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

Pan J, Mestas J, Burdick MD, Phillips RJ, Thomas GV, Reckamp K, Belperio JA, Strieter RM - Mol. Cancer (2006)

Bottom Line: We demonstrated that CXCR4 was significantly expressed on circulating cytokeratin+ RCC cells from patients with known metastatic RCC.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA. jpan@mednet.ucla.edu

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.

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SN12C-VC and SN12C-VHL-KD chemotaxis in the presence of CXCL12 (1, 10 and 100 ng/ml) after 24 hours incubation under normoxic or hypoxic conditions as described previously. Results are expressed as the number of cells that migrated per high-power field (HPF). Data represent the mean ± SEM from five HPFs.
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Figure 3: SN12C-VC and SN12C-VHL-KD chemotaxis in the presence of CXCL12 (1, 10 and 100 ng/ml) after 24 hours incubation under normoxic or hypoxic conditions as described previously. Results are expressed as the number of cells that migrated per high-power field (HPF). Data represent the mean ± SEM from five HPFs.

Mentions: After confirming the role of the HIF-1α/VHL axis in the up-regulation of CXCR4 mRNA and protein expression, we assessed whether this led to functional differences in migration in response to the CXCR4 ligand, CXCL12. SN12C-P, SN12C-VC, and SN12C-VHL-KD cells were exposed to either normoxia or preconditioned with hypoxia for 24 hours followed by analysis of chemotaxis in response to CXCL12. SN12C-VHL-KD cells demonstrated a dose-dependent increase in chemotaxis in response to CXCL12 under both conditions of normoxia and hypoxia (Fig. 3). Hypoxia preconditioning of the SN12C-VC and SN12C-P cells also resulted in a dose-dependent increase in chemotactic activity (Fig. 3 and data not shown). The levels of chemotactic activities of SN12C-VC were not significantly different from those of SN12C-P cells under either normoxic or hypoxic conditions (data not shown). These results confirmed that the loss of function of VHL results in augmented chemotactic activity in response to CXCL12. Moreover, in cells with functional VHL, hypoxia plays a role to increase this response.


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

Pan J, Mestas J, Burdick MD, Phillips RJ, Thomas GV, Reckamp K, Belperio JA, Strieter RM - Mol. Cancer (2006)

SN12C-VC and SN12C-VHL-KD chemotaxis in the presence of CXCL12 (1, 10 and 100 ng/ml) after 24 hours incubation under normoxic or hypoxic conditions as described previously. Results are expressed as the number of cells that migrated per high-power field (HPF). Data represent the mean ± SEM from five HPFs.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1636662&req=5

Figure 3: SN12C-VC and SN12C-VHL-KD chemotaxis in the presence of CXCL12 (1, 10 and 100 ng/ml) after 24 hours incubation under normoxic or hypoxic conditions as described previously. Results are expressed as the number of cells that migrated per high-power field (HPF). Data represent the mean ± SEM from five HPFs.
Mentions: After confirming the role of the HIF-1α/VHL axis in the up-regulation of CXCR4 mRNA and protein expression, we assessed whether this led to functional differences in migration in response to the CXCR4 ligand, CXCL12. SN12C-P, SN12C-VC, and SN12C-VHL-KD cells were exposed to either normoxia or preconditioned with hypoxia for 24 hours followed by analysis of chemotaxis in response to CXCL12. SN12C-VHL-KD cells demonstrated a dose-dependent increase in chemotaxis in response to CXCL12 under both conditions of normoxia and hypoxia (Fig. 3). Hypoxia preconditioning of the SN12C-VC and SN12C-P cells also resulted in a dose-dependent increase in chemotactic activity (Fig. 3 and data not shown). The levels of chemotactic activities of SN12C-VC were not significantly different from those of SN12C-P cells under either normoxic or hypoxic conditions (data not shown). These results confirmed that the loss of function of VHL results in augmented chemotactic activity in response to CXCL12. Moreover, in cells with functional VHL, hypoxia plays a role to increase this response.

Bottom Line: We demonstrated that CXCR4 was significantly expressed on circulating cytokeratin+ RCC cells from patients with known metastatic RCC.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA. jpan@mednet.ucla.edu

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.

Show MeSH
Related in: MedlinePlus