Colon Cancer Stem Cells Dictate Tumor Growth and Resist Cell Death by Production of Interleukin-4

A novel paradigm in tumor biology suggests that cancer growth is driven by stem-like cells within a tumor. Here, we describe the identification and characterization of such cells from colon carcinomas using the stem cell marker CD133 that accounts around 2% of the cells in human colon cancer. The CD133+ cells grow in vitro as undifferentiated tumor spheroids, and they are both necessary and sufficient to initiate tumor growth in immunodeficient mice. Xenografts resemble the original human tumor maintaining the rare subpopulation of tumorigenic CD133+ cells. Further analysis revealed that the CD133+ cells produce and utilize IL-4 to protect themselves from apoptosis. Consistently, treatment with IL-4Rα antagonist or anti-IL-4 neutralizing antibody strongly enhances the antitumor efficacy of standard chemotherapeutic drugs through selective sensitization of CD133+ cells. Our data suggest that colon tumor growth is dictated by stem-like cells that are treatment resistant due to the autocrine production of IL-4

Crucial role of interleukin-4 in the survival of colon cancer stem cells

Colon tumors may be maintained by a rare fraction of cancer stem-like cells (CSC) that express the cell surface marker CD133. Self-renewing CSCs exhibit relatively greater resistance to clinical cytotoxic therapies and recent work suggests that this resistance may be mediated in part by an autocrine response to the immune cytokine interleukin 4 (IL-4). Blocking IL-4 signaling can sensitize CSCs to apoptotic stimuli and increase the in vivo efficacy of cytotoxic therapy. These findings suggest that inhibitors of IL-4 signaling may offer a new therapeutic tool in colon carcinom

Disruption of the ribosomal P complex leads to stress-induced autophagy

<p>The human ribosomal P complex, which consists of the acidic ribosomal P proteins RPLP0, RPLP1, and RPLP2 (RPLP proteins), recruits translational factors, facilitating protein synthesis. Recently, we showed that overexpression of RPLP1 immortalizes primary cells and contributes to transformation. Moreover, RPLP proteins are overexpressed in human cancer, with the highest incidence in breast carcinomas. It is thought that disruption of the P complex would directly affect protein synthesis, causing cell growth arrest and eventually apoptosis. Here, we report a distinct mechanism by which cancer cells undergo cell cycle arrest and induced autophagy when RPLP proteins are downregulated. We found that absence of RPLP0, RPLP1, or RPLP2 resulted in reactive oxygen species (ROS) accumulation and MAPK1/ERK2 signaling pathway activation. Moreover, ROS generation led to endoplasmic reticulum (ER) stress that involved the EIF2AK3/PERK-EIF2S1/eIF2α-EIF2S2-EIF2S3-ATF4/ATF-4- and ATF6/ATF-6-dependent arms of the unfolded protein response (UPR). RPLP protein-deficient cells treated with autophagy inhibitors experienced apoptotic cell death as an alternative to autophagy. Strikingly, antioxidant treatment prevented UPR activation and autophagy while restoring the proliferative capacity of these cells. Our results indicate that ROS are a critical signal generated by disruption of the P complex that causes a cellular response that follows a sequential order: first ROS, then ER stress/UPR activation, and finally autophagy. Importantly, inhibition of the first step alone is able to restore the proliferative capacity of the cells, preventing UPR activation and autophagy. Overall, our results support a role for autophagy as a survival mechanism in response to stress due to RPLP protein deficiency.</p

Autocrine production of interleukin-4 and interleukin-10 is required for survival and growth of thyroid cancer cells

Although CD95 and its ligand are expressed in thyroid cancer, the tumor cell mass does not seem to be affected by such expression. We have recently shown that thyroid carcinomas produce interleukin (IL)-4 and IL-10, which promote resistance to chemotherapy through the up-regulation of Bcl-xL. Here, we show that freshly purified thyroid cancer cells were completely refractory to CD95-induced apoptosis despite the consistent expression of Fas-associated death domain and caspase-8. The analysis of potential molecules able to prevent caspase-8 activation in thyroid cancer cells revealed a remarkable up-regulation of cellular FLIPL (cFLIPL) and PED/PEA-15, two antiapoptotic proteins whose exogenous expression in normal thyrocytes inhibited the death-inducing signaling complex of CD95. Additionally, small interfering RNA FLIP and PED antisense sensitized thyroid cancer cells to CD95-mediated apoptosis. Exposure of normal thyrocytes to IL-4 and IL-10 potently up-regulated cFLIP and PED/PEA-15, suggesting that these cytokines are responsible for thyroid cancer cell resistance to CD95 stimulation. Moreover, treatment with neutralizing antibodies against IL-4 and IL-10 or exogenous expression of suppressor of cytokine signaling-1 of thyroid cancer cells resulted in cFLIP and PED/PEA-15 down-regulation and CD95 sensitization. More importantly, prolonged IL-4 and IL-10 neutralization induced cancer cell growth inhibition and apoptosis, which were prevented by blocking antibodies against CD95 ligand. Altogether, autocrine production of IL-4 and IL-10 neutralizes CD95-generated signals and allows survival and growth of thyroid cancer cells. Thus, IL-4 and IL-10 may represent key targets for the treatment of thyroid cancer. \uc2\ua92006 American Association for Cancer Research

