Dairy vs beef production - expert views on welfare of cattle in common food production systems.

Consumers' views and concerns about the welfare of farm animals may play an important role in their decision to consume dairy, meat and/or plants as their primary protein source. As animals are killed prematurely in both dairy and beef industries, it is important to quantify and compare welfare compromises in these two sectors before the point of death. Seventy world-leading bovine welfare experts based in 23 countries were asked to evaluate the likelihood of a bovine to experience 12 states of potential welfare concern, inspired by the Welfare Quality® protocol. The evaluation focused on the most common beef and dairy production systems in the experts' country and was carried out separately for dairy/beef calves raised for red meat, dairy/beef calves raised for veal, dairy/beef calves raised as a replacement, and for dairy/beef cows. The results show experts rated the overall likelihood of a negative welfare state (i.e. welfare risk) to be higher in animals from dairy herds than from beef herds, for all animal categories, regardless of whether they were used to produce milk, red meat or veal. These findings suggest that consuming food products derived from common dairy production systems (dairy or meat) may be more harmful to the welfare of animals than consuming products derived from common beef production systems (i.e. from animals solely raised for their meat). Raising awareness about the linkage between dairy and meat production, and the toll of milk production on the welfare state of animals in the dairy industry, may encourage a more sustainable and responsible food consumption.

Soiling of Pig Pens: A Review of Eliminative Behaviour.

This is a comprehensive review on the pigs' normal eliminatory behaviour (i.e., defaecation and urination) and pen soiling. This review is aimed primarily at solving issues with pen soiling in current systems, and ultimately at the future design of a well-functioning pig toilet, which we intend to elaborate on in a subsequent publication. In this paper, first, normal elimination is described in relation to what is known about its phylogeny, ontogeny, causation, and function, i.e., according to Tinbergen's four why questions concerning animal behaviour. Then, pen soiling is described as if it were a medical disorder, highlighting its importance, aetiology, symptoms, diagnosis, pathogenesis, treatment, and prevention. Due to its negative consequences in terms of animal welfare, health, workload, and environmental emissions, possible methods to address pen soiling in current systems are described. Probably, pigs do not choose a specific place to eliminate but rather choose the most comfortable place for resting, and avoid eliminating there. We identified four main strategies to reduce pen soiling: (1) reducing the suitability of the designated elimination area to be used for other functions, especially resting or thermoregulation; (2) improving the suitability of other functional areas in the pen to be used for their specific function, such as resting and activity; (3) reducing the suitability of other functional areas to be used for elimination; and (4) improving the suitability of the elimination area for elimination. These prevention strategies and the encompassing disease framework provide a structured approach to deal with pen soiling in existing systems and to support the future design, development, and implementation of a well-functioning pig toilet that can help to achieve some of the main goals of modern pig production, namely reducing environmental emissions as well as substantially improving pig welfare.

Broiler welfare trade-off: A semi-quantitative welfare assessment for optimised welfare improvement based on an expert survey.

