WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics

Prostate cancer cells with stem cell characteristics were identified in human prostate cancer cell lines by their ability to form from single cells self-renewing prostaspheres in non-adherent cultures. Prostaspheres exhibited heterogeneous expression of proliferation, differentiation and stem cell-associated makers CD44, ABCG2 and CD133. Treatment with WNT inhibitors reduced both prostasphere size and self-renewal. In contrast, addition of Wnt3a caused increased prostasphere size and self-renewal, which was associated with a significant increase in nuclear Β-catenin, keratin 18, CD133 and CD44 expression. As a high proportion of LNCaP and C4-2B cancer cells express androgen receptor we determined the effect of the androgen receptor antagonist bicalutamide. Androgen receptor inhibition reduced prostasphere size and expression of PSA, but did not inhibit prostasphere formation. These effects are consistent with the androgen-independent self-renewal of cells with stem cell characteristics and the androgen-dependent proliferation of transit amplifying cells. As the canonical WNT signaling effector Β-catenin can also associate with the androgen receptor, we propose a model for tumour propagation involving a balance between WNT and androgen receptor activity. That would affect the self-renewal of a cancer cell with stem cell characteristics and drive transit amplifying cell proliferation and differentiation. In conclusion, we provide evidence that WNT activity regulates the self-renewal of prostate cancer cells with stem cell characteristics independently of androgen receptor activity. Inhibition of WNT signaling therefore has the potential to reduce the self-renewal of prostate cancer cells with stem cell characteristics and improve the therapeutic outcome.Peer reviewe

Inflammatory response gene polymorphisms and their relationship with colorectal cancer risk

<p>Abstract</p> <p>Backgroud</p> <p>Patients with chronic inflammatory bowel disease (IBD) are at an increased risk of colorectal cancer (CRC) and it is estimated that one in six persons diagnosed with IBD will develop CRC. This fact suggests that genetic variations in inflammatory response genes may act as CRC disease risk modifiers.</p> <p>Methods</p> <p>In order to test this hypothesis we investigated a series of polymorphisms in 6 genes (NOD2, DLG5, OCTN1, OCTN2, IL4, TNFα) associated with the inflammatory response on a group of 607 consecutive newly diagnosed colorectal cancer patients and compared the results to controls (350 consecutive newborns and 607 age, sex and geographically matched controls).</p> <p>Results</p> <p>Of the six genes only one polymorphism in TNFα(-1031T/T) showed any tendency to be associated with disease risk (64.9% for controls and 71.4% for CRC) which we further characterized on a larger cohort of CRC patients and found a more profound relationship between the TNFα -1031T/T genotype and disease (64.5% for controls vs 74.7% for CRC cases above 70 yrs). Then, we investigated this result and identified a suggestive tendency, linking the TNFα -1031T/T genotype and a previously identified change in the CARD15/NOD2 gene (OR = 1.87; p = 0,02 for CRC cases above 60 yrs).</p> <p>Conclusion</p> <p>The association of polymorphisms in genes involved in the inflammatory response and CRC onset suggest that there are genetic changes capable of influencing disease risk in older persons.</p

The VEGF -634G>C promoter polymorphism is associated with risk of gastric cancer

<p>Abstract</p> <p>Background</p> <p>Both TGF-β1 and VEGF play a critic role in the multiple-step process of tumorgenesis of gastric cancer. Single nucleotide polymorphisms (SNPs) of the <it>TGFB1 </it>and <it>VEGF </it>genes have been associated with risk and progression of many cancers. In this study, we investigated the association between potentially functional SNPs of these two genes and risk of gastric cancer in a US population.</p> <p>Methods</p> <p>The risk associated with genotypes and haplotypes of four <it>TGFB1 </it>SNPs and four <it>VEGF </it>SNPs were determined by multivariate logistic regression analysis in 171 patients with gastric cancer and 353 cancer-free controls frequency-matched by age, sex and ethnicity.</p> <p>Results</p> <p>Compared with the <it>VEGF</it>-634GG genotype, the -634CG genotype and the combined -634CG+CC genotypes were associated with a significantly elevated risk of gastric cancer (adjusted OR = 1.88, 95% CI = 1.24-2.86 and adjusted OR = 1.56, 95% CI = 1.07-2.27, respectively). However, none of other <it>TGFB1 </it>and <it>VEGF </it>SNPs was associated with risk of gastric cancer.</p> <p>Conclusion</p> <p>Our data suggested that the <it>VEGF</it>-634G>C SNP may be a marker for susceptibility to gastric cancer, and this finding needs to be validated in larger studies.</p

