Expression of CXCR4 and CXCL12 (SDF‐1) in human prostate cancers (PCa) in vivo

Abstract

Human prostate cancers (PCa) express great variability in their ability to metastasize to bone. The identification of molecules associated with aggressive phenotypes will help to define PCa subsets and will ultimately lead to better treatment strategies. The chemokine stromal-derived factor-1 (SDF-1 or CXCL12) and its receptor CXCR4 are now known to modulate the migration and survival of an increasing array of normal and malignant cell types including breast, pancreatic cancers, glioblastomas, and others. The present investigation extends our previous investigations by determining the expression of CXCR4 and CXCL12 in humans using high-density tissue microarrays constructed from clinical samples obtained from a cohort of over 600 patients. These data demonstrate that CXCR4 protein expression is significantly elevated in localized and metastastic cancers. At the RNA level, human PCa tumors also express CXCR4 and message, but overall, they were not significantly different suggesting post-transcriptional regulation of the receptor plays a major role in regulating protein expression. Similar observations were made for CXCL12 message, but in this case more CXCL12 message was expressed by metastastic lesions as compared to normal tissues. PCa cell lines also express CXCL12 mRNA, and regulate mRNA expression in response to CXCL12 and secrete biologically active protein. Furthermore, neutralizing antibody to CXCL12 decreased the proliferation of bone homing LNCaP C4-2B and PC3 metastastic tumor cells. These investigations provide important new information pertaining to the molecular basis of how tumors may 'home' to bone, and the mechanisms that may account for their growth in selected end organs.

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

“…Both BPH and localised CaP sections show strong CXCR4 nuclear staining while the prostate bone metastases, a poor prognostic indicator, showed strong CXCR4 nuclear and cytoplasmic staining. Our results also confirm the observation of Sun et al (2003) that the level of CXCR4 expression increased with increasing malignancy, with the greatest expression being observed in the aggressively metastatic cell line PC-3 and in the human bone metastasis sections. This increasing expression suggests that CXCR4/SDF-1 signalling may be one of the key signalling pathways for metastatic spread to the bone.…”

“…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.…”

“…It has been shown that SDF-1, expressed by both BMS and BMECs (Aiuti et al, 1997), and its receptor CXCR4 play an important role in targeting not just blood cells but also prostate epithelial cells towards the BMS (Taichman et al, 2002;Sun et al, 2003). Therefore, we examined the ability of SDF-1, and its specific peptide inhibitor T140, to stimulate invasion of prostate epithelial cells in our models.…”

“…This model is supported by the facts that both bone marrow endothelial cells and osteoblasts express SDF-1 (Aiuti et al, 1997;Hamada et al, 1998;Ponomaryov et al, 2000), CXCR4 knockouts do not show haematopoietic engraftment of the bone marrow (Aiuti et al, 1999) and that the level of CXCR4 expression by HSC determines their ability to engraft the bone marrow (Peled et al, 1999). It has been shown recently that the CXCR4/CXCL12 axis also plays a crucial role in the targeting of several solid tumour metastases, including breast (Muller et al, 2001) kidney (Staller et al, 2003), lung (Burger et al, 2003), pancreas (Koshiba et al, 2000) and CaP (Taichman et al, 2002;Sun et al, 2003) to the bone marrow. It has been shown in vitro that CXCR4 and CXCL12 interactions alongside CCR7/CCL21 interactions trigger pseudopodial invasion by malignant breast epithelial cells by actin polymerisation (Muller et al, 2001).…”

Homing of Cancer Cells to the Bone

“…Antibody to CXCR4 significantly reduces skeletal metastases [67]. High-density tissue microarrays constructed from clinical samples obtained from a cohort of over 600 patients demonstrates that CXCR4 protein expression is significantly elevated in localized and metastatic cancers [68]. It has also been demonstrated that metastatic human prostate cell lines DU145, LNCAP and PC3 express functional CXCR4 receptor and that SDF-1 enhances their migratory capabilities [69].…”