In order to support decision making on how to most effectively improve broiler welfare an innovative expert survey was conducted based on principles derived from semantic modelling. Twenty-seven experts, mainly broiler welfare scientists (n = 20; and 7 veterinarians), responded (response rate 38%) by giving welfare scores (GWS, scale 0-10) to 14 benchmarking housing systems (HSs), and explaining these overall scores by selecting, weighing and scoring main welfare parameters, including both input and output measures. Data exploration followed by REML (Linear Mixed Model) and ALM (Automatic Linear Modelling) analyses revealed 6 clusters of HSs, sorted from high to low welfare, i.e. mean GWS (with superscripts indicating significant differences): 1. (semi-natural backyard) Flock (8.8a); 2. Nature (7.7ab), Label Rouge II (7.4ab), Free range EU (7.2ab), Better Life (7.2ab); 3. Organic EU (7.0bc), Freedom Food (6.2bc); 4. Organic US (5.8bcd), Concepts NL (5.6abcdef), GAP 2 (4.9bcd); 5. Conventional EU (3.7de), Conventional US (2.9ef), Modern cage (2.9abcdef); 6. Battery cage (1.3f). Mean weighting factors (WF, scale 0-10) of frequently (n> = 15) scored parameters were: Lameness (8.8), Health status (8.6), Litter (8.3), Density (8.2), Air quality (8.1), Breed (8.0), Enrichment (7.0) and Outdoor (6.6). These did not differ significantly, and did not have much added value in explaining GWS. Effects of Role (Scientist/Vet), Gender (M/F) and Region (EU/non-EU) did not significantly affect GWS or WF, except that women provided higher WF than men (7.2 vs 6.4, p<0.001). The contribution of welfare components to overall welfare has been quantified in two ways: a) using the beta-coefficients of statistical regression (ALM) analyses, and b) using a semantic-modelling type (weighted average) calculation of overall scores (CalcWS) from parameter level scores (PLS) and WF. GWS and CalcWS were highly correlated (R = ~0.85). CalcWS identified Lameness, Health status, Density, Breed, Air quality and Litter as main parameters contributing to welfare. ALM showed that the main parameters which significantly explained the variance in GWS based on all PLS, were the output parameter Health status (with a beta-coefficient of 0.38), and the input parameters (stocking) Density (0.42), Litter (0.14) and Enrichment (0.27). The beta-coefficients indicated how much GWS would improve from 1 unit improvement in PLS for each parameter, thus the potential impact on GWS ranged from 1.4 welfare points for Litter to 4.2 points for Density. When all parameters were included, 81% of the variance in GWS was explained (77% for inputs alone; 39% for outputs alone). From this, it appears that experts use both input and output parameters to explain overall welfare, and that both are important. The major conventional systems and modern cages for broilers received low welfare scores (2.9-3.7), well below scores that may be considered acceptable (5.5). Also, several alternatives like GAP 2 (4.9), Concepts NL (5.6), Organic US (5.8) and Freedom Food (6.2) are unacceptable, or at risk of being unacceptable due to individual variation between experts and farms. Thus, this expert survey provides a preliminary semi-quantified decision-support tool to help determine how to most effectively improve broiler welfare in a wide range of HSs.

Expert opinion on metal chains and other indestructible objects as proper enrichment for intensively-farmed pigs.

EC Directive 2001/93 requires that all pigs have access to proper investigation and manipulation materials. Intensively farmed pigs in Europe are frequently provided with a short metal chain with or without an indestructible object attached to the chain. To date authorities are regarding this as proper enrichment, perhaps with (in)direct reference to the RICHPIG model as a justification. However, it has become increasingly clear that the chains do not provide proper enrichment, and that adding an indestructible object to the end of the chain may even reduce rather than improve pig welfare. To test this hypothesis an expert survey was conducted containing 26 more or less compound questions. On a scale from 0 to 10 experts specified their level of agreement with the hypothesis, the prevalence and welfare scores of nine indestructible enrichment materials. In total 36 experts, mostly pig-welfare scientists, responded (response rate: 39%). Indestructible objects are less prevalent in countries that provide straw (like Sweden and the UK) and outside the EU (US). They are more prevalent in the Netherlands, Belgium, France and Finland, while the prevalence seems to be low in Spain. Balls, wood and pipes were provided most frequently: hard wood especially in the UK (as specified in farm assurance); indestructible balls and pipes in Germany and the Netherlands. The experts' score for agreement with the hypothesis was only 4.6 on average (scale 0-10; n = 25). Enrichment materials, ranked from high to low welfare score, were grouped in 5 significance levels as indicated by different superscripts based on Wilcoxon signed rank tests: Branched chains (5.1a), Chain on the floor (4.4b), Hard wood (3.7bc), Pipe (3.5c), Bare chain (3.3c), Short chain (3.1d), Small ball (2.8d), Big ball (2.5d), and Chain hanging too high (1.3e). Branched chains scored significantly better than all other indestructible materials and its welfare score (5.1 on average) was close to the pre-defined level of acceptability (5.5 on a scale from 0, worst, to 10, best). The welfare benefits of adding balls, pipes or hard wood to the metal chain were marginal, and well below what the experts considered acceptable enrichment. The branched-chains design, by contrast, appears to be the most viable alternative. It involves providing a longer chain, i.e. with the free end reaching to floor level, adding 'branches', i.e. several short chains ending at the nose height of the pigs, and providing more chains per pen (i.e. 1 branched chain per 5 pigs). Branched chains should be implemented widely and in the short term as a first step towards, and benchmark for, providing proper enrichment to intensively-farmed pigs.

Selective pharmacological inhibitors of HDAC6 reveal biochemical activity but functional tolerance in cancer models.