Characterization of colon cancer cells: a functional approach characterizing CD133 as a potential stem cell marker

<p>Abstract</p> <p>Background</p> <p>Isolation and characterization of tumourigenic colon cancer initiating cells may help to develop novel diagnostic and therapeutic procedures.</p> <p>Methods</p> <p>We characterized a panel of fourteen human colon carcinoma cell lines and their corresponding xenografts for the surface expression of potential stem cell markers CD133, CD24, CD44, CDCP1 and CXCR4. In five cell lines and nine xenografts, mRNA expression of these markers was determined. Tumour growth behaviour of CD133+, CD133- and unsorted SW620 cells was evaluated <it>in vivo</it>.</p> <p>Results</p> <p>All five putative stem cell markers showed distinct expression patterns in the tumours examined. Two patient-derived cell lines highly expressed CD133 (> 85% of positive cells) and three other cell lines had an expression level of about 50% whereas in long-term culture based models CD133 expression ranged only from 0 to 20%. In 8/14 cell lines, more than 80% of the cells were positive for CD24 and 11/14 were over 70% positive for CD44. 10/14 cell lines expressed CDCP1 on ≥ 83% of cells. CXCR4 expression was determined solely on 94 L and SW480.</p> <p>Analyses of the corresponding xenografts revealed a significant reduction of cell numbers expressing the investigated surface markers and showed single cell fractions expressing up to three markers simultaneously.</p> <p>Statistical analysis revealed that the CXCR4 mRNA level correlates negatively with the protein expression of CD133, CD44, CD24 and CDCP1 in cell lines and xenografts.</p> <p>A lower differentiation grade of donor material correlated with a higher CDCP1 mRNA expression level in the respective tumour model.</p> <p><it>In vivo </it>growth behaviour studies of SW620 revealed significantly higher take rates and shorter doubling times in the tumour growth of CD133 positive subclones in comparison to the unsorted cell line or CD133 negative subclones.</p> <p>Conclusions</p> <p>Our data revealed correlations in the expression of surface markers CD44 and CD24 as well as CD44 and CDCP1 and strongly suggest that CD133 is a stem cell marker within our colon carcinoma panel. Further studies will elucidate its role as a potential therapeutic target.</p

Transforming growth factor-β in breast cancer: too much, too late

The contribution of transforming growth factor (TGF)β to breast cancer has been studied from a myriad perspectives since seminal studies more than two decades ago. Although the action of TGFβ as a canonical tumor suppressor in breast is without a doubt, there is compelling evidence that TGFβ is frequently subverted in a malignant plexus that drives breast cancer. New knowledge that TGFβ regulates the DNA damage response, which underlies cancer therapy, reveals another facet of TGFβ biology that impedes cancer control. Too much TGFβ, too late in cancer progression is the fundamental motivation for pharmaceutical inhibition

Weak signals and wild cards in water and sanitation services : exploring an approach for water utilities

Weak signals and wild cards are used to scan the environment and make systems more sensitive to emerging changes. In this paper, the applicability of weak signals and wild cards is experimented in a case of a highly reliable and conservative sector, water and sanitation services. The aim is to explore an approach suitable for water utilities. The paper discusses different theoretical and methodological approaches to weak signals and wild cards, and reflects these in relation to the chosen approach. It is argued that the process of weak signals and wild cards can serve as a communication and reflection exercise for an organisation like a water utility. Furthermore, incorporating weak signals and wild cards can be an essential part in futures thinking, challenge prevailing mental models, and make systems more open to sense and learn from their environment. It is recommended for water utilities to apply a loose approach on weak signals and wild cards and embed it as a part of their organisational culture. However, it should be remembered that the approach should always be chosen to match the overall objectives and context.Peer reviewe