Internkommunikation av ett varumärke - En jämförande studie inom Norrköpings kommun

Norrköpings kommun är en organisation med många verksamhetsområden. Att få alla verksamheter att uppfatta och ta till sig samma värdegrund kan vara svårt, men viktigt om varumärket ska kommuniceras korrekt utåt av alla verksamheter. En medarbetarenkät som gjorts av kommunen ligger till grund för studien då denna visar på medarbetarna inte tänker på sin arbetsplats som en del av kommun. Därför vidtogs åtgärder för att öka kännedomen om varumärket Norrköpings kommun med hjälp av kommunikationsplattformen  Let’s Create Norrköping. Kommunen vet dock ännu inte om medarbetarna har tagit till sig informationen och vad de tycker om varumärket. För att undersöka detta har en fallstudie genomförts som syftar till att undersöka hur varumärket Norrköping kommuniceras genom Let´s Create Norrköping samt hur det uppfattas av medarbetarna på Norrköpings kommun. För att besvara syftet har en datainsamling gjorts vilken utgörs av intervjuer i två delar. I den första delen utfördes en intervju med varumärkesutvecklare Tina Vennerholm. Den gick ut på att klargöra budskapet med Let´s Create Norrköping och bakgrunden till kommunikationsplattformen. Den andra delen genomfördes med fem medarbetare på Norrköpings kommun och gick ut på att undersöka deras uppfattning av varumärket och hur de tar emot information på sina respektive arbetsplatser. De slutsatser som kan dras utifrån studien är att medarbetarna saknar kommunens närvaro på deras respektive arbetsplatser men att de överlag är positivt inställda till kommunikationsplattformen Let´s Create Norrköping. Det framgår dock att de ej fått någon kännedom om Let´s Create Norrköping internt utan att den information de fått kommer från den externa marknadsföring de tar del av i form av invånare i Norrköping. Detta leder till att medarbetarna har svårt att implementera och förstå Let´s Create Norrköpings budskap i sitt arbete. Rekommendationerna som ges till Norrköpings kommun är att synas mer på de olika arbetsplatserna, visa upp vilka från kommunen som ansvariga för kommunikation och liknande. Detta för att medarbetarna ska få en personlig koppling till källan för informationen och på så sätt kunna ta till sig och acceptera den lättare. Medarbetarna har mycket positiva bilder av Norrköping som stad. En rekommendation blir därför att kommunen ska arbeta med att tydligare länka sitt arbete till de olika positiva delar i Norrköpings stad. Detta för att engagera och motivera medarbetarna och få dem att se sin koppling till Norrköpings kommun och det arbete som kommunen utför i staden Norrköping.The municipality of Norrköping is a large organization with lots of different areas of expertise. To make sure that the values are the same throughout the organization is a heavy task but important if you want the brand to be communicated in the right way in all instances of the organization. An internal review of the employees opinions takes place every other year with the last one taking place in 2013. The results from the review made the municipality of Norrköping realise that they needed to increase their internal work with brand knowledge. The municipality of Norrköping took action and created a platform of communications called Let´s Create Norrköping. The problem they stand before now is that they're not sure if the employees have interpreted the information the correct way regarding the brand. This case study aims to investigate how the brand Norrköping is communicated throughout the plattform Let´s Create Norrköping and how the employees perceives the brand of the municipality of Norrköping. To answer the cause of the report a data collection has been made with interviews divided into two parts. The first part consists of an interview with Tina Vennerholm, brand developer at the communications department of the municipality of Norrköping. The main objective of this interviews was to conclude the main objectives of the platform Let´s Create Norrköping. The second part was conducted with five employees within the organization of the municipality of Norrköping. It was conducted to conclude their point of view of the platform Let´s Create Norrköping. Conclusions that can be drawn from the study include that the employees lack the presence of the representatives of the municipality of Norrköping at their working places. The employees have a positive opinion regarding the platform Let´s Create Norrköping although they have not received any internal information regarding the plattform. The reason to their positive opinions ought to be that they have been affected by external marketing regarding the plattform. This leads to the employees having a hard time with implementing the message of the platform in their work. Recommendations given to the municipality of Norrköping is to be visible at the various working places, to show the worker which people who are responsible for the communication at their workplace. to give the employees a personal connection to the source of the information that is given which makes it easier for the worker to accept and implement the information. The employees all have positive connections to the city of Norrköping. That is why the conductors of this study recommend that the municipality of Norrköping should make a connection to the city with the work that is made by the employees on all the different areas in the organization. This is to engage and motivate the employees and make them see and understand the connection between the city and the organization and the part that they play in it