Our study investigates the biochemical and functional impact of selective histone deacetylase 6 (HDAC6) inhibitors, a promising class of novel therapeutics, in several cancer models. Selective HDAC6 inhibitors (Tubathian A, Tubastatin A, Tubacin and Ricolinostat) and a non-selective HDAC inhibitor (Vorinostat) were evaluated on cancer cell lines derived from multiple tumour types in both an in vitro and in vivo setting as potential cancer therapeutics. Selective HDAC6 inhibitors resulted in α-tubulin acetylation with no impact on histone acetylation but failed to show any anti-cancer properties. Only the use of high concentrations of selective HDAC6 inhibitors resulted in co-inhibition of other HDAC enzymes and consequently in reduced growth, migratory and/or invasive activity of cancer cells in vitro as well as in vivo. The specificity of HDAC6 inhibition was confirmed using a CRISPR/Cas9 knockout cell line. Our results suggest that selective HDAC6 inhibitors may fall short as potential single agent anti-cancer drugs and prove that many previous data regarding this promising class of compounds need to be interpreted with great care due to their use in high concentrations resulting in low selectivity and potential off-target effects.

Heterocellular 3D scaffolds as biomimetic to recapitulate the tumor microenvironment of peritoneal metastases in vitro and in vivo.

Peritoneal metastasis is a major cause of death and preclinical models are urgently needed to enhance therapeutic progress. This study reports on a hybrid hydrogel-polylactic acid (PLA) scaffold that mimics the architecture of peritoneal metastases at the qualitative, quantitative and spatial level. Porous PLA scaffolds with controllable pore size, geometry and surface properties are functionalized by type I collagen hydrogel. Co-seeding of cancer-associated fibroblasts (CAF) increases cancer cell adhesion, recovery and exponential growth by in situ heterocellular spheroid formation. Scaffold implantation into the peritoneum allows long-term follow-up (>14 weeks) and results in a time-dependent increase in vascularization, which correlates with cancer cell colonization in vivo. CAF, endothelial cells, macrophages and cancer cells show spatial and quantitative aspects as similarly observed in patient-derived peritoneal metastases. CAF provide long-term secretion of complementary paracrine factors implicated in spheroid formation in vitro as well as in recruitment and organization of host cells in vivo. In conclusion, the multifaceted heterocellular interactions that occur within peritoneal metastases are reproduced in this tissue-engineered implantable scaffold model.

Glucocorticoids indirectly decrease colon cancer cell proliferation and invasion via effects on cancer-associated fibroblasts.

Cancer-associated fibroblasts (CAFs) support cancer growth, invasion, and metastasis. Glucocorticoids (GCs), drugs often administered together with chemotherapy, are steroidal ligands of the glucocorticoid receptor (GR), a transcription factor which upon activation regulates expression of multiple genes involved in suppression of inflammation. We have previously shown that in dexamethasone (Dex)-treated CAFs derived from colon cancer, production and secretion of several factors related to cancer progression, such as tenascin C (TNC) and hepatocyte growth factor (HGF), were strongly suppressed. In this study we show that GCs can neutralize the cancer cell-promoting properties of CAFs. Conditioned medium from solvent-treated CAFs (CMCTRL) stimulates proliferation, motility and stretched morphotype of GR-deficient HCT8/E11 colon cancer cells. Yet, HCT8/E11 proliferation and stretched morphotype are impaired upon treatment with conditioned medium from Dex-treated CAFs (CMDEX), but HCT8/E11 cell migration is slightly increased under these conditions. Moreover, expression and potential activity of MMP-2 is also reduced in CMDEX compared with CMCTRL. These combined in vitro results concur with the results from in vivo chick chorioallantoic membrane assays, where the co-cultures of CAFs with colon cancer cells displayed impaired tumor formation and cancer cell invasion due to Dex administration. Combined, GC treatment influences cancer cell behavior indirectly through effects on CAFs.

Radiotherapy-Activated Cancer-Associated Fibroblasts Promote Tumor Progression through Paracrine IGF1R Activation.

