CXCR4/CXCL12 expression and signalling in kidney cancer

Abstract

CXCL12 (SDF-1), a CXC-chemokine, and its specific receptor, CXCR4, have recently been shown to be involved in tumourgenesis, proliferation and angiogenesis. Therefore, we analysed CXCL12α/CXCR4 expression and function in four human kidney cancer cell lines (A-498, CAKI-1, CAKI-2, HA-7), 10 freshly harvested human tumour samples and corresponding normal kidney tissue. While none of the analysed tumour cell lines expressed CXCL12α, A-498 cells were found to express CXCR4. More importantly, real-time RT–PCR analysis of 10 tumour samples and respective adjacent normal kidney tissue disclosed a distinct and divergent downregulation of CXCL12α and upregulation of CXCR4 in primary tumour tissue. To prove that the CXCR4 protein is functionally active, rhCXCL12α was investigated for its ability to induce changes of intracellular calcium levels in A-498 cells. Moreover, we used cDNA expression arrays to evaluate the biological influence of CXCL12α. Comparing gene expression profiles in rhCXCL12α stimulated vs unstimulated A-498 kidney cancer cells revealed specific regulation of 31 out of 1176 genes tested on a selected human cancer array, with a prominent stimulation of genes involved in cell-cycle regulation and apoptosis. The genetic changes reported here should provide new insights into the developmental paths leading to tumour progression and may also aid the design of new approaches to therapeutic intervention. British Journal of Cancer (2002) 86 , 1250–1256. DOI: 10.1038/sj/bjc/6600221 www.bjcancer.com © 2002 Cancer Research UK

Roles of Chemokine Receptor 4 (CXCR4) and Chemokine Ligand 12 (CXCL12) in Metastasis of Hepatocellular Carcinoma Cells

“…Although the predominant function of CXCL12-CXCR4 in tumorigenesis is to induce metastases, studies have also indicated that this chemokine ligand-receptor pair is important in promoting angiogenesis (33,34). CXCL12 may be involved in up-regulating expression levels of vascular endothelial growth factor and basic fibroblast growth factor in that subcutaneous injection of CXCL12 into mice induced formation of local small blood vessels (35,36).…”

Invasive characteristics of human prostatic epithelial cells: understanding the metastatic process

“…The chemokine receptor, CXCR4, and its endogenous ligand SDF-1 have been shown to be key components in both chemokineinduced leucocyte trafficking (Aiuti et al, 1997(Aiuti et al, , 1999Hamada et al, 1998) and the migration of malignant epithelial cells to the BMS (Koshiba et al, 2000;Muller et al, 2001;Robledo et al, 2001;Murakami et al, 2002;Schrader et al, 2002;Taichman et al, 2002; Sun et al, 2003). This has led to the hypothesis that CXCR4 is the key component of metastatic implantation in bone marrow and that it represents an important therapeutic target for metastatic bone disease.…”

“…These include cancers of the prostate (Taichman et al, 2002), kidney (Schrader et al, 2002), lung (Burger et al, 2003) breast (Muller et al, 2001) and skin (Robledo et al, 2001;Murakami et al, 2002). Cells from these tumour types share many of the trafficking characteristics of haematopoietic stem cells (HSC) (Muller et al, 2001).…”

Epigenetic silencing of CXCL12 increases the metastatic potential of mammary carcinoma cells

“…Metastatic cells of solid tumors hijack the chemokine signaling network leading to colonization of ectopic tissues with those carcinomas, with CXCR4 and CXCL12 receiving the most attention in regards to metastasis of colon, breast, kidney and lung carcinomas (Muller et al, 2001;Schrader et al, 2002;Phillips et al, 2003;Zeelenberg et al, 2003). This research has lead to the current model wherein CXCR4 expression on metastatic cells enables those cells to home to organs abundantly expressing CXCL12.…”