas Javier,
Belperio John A,
Xue Ying Ying,
Strieter Robert M
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1329
RATIONALE Renal cell carcinoma (RCC) is characterized by organ‐specific metastasis. The chemokine stromal derived factor‐1 (CXCL12) and its receptor CXCR4 have been shown to regulate organ‐specific metastasis in various other cancers. We hypothesized that the biological axis of CXCL12/CXCR4 is a major mechanism for organ‐specific metastasis of RCC. METHODS We examined the expression of CXCR4 on circulating cells from patients with metastatic RCC and in human RCC cells (SN12C) with stable knockdown of VHL by RNA interference. We further studied RCC metastasis using both heterotopic and orthotopic severe combined immunodeficiency (SCID) mouse models of human RCC. RESULTS CXCR4 was significantly expressed on circulating pan‐cytokeratin positive cells from patients with metastatic RCC. CXCR4 mRNA and protein levels were upregulated by either knocking down VHL in SN12C, or incubating the cells under hypoxia. Furthermore, the expression of CXCR4 on human RCC directly correlates with their metastatic ability in vivo. The administration of neutralizing anti‐CXCL12 antibodies to SCID mice bearing human RCC abrogated metastasis to target organs expressing high levels of CXCL12, without altering cellular proliferation, apoptosis, or tumor‐associated angiogenesis. CONCLUSIONS Our data suggests that the CXCL12/CXCR4 biological axis plays an important role in regulating organ‐specific metastasis of RCC. FUNDED BY: NIH Grants CA87879, P50CA90388, HL66027, and P50HL67665.