Preoperative radiotherapy (RT) is a mainstay in the management of rectal cancer, a tumor characterized by desmoplastic stroma containing cancer-associated fibroblasts (CAF). Although CAFs are abundantly present, the effects of RT to CAF and its impact on cancer cells are unknown. We evaluated the damage responses of CAF to RT and investigated changes in colorectal cancer cell growth, transcriptome, metabolome, and kinome in response to paracrine signals emerging from irradiated CAF. RT to CAF induced DNA damage, p53 activation, cell-cycle arrest, and secretion of paracrine mediators, including insulin-like growth factor-1 (IGF1). Subsequently, RT-activated CAFs promoted survival of colorectal cancer cells, as well as a metabolic switch favoring glutamine consumption through IGF1 receptor (IGF1R) activation. RT followed by IGF1R neutralization in orthotopic colorectal cancer models reduced the number of mice with organ metastases. Activation of the downstream IGF1R mediator mTOR was significantly higher in matched (intrapatient) samples and in unmatched (interpatient) samples from rectal cancer patients after neoadjuvant chemoradiotherapy. Taken together, our data support the notion that paracrine IGF1/IGF1R signaling initiated by RT-activated CAF worsens colorectal cancer progression, establishing a preclinical rationale to target this activation loop to further improve clinical responses and patient survival.Significance: These findings reveal that paracrine IGF1/IGF1R signaling promotes colorectal cancer progression, establishing a preclinical rationale to target this activation loop. Cancer Res; 78(3); 659-70. ©2017 AACR.

A 'meta-analysis' of effects of post-hatch food and water deprivation on development, performance and welfare of chickens.

A 'meta-analysis' was performed to determine effects of post-hatch food and water deprivation (PHFWD) on chicken development, performance and welfare (including health). Two types of meta-analysis were performed on peer-reviewed scientific publications: a quantitative 'meta-analysis' (MA) and a qualitative analysis (QA). Previously reported effects of PHFWD were quantified in the MA, for variables related to performance, mortality and relative yolk sac weight. The QA counted the number of studies reporting (non-)significant effects when five or more records were available in the data set (i.e. relative heart, liver and pancreas weight; plasma T3, T4 and glucose concentrations; relative duodenum, jejunum and ileum weight; duodenum, jejunum and ileum length; and villus height and crypt depth in duodenum, jejunum and ileum). MA results indicated that 24 hours of PHFWD (i.e. ≥12-36 hours) or more resulted in significantly lower body weights compared to early-fed chickens up to six weeks of age. Body weights and food intake were more reduced as durations of PHFWD (24, 48, 72, ≥84 hours) increased. Feed conversion rate increased in chickens up to 21 and 42 days of age after ≥84 hours PHFWD in comparison with chickens fed earlier. Total mortality at day 42 was higher in chickens after 48 hours PHFWD compared to early fed chickens or chickens after 24 hours PHFWD. First week mortality was higher in chickens after ≥84 hours PHFWD than in early fed chickens. The MA for relative yolk sac weight was inconclusive for PHFWD. The QA for plasma T3, T4 and glucose concentrations indicated mainly short-term decreases in T3 and glucose in PHFWD chickens compared to early fed chickens, and no effects of PHFWD on T4 concentrations. Relative weights of liver, pancreas and heart were lower after PHFWD, but only in the first week of life. A retarded development of gut segments (duodenum, jejunum and ileum) was found in the first week of life, measured as shorter, lower relative weight, and lower villus height and crypt depth. It is concluded that 48 hours (≥36-60 hours) PHFWD leads to lower body weights and higher total mortality in chickens up to six weeks of age, the latter suggesting compromised chicken welfare, but effects of PHFWD on organ development and physiological status appear to be mainly short-term.

Exploration Feeding and Higher Space Allocation Improve Welfare of Growing-Finishing Pigs.

Lack of environmental enrichment and high stocking densities in growing-finishing pigs can lead to adverse social behaviors directed to pen mates, resulting in skin lesions, lameness, and tail biting. The objective of the study was to improve animal welfare and prevent biting behavior in an experiment with a 2 × 2 × 2 factorial design on exploration feeding, stocking density, and sex. We kept 550 pigs in 69 pens from 63 days to 171 days of life. Pigs were supplemented with or without exploration feeding, kept in groups of seven (1.0 m²/pig) or nine animals (0.8 m²/pig) and separated per sex. Exploration feeding provided small amounts of feed periodically on the solid floor. Skin lesion scores were significantly lower in pens with exploration feeding (p = 0.028, p < 0.001, p < 0.001 for front, middle, and hind body), in pens with high compared to low space allowance (p = 0.005, p = 0.006, p < 0.001 for front, middle and hind body), and in pens with females compared to males (p < 0.001, p = 0.005, p < 0.001 for front, middle and hind body). Males with exploration feeding had fewer front skin lesions than females with exploration feeding (p = 0.022). Pigs with 1.0 m² compared to 0.8 m² per pig had a higher daily gain of 27 g per pig per day (p = 0.04) and males compared to females had a higher daily gain of 39 g per pig per day (p = 0.01). These results indicate that exploration feeding might contribute to the development of a more welfare-friendly pig husbandry with intact tails in the near future.

