The
cancer stem cell
(
CSC
) model has recently been approached also in renal cell carcinoma (RCC). A few populations of putative renal tumor-initiating cells (TICs) were identified, but they are ...indifferently understood; however, the first and most thoroughly investigated are CD105-positive
CSCs
. The article presents a detailed comparison of all renal
CSC
-like populations identified by now as well as their presumable origin. Hypoxic activation of hypoxia-inducible factors (HIFs) contributes to tumor aggressiveness by multiple molecular pathways, including the governance of immature stem cell-like phenotype and related epithelial-to-mesenchymal transition (EMT)/de-differentiation, and, as a result, poor prognosis. Due to intrinsic von Hippel-Lindau protein (pVHL) loss of function,
clear-cell
RCC (ccRCC) develops unique pathological intra-cellular pseudo-hypoxic phenotype with a constant HIF activation, regardless of oxygen level. Despite satisfactory evidence concerning pseudo-hypoxia importance in RCC biology, its influence on putative renal
CSC
-like largely remains unknown. Thus, the article discusses a current knowledge of HIF-1α/2α signaling pathways in the promotion of undifferentiated tumor phenotype in general, including some experimental findings specific for pseudo-hypoxic ccRCC, mostly dependent from HIF-2α oncogenic functions. Existing gaps in understanding both putative renal
CSCs
and their potential connection with hypoxia need to be filled in order to propose breakthrough strategies for RCC treatment.
This study was designed to analyze the impact of multi-targeted tyrosine kinase inhibitors on the cancer stem cell subpopulation in renal cell cancer. The second objective was to evaluate the effect ...of tumor growth inhibition related to a tumor niche factor - oxygen deprivation - as hypoxia develops along with the anti-angiogenic activity of tyrosine kinase inhibitors in renal tumors. Cells were treated with tyrosine kinase inhibitors, sunitinib, sorafenib and axitinib, in 2D and 3D culture conditions. Cell proliferation along with drug toxicity were evaluated. It was shown that the proliferation rate of cancer stem cells was decreased by the tyrosine kinase inhibitors. The efficacy of the growth inhibition was limited by hypoxic conditions and 3D intratumoral cell-cell interactions. We conclude that understanding the complex molecular interaction feedback loops between differentiated cancer cells, cancer stem cells and the tumor microenvironment in 3D culture should aid the identification of novel treatment targets and to evalute the efficacy of renal cancer therapies. Cell-cell interaction may represent a critical microenvironmental factor regulating cancer stem cell self-renewal potential, enhancing the stem cell phenotype and limiting drug toxicity. At the same time the role of hypoxia in renal cancer stem cell biology is also significant.
The last few years have brought advances in the understanding of the molecular biology of metastatic clear cell renal cell carcinoma (RCC). Both preclinical research and clinical trials brought ...together results from the latest advancements in RCC diagnostic and staging. Understanding of the complex molecular alterations involved in the development and progression of RCC enables development of immunohistochemical and genetic diagnostic tools and is also opening the doors for experimental targeted therapies. At the same time, improvements of medical and molecular imaging improves the sensitivity and specificity of metastatic disease diagnosis. Moreover, independent validation of molecular profiles across high-throughput platforms, methods, laboratories and cancer populations has recently been successfully performed in RCC. Generation of informative, clinical diagnostic tools is likely to contribute to development of novel personalized diagnostic and treatment protocols and ensure prolonged survival of RCC patient in the near future.
Novel experimental conditions of cancer cell line culture have evolved throughout the recent years, with significantly growing interest in xeno-free, serum-free and three-dimensional culture ...variants. The choice of proper culture media may enable to mimic tumor microenvironment and promotion of cancer stem cells proliferation. To assess whether stem-like phenotype inducing media may be applied in renal cancer stem cell research, we performed a widespread screening of 13 cell culture media dedicated for mesenchymal cells, stem cells as well as mesenchymal stem cells. We have also screened extracellular matrix compounds and selected optimal RCC 3D—ECM supported culture model. Our results revealed that 786-O as well as HKCSCs cell line cultures in xeno-free media (NutriStem/StemXvivo) and laminin coated plates provide a useful tool in RCC cancer biology research and at the same time enable effective drug toxicity screening. We propose bio-mimic 3D RCC cell culture model with specific low-serum and xeno-free media that promote RCC cell viability and stem-like phenotype according to the tested genes encoding stemness factors including E-cadherin, N-cadherin,
HIF1
,
HIF2
,
VEGF
,
SOX2
,
PAX2
and
NESTIN
.
