Clinical relevance of maspin expression in bladder cancer.

Transitional cell carcinoma (TCC) of the bladder is a solid tumor that induces angiogenesis to maintain nutrition and oxygenation of tumor cells. Maspin, a serpin with tumor suppressing activity, has recently been identified as an inhibitor of angiogenesis. This study examined the impact of maspin expression in the growth pattern of TCC of the bladder. Maspin was identified in a panel of normal tissues, in several bladder carcinoma cell lines, and 51 patient samples of TCC of the bladder. Expression was detected by RT-PCR and immunohistochemistry. Furthermore, the level of maspin was correlated to the growth rate of bladder tumor cell lines in vitro and in vivo. Maspin expression was found in high quantities in normal urothelium. Maspin expression was preserved in superficial bladder cancers but was significantly diminished in invasive carcinomas. Within the group of invasive TCCs, maspin expression was inversely correlated to the patient prognosis. Furthermore, low maspin expression level was coupled to an increased tumor cell growth in vivo. Down-regulation of maspin expression seems to be a specific event in the progression of invasive bladder carcinoma. Maspin might be a useful marker to determine the prognosis of invasive TCC. Furthermore, maspin re-expression might become a therapeutic option in the treatment of invasive, metastatic TCC.

CXCR4 chemokine receptor mediates prostate tumor cell adhesion through alpha5 and beta3 integrins.

The mechanisms leading to prostate cancer metastasis are not understood completely. Although there is evidence that the CXC chemokine receptor (CXCR) 4 and its ligand CXCL12 may regulate tumor dissemination, their role in prostate cancer is controversial. We examined CXCR4 expression and functionality, and explored CXCL12-triggered adhesion of prostate tumor cells to human endothelium or to extracellular matrix proteins laminin, collagen, and fibronectin. Although little CXCR4 was expressed on LNCaP and DU-145 prostate tumor cells, CXCR4 was still active, enabling the cells to migrate toward a CXCL12 gradient. CXCL12 induced elevated adhesion to the endothelial cell monolayer and to immobilized fibronectin, laminin, and collagen. Anti-CXCR4 antibodies or CXCR4 knock out significantly impaired CXCL12-triggered tumor cell binding. The effects observed did not depend on CXCR4 surface expression level. Rather, CXCR4-mediated adhesion was established by alpha5 and beta3 integrin subunits and took place in the presence of reduced p38 and p38 phosphorylation. These data show that chemoattractive mechanisms are involved in adhesion processes of prostate cancer cells, and that binding of CXCL12 to its receptor leads to enhanced expression of alpha5 and beta3 integrins. The findings provide a link between chemokine receptor expression and integrin-triggered tumor dissemination.

Prostate tumor CXC-chemokine profile correlates with cell adhesion to endothelium and extracellular matrix.

Though chemokines of the CXC family are thought to play key roles in neoplastic transformation and tumor invasion, information about CXC chemokines in prostate cancer is sparse. To evaluate the involvement of CXC chemokines in prostate cancer, we analyzed the CXC coding mRNA of both chemokine ligands (CXCL) and chemokine receptors (CXCR), using the prostate carcinoma cell lines PC-3, DU-145 and LNCaP. CXCR proteins were further evaluated by Western blot, CXCR surface expression by flow cytometry and confocal microscopy. The expression pattern was correlated to adherence of the tumor cells to an endothelial cell monolayer or to extracellular matrix components. Based on growth and adhesion capacity, PC-3 and DU-145 were identified to be highly aggressive tumor cells (PC-3>DU-145), whereas LNCaP belonged to the low aggressive phenotype. CXCL1, CXCL3, CXCL5 and CXCL6 mRNA, chemokines with pro-angiogenic activity, were strongly expressed in DU-145 and PC-3, but not in LNCaP. CXCR3 and CXCR4 surface level differed in the following order: LNCaP>DU-145>PC-3. The differentiation factor, fatty acid valproic acid, induced intracellular CXCR accumulation. Therefore, prostate tumor malignancy might be accompanied by enhanced synthesis of angiogenesis stimulating CXC chemokines. Further, shifting CXCR3 and CXCR4 from the cell surface to the cytoplasm might activate pro-tumoral signalling events and indicate progression from a low to a highly aggressive phenotype.