Secretome analysis of breast cancer-associated adipose tissue to identify paracrine regulators of breast cancer growth.

Adipose tissue secretes a plethora of adipokines as evidenced by characterization of subcutaneous and visceral adipose tissue secretomes. However, adipose tissue composition and secretion pattern is depot and disease dependent, influencing the adipose tissue secretome. We investigated the secretome of cancer-associated adipose tissue (CAAT) explants from breast cancer patients and explored its role in breast cancer proliferation. CAAT proteins were identified by LC-MS/MS and human protein antibody arrays and stimulated proliferation of three breast cancer cell lines. Kinomics and transcriptomics of MCF-7 breast cancer cells treated with the secretome of CAAT revealed activation of Akt-, ERK- and JNK-pathways and differential expression of activator protein 1 (AP-1) and cAMP responsive element-binding protein (CREB) target genes. The cyclin-dependent kinase (CDK)4/6-inhibitor palbociclib significantly abrogated CAAT-enhanced breast cancer cell proliferation. Our work characterizes the specific breast CAAT protein secretome and reveals its pro-proliferative potency in breast cancer.

Improved synthesis and comparative analysis of the tool properties of new and existing D-ring modified (S)-blebbistatin analogs.

(S)-Blebbistatin is a widely used research tool to study myosin II, an important regulator of many motility based diseases. Its potency is too low to be of clinical relevance, but identification of analogs with enhanced potency could deliver leads for targeted pharmacotherapeutics. This, however, requires a profound insight into the structure-activity relationship of the (S)-blebbistatin scaffold. Therefore, new D-ring modified (S)-blebbistatin derivatives were prepared to extend the existing small library of analogs. These molecules were obtained via an improved synthesis pathway and their myosin II inhibitory properties were evaluated in vitro. Finally, all new and known D-ring modified (S)-blebbistatin analogs were compared and the most potent ones underwent a screening of their physicochemical properties.

Insights into the myosin II inhibitory potency of A-ring-modified (S)-blebbistatin analogs.

Myosin II is an interesting target for therapeutic intervention, as it is involved in a large number of motility-based diseases. (S)-Blebbistatin is a known micromolar inhibitor of this protein. A new series of (S)-blebbistatin derivatives with a modified A-ring was synthesized and the myosin II inhibitory properties were evaluated in vitro. In this way, we gained insight into the influence of structural modifications in this part of the scaffold on myosin II inhibitory potency. Our results indicate there are few possibilities for potency enhancement via ring A modification of the blebbistatin scaffold.

Corrigendum to The Competence of 7,8-Diacetoxy-4-Methylcoumarin and Other Polyphenolic Acetates in Mitigating the Oxidative Stress and their Role in Angiogenesis.

In the Original Research Article entitled "The Competence of 7, 8-Diacetoxy-4-methylcoumarin and other Polyphenolic Acetates in Mitigating the Oxidative Stress and their Role in Angiogenesis" Published in Current Topics in Medicinal Chemistry, 2015, Vol. 15, No. 2, on page no. 179, the order of author names was rearranged because second authorship is acceptable as they only acknowledge the first and the second authorship as per the new policies of Medical Council of India. The order of authors should be read as follows: Rini Joshi, Vishwajeet Rohil, Shvetambri Arora, Sushma Manral, Ajit Kumar, Sanjay Goel, Nivedita Priya, Prabhjoth Singh, Prija Ponnan, Suvro Chatterji, Bilikere S. Dwarakanath, Daman Saluja, Diwan S. Rawat, Ashok K. Prasad, Luciano Saso, Ekta Kohli, Anthony L. DePass, Marc E. Bracke, Virinder S. Parmar and Hanumantharao G. Raj.