Everolimus is a mTOR inhibitor that demonstrates antitumor and antiangiogenic activities. In a randomized Phase III trial, patients with metastatic renal cell carcinoma who progressed on ...sunitinib/sorafenib were treated with everolimus and showed significant improvement in progression-free survival compared with best supportive care. Novel approaches in treatment are expected to ensure less toxic therapies and increase efficacy of everolimus. To provide a new perspective for mTOR inhibitor research and therapy, we discuss renal cell carcinoma cancer stem cells as a potential target for mTOR inhibitors and present new concepts on emerging antiangiogenic therapies. Finally, we point why systems biology approach with reverse molecular engineering may also contribute to the field of drug discovery in renal cell carcinoma.
The aim of this study was to compare effect of everolimus on growth of different renal cell carcinoma (RCC) populations and develop experimental design to measure the early response of everolimus in ...clear cell RCC (ccRCC) cell lines including renal cancer stem cells. Effect of everolimus on RCC cell lines which include primary (786-0) and metastatic (ACHN) RCC cell lines as well as heterogenous populations of tumor cells of different histological RCC subtypes (clear cell RCC and papillary RCC) was measured when treated with everolimus in the range of 1–9 µM. Gene expression profiling using microarray was performed to determine the early response to everolimus in ccRCC cell lines after optimizing concentration of drug. Gene Set Enrichment Analysis (GSEA) was done which mainly focused on basic genes related to mTOR, hormonal and metabolic pathways. Everolimus acts on RCC cells in a dose—dependent manner. In all examined cell lines IC50 dose was possible to calculate after the third day of treatment. In ccRCC lines (parental and stem cell) everolimus changes expression of mTOR complexes elements and elements of related pathways when treated with optimized doses of drug. Characteristic expression profile for ccRCC cells at an early exposure time to everolimus is to elucidate. Wevarie include some basic observations derived from data analysis in the context of mechanism of action of drug with a view to better understand biology of renal cancer cells.
Abstract Abnormalities in pain perception are a part of the clinical picture in Parkinson’s disease (PD) and belong to the category of non-motor symptoms. Two groups of patients were included in this ...study: (i) an experimental group of 36 patients with PD who were eligible for subthalamic deep brain stimulation (the experimental group EG) and (ii) a control group (CG) of 34 patients with a space-occupying lesion who were admitted for a framed stereotactic biopsy. Stereotactic frame fixation was used in both groups as a nociceptive stimulus. All participants were assessed for pain perception with two kinds of visual analogue scales (VAS) (a non-color VAS ncVAS and a color VAS cVAS) immediately after the stimulus (EG – ncVAS 1 and cVAS 1; CG – ncVAS 3 and cVAS 3) and 24 hours later (EG – ncVAS 2 and cVAS 2; CG – ncVAS 4 and cVAS 4). The means for the two pain scores assessed directly after frame fixation were 3.59 (ncVAS 1) and 3.06 (cVAS 1) for patients in the EG, while the mean ncVAS was 3, and the mean cVAS 3 was 6.1 for those in the CG. The pain intensity was significantly lower for patients with PD (EG) compared to those in the CG for both ncVAS and cVAS ( p < 0.05 for each measure). The mean pain scores for ncVAS and cVAS measured 24 hours after the procedure were 3.18 and 2.79 for patients with PD (EG) and 6.10 and 5.77 for those in the CG, respectively. Pain intensity measured 24 hours after the procedure was significantly lower in those with PD (EG) compared to the CG. This study has demonstrated that pain perception in patients with PD is significantly lower than pain perception in non-parkinsonian patients.
PDF
