Plexin B1 is downregulated in renal cell carcinomas and modulates cell growth.

Plexins are a family of transmembrane receptors that interact with the repulsive axon guidance molecules (Semaphorins) in neural tissues. In extraneural tissues, plexins are involved in other cellular functions often altered in neoplastic cells, such as adhesion, migration, and apoptosis. Plexin B1 has been implicated in the regulation of Akt, which is an activated pathway in renal cell neoplasms, and only 1 report has emphasized its role as an oncogenic factor. Furthermore, plexin B1 is located in 3p21, which is a chromosomal region deleted frequently in renal cell carcinomas. In accordance with a hypothetical oncogenic role for plexin B1, we have shown by reverse transcription-polymerase chain reaction that plexin B1 is expressed in nonneoplastic renal tissue, and it is severely downregulated in clear cell renal carcinomas. We have also demonstrated by immunohistochemistry on tissue microarrays that plexin B1 protein is absent in more than 80% of renal cell carcinomas (169 in 209 carcinomas examined). Otherwise, all kinds of renal tubules showed strong membrane reactivity. Moreover, when we have induced plexin B1 expression with an expression vector in the renal adenocarcinoma cell line ACHN, a marked reduction in proliferation rate was produced. Altogether, this evidence suggests a possible role for plexin B1 in renal oncogenesis.

A scan for signatures of positive selection in candidate loci for skin pigmentation in humans.

Although the combination of pale skin and intense sun exposure results in an important health risk for the individual, it is less clear if at the population level this risk has possessed an evolutionary meaning. In this sense, a number of adaptive hypotheses have been put forward to explain the evolution of human skin pigmentation, such as photoprotection against sun-induced cancer, sexual selection, vitamin D synthesis or photoprotection of photolabile compounds, among others. It is expected that if skin pigmentation is adaptive, we might be able to see the signature of positive selection on some of the genes involved. In order to detect this signature, we analyze a battery of 81 candidate loci by means of phylogenetic and population genetic tests. Our results indicate that both light and dark skin may possess adaptive value. Of the main loci presenting this signature, TP53BP1 shows clear evidence of adaptive selection in Africans, whereas TYRP1 and SLC24A5 show evidence of adaptive selection in Caucasians. Although we cannot offer a mechanism that based on these genes explains the advantage of light skin, if TP53BP1, and perhaps RAD50, have truly conferred an adaptive value to the African population analyzed, photoprotection against sun-induced skin damage/cancer might be proposed as a mechanism that has driven the evolution of human skin pigmentation.

Tendon xanthomas in familial hypercholesterolemia are associated with a differential inflammatory response of macrophages to oxidized LDL.

Tendon xanthomas (TX) are pathognomonic lipid deposits commonly found in familial hypercholesterolemia (FH) patients. The aim of this study was to determine whether macrophages from FH patients with TX (TX+) have higher predisposition to foam cells formation after oxidized LDL (oxLDL) overload than those from FH patients without TX (TX-), and if their differential gene expression profile could explain these different phenotypes. Total RNA pools from macrophages from FH patients TX+ and TX- were analyzed using Affymetrix oligonucleotide arrays to evaluate the gene expression profile in presence and absence of oxLDL. Also, the intracellular lipid content was measured by fluorescence flow cytometry. Results of these studies suggest that macrophages from FH subjects TX+ compared to those TX- have a differential response to oxLDL, since they show higher intracellular cholesterol ester accumulation and a differential gene expression profile. The gene array data were validated by relative quantitative real-time RT-PCR and quantitative ELISA in culture media and plasma samples. FH subjects TX+ showed increased plasma tryptase, TNF-alpha, IL-8 and IL-6 concentrations. We propose that TX formation are associated with higher intracellular lipid content, and higher inflammatory response of macrophages in response to oxLDL.

Fibroblast growth factor receptor 3 is overexpressed in urinary tract carcinomas and modulates the neoplastic cell growth.

PURPOSE: Fibroblast growth factor receptor 3 (FGFR3) mutations have been associated with achondroplastic syndromes and urinary bladder carcinomas. Here we describe changes in FGFR3 mRNA and protein expression in transitional carcinomas and determine the effect of monoclonal antibodies against FGFR3 in RT-112 cell line proliferation. EXPERIMENTAL DESIGN: We used microarray tools to evaluate FGFR3 mRNA expression in 22 urinary bladder carcinomas at different stages (noninvasive pTa, lamina propria invasive pT1, and muscular invasive pT2) and 7 nonneoplastic tissue controls. FGFR3 protein expression was evaluated by Western blotting in 15 different carcinomas and 3 nonneoplastic controls. Two hundred thirty-seven urinary bladder and renal pelvis carcinomas and 21 negative controls were tested on tissue microarrays by immunohistochemistry. The effect on cell proliferation in the RT-112 bladder cancer cell line of monoclonal antibodies against FGFR3 was also evaluated. RESULTS: Overexpression of FGFR3 mRNA was found in pTa and pT1 stage carcinomas (fold change >8) and in pT2 carcinomas (fold change >4). Nonneoplastic urinary bladder samples do not express FGFR3 protein. However, 83% of pTa, 100% of pT1, and 50% of pT2 carcinomas expressed FGFR3 as determined by Western blotting. By immunohistochemistry, FGFR3 was positive in 71.4% of pTa, 72% of pT1, and 49.2% of pT2 cases as well as 61.5% of upper urinary tract carcinomas. Proliferation of the RT-112 cell line was inhibited with monoclonal antibodies against FGFR3. CONCLUSIONS: FGFR3 seems to play an important role in transitional cell carcinoma development. Our results suggest that FGFR3 antagonists could be developed as possible therapeutics for treatment of urinary tract carcinoma.