The goal of this study was to define Na,K-ATPase α and β subunit isoform expression and isozyme composition in colorectal cancer cells and liver metastases. The α1, α3, and β1 isoforms were the most highly expressed in tumor cells and metastases; in the plasma membrane of non-neoplastic cells and mainly in a cytoplasmic location in tumor cells. α1β1 and α3β1 isozymes found in tumor and metastatic cells exhibit the highest and lowest Na+ affinity respectively and the highest K+ affinity. Mesenchymal cell isozymes possess an intermediate Na+ affinity and a low K+ affinity. In cancer, these ions are likely to favor optimal conditions for the function of nuclear enzymes involved in mitosis, especially a high intra-nuclear K+ concentration. A major and striking finding of this study was that in liver, metastasized CRC cells express the α3β1 isozyme. Thus, the α3β1 isozyme could potentially serve as a novel exploratory biomarker of CRC metastatic cells in liver.

CD341 adipose stromal cells are scattered in the adipose tissue and found in the CD341 population of the stromal vascular fraction (SVF). This fraction includes adipose-derived stromal/stem/progenitor cells (ASCs), which have attracted considerable attention and show great promise for the future of regenerative medicine. Studies in this field have been undertaken mainly in vitro. In this work, however, we assessed the characteristics of human adipose tissue-resident CD341 stromal cells in normal conditions and when activated in vivo during inflammatory/repair processes at different stages of evolution. In normal adipose tissue, these cells showed a characteristic location (peri/paravascular and between adipocytes), a fusiform or stellate morphology, long and moniliform processes, and scarce organelles. During inflammatory/repair stages, native CD341 stromal cells increased in size, proliferated, developed numerous organelles of synthesis, lost CD34 expression, and differentiated into myofibroblasts (aSMA expression and typical ultrastructure). In double-stained sections, cells expressing both CD34 and aSMA were observed. CD34 expression correlated positively with a high proliferative capacity (Ki-67 expression). Conversely, CD34 expression was lost with successive mitoses and with increased numbers of macrophages in the granulation tissue. CD341 stromal cell behavior varied depending on proximity to (with myofibroblast differentiation) or remoteness from (with activated plump cells conserving CD34 expression) injury. In conclusion, our observations point to human adipose tissue-resident CD341 stromal cells as an important source of myofibroblasts during inflammatory/ repair processes. Moreover, stromal cell activation may occur with or without aSMA expression (with or without myofibroblast transformation) and with

The immunophilin FK506-binding protein 5 (FKBP51) is a scaffold protein that serves a pivotal role in the regulation of multiple signaling pathways, integrating external and internal stimuli into distinct signal outputs. In a previous study, we identified several genes that are significantly up- or downregulated in the peripheral white cells (PWCs) of colorectal adenocarcinoma (CRC) patients undergoing oxaliplatin-based chemotherapy. In our screening, FKBP51 gene expression was downregulated following chemotherapy. In order to determine whether this alteration in gene expression observed in PWCs may be detected at the protein level in tumors and metastases following the administration of adjuvant chemotherapy, an immunohistochemical analysis of FKBP51 in CRC and primary metastasis tissues was performed. The present study confirmed the downregulation of FKBP51 gene expression elicited by chemotherapy with folinic acid (leucovorin), fluorouracil and oxaliplatin in metastasized liver tissue that had been resected after the oxaliplatin-based chemotherapy, compared with tissue section samples of CRC from patients (prior to antineoplastic treatment). Furthermore, the results indicated that, in CRC tissue sections, the expression of FKBP51 protein is associated with an immature phenotype of stromal fibroblasts and with the epithelial-to-mesenchymal transition (EMT) phenotype, suggesting a role for this protein in the EMT process in CRC. Finally, the observation that only certain cells of the stroma express FKBP51 protein suggests a potential role for this immunophilin as a stroma cell subtype marker.

Scaffold proteins play pivotal roles in the regulation of signaling pathways, integrating external and internal stimuli to various cellular outputs. We report the pattern of cellular and subcellular expression of scaffoldins angiomotin-like 2 (AmotL2), FK506 binding protein 5 (FKBP51) and IQ motif containing GTPase-activating protein 1 (IQGAP1) in colorectal cancer (CRC) and metastases in liver resected after oxaliplatin-based chemotherapy (CT). Positive immunostaining for the three scaffoldins was found in most cells in healthy colon, tumor, healthy liver and metastasized liver. The patterns of expression of AmotL2, FKBP51 and IQGAP1 show the greatest variability in immune system cells and neurons and glia cells and the least in blood vessel cells. The simultaneous subcellular localization in tumor cells and other cell types within the tumor suggest an involvement of these three scaffoldins in cancer biology, including a role in Epithelial Mesenchymal Transition. The display in differential localization and quantitative expression of AmotL2, FKBP51, and IQGAP1 could be used as biomarkers for more accurate tumor staging and as potential targets for anti-cancer therapeutics by blocking or slowing down their interconnecting functions. Tough further research needs to be done in order to improve these assessments.

Recently, we demonstrated that in human intravascular papillary endothelial hyperplasia (IPEH), vein wall vascularization occurs in association with myriad papillae, a large part of which formed in the vascularized vein wall. Previously, using an animal model, we observed that PGE2 and glycerol administration around the femoral vein originates intense vascularization of the vein wall from its intimal endothelial cells (ECs). This vascularization is similar to that in IPEH. The aim of this study is to assess the mechanism of papillary formation, using this model after demonstrating papillary development in neo-vascularized femoral vein walls. In semithin and ultrathin sections, the sequential vascular and papillary development was as follows: (a) activation of vein intimal ECs, (b) sprouting of intimal ECs towards the vein media layer and microvessel development, (c) interconnection between neighboring microvessels originated elementary loops, which encircled vein wall components and formed papillae. The encircling ECs formed the papillary cover, and the encircled component formed the core. The papillae showed a similar structure to that of folds and pillars in intussusceptive angiogenesis, and (d) origin of secondary and complex loop systems by interconnection of neighboring elementary loops and by splitting of papillae by new loops, with abundant papillary development. In conclusion, the results support a piecemeal angiogenic mechanism in papillary formation, with association of sprouting and intussusceptive types of angiogenesis. Further studies are needed to assess whether the intravascular papillae described in several pathologic processes, including vessel tumors, such as Dabska's tumor, retiform hemangioendothelioma, and angiosarcoma, follow a similar mechanism. Anat Rec, 2017. © 2017 Wiley Periodicals, Inc. Anat Rec, 300:1781-1792, 2017. © 2017 Wiley Periodicals, Inc.