ADAM-17/FHL2 colocalisation suggests interaction and role of these proteins in colorectal cancer.

FHL2 is a multifunctional scaffolding protein; its expression is associated with poor prognosis in colorectal cancer. ADAM-17 is a metalloprotease implicated in ectodomain shedding. FHL2 regulates ADAM-17 plasma membrane localisation, and FHL2 deficiency leads to decreased activity of ADAM-17 in mouse macrophages. Presence and relationship of the ADAM-17/FHL2 complex with colorectal cancer progression is unknown. We studied FHL2 and ADAM-17 expression in several colon cancer cell lines by immunocytochemistry and western blot. To highlight the interaction between both molecules, we used the Duolink® kit for proximity ligation assay on SW480 cells. We also performed proximity ligation assay on biopsies and surgical specimens of colorectal adenocarcinoma and on matched normal mucosa. Furthermore, biopsies of colorectal adenoma with matched normal mucosa were selected. For quantification, pictures of the malignant, adenomatous and normal tissues were taken. Proximity ligation assay signals were quantified. Mean numbers of proximity ligation assay signals and of proximity ligation assay signals/nucleus were calculated. All cell lines showed FHL2 immunoreactivity; strongest positivity was observed in SW480 cells. ADAM-17 was expressed in all cell lines. Proximity ligation assay signals were present in SW480 cells. Quantitative analysis revealed that the interaction between FHL2 and ADAM-17 is more frequent in malignant than in normal tissue (p = 0.005). The mean number of ADAM-17/FHL2 proximity ligation assay signals was higher in colorectal adenocarcinoma than in adenoma with low-grade dysplasia (p = 0.0004). FHL2 interacts with ADAM-17 in normal, dysplastic and malignant colon epithelial cells. Colocalisation of these proteins is more frequent in malignant than in normal and dysplastic cells, suggesting a role for ADAM-17/FHL2 complex in the development of colorectal cancer.

Discovery of (S)-3'-hydroxyblebbistatin and (S)-3'-aminoblebbistatin: polar myosin II inhibitors with superior research tool properties.

In search of myosin II inhibitors with superior research tool properties, a chemical optimization campaign of the blebbistatin scaffold was conducted in this paper. (S)-Blebbistatin is the best known small-molecule inhibitor of myosin II ATPase activity. Unfortunately, as a research tool this compound has several deficiencies: it is photolabile and (photo)toxic, has low water solubility, and its (fluorescent) precipitates interfere in (fluorescence) readouts. In view of obtaining tool compounds with improved properties, both enantiomers of a series of D-ring modified polar analogs were prepared. We identified (S)-3'-hydroxyblebbistatin (S)-2 and (S)-3'-aminoblebbistatin (S)-3 as two myosin II inhibitors with a 30-fold higher water solubility than (S)-blebbistatin. These molecules furthermore do not cause interference in (fluorescence) readouts. (S)-2 and (S)-3 thus are superior alternatives to (S)-blebbistatin as research tools to study myosin II.

When Neighbors Talk: Colon Cancer Cell Invasion and Tumor Microenvironment Myofibroblasts.

Historically, the word cancer is derived from the Latin cancer, as the red swollen arteries near a tumor reminded the physician Galenus and his fellow Romans of a red crab. Currently, cancer remains the disease to beat as it remains a leading cause of death worldwide (WHO). Tumors do not simply consist of cancer cells, as they can recruit normal cells, which will form the tumor-associated stroma. These stromal cells together with the extracellular matrix, constitute the tumor microenvironment. Reciprocal communication between tumor-associated stromal cells and cancer cells is important for the induction of epithelial-to-mesenchymal transition and invasion. A detailed knowledge of this communication can spark the development of novel therapeutic strategies aimed at tackling yet unaddressed regulators of invasion and thus metastasis. Therefore, this review will focus not only on epithelial-to-mesenchymal transition and invasion, but also on communication between tumor cells, in particular colon cancer cells, and their stroma, with a primordial focus on cancer-associated fibroblasts, and lastly this review will discuss how this communication can affect the cancer cell's ability to invade its surroundings and form metastases.

Colon cancer-derived myofibroblasts increase endothelial cell migration by glucocorticoid-sensitive secretion of a pro-migratory factor.

Angiogenesis is important in cancer progression and can be influenced by tumor-associated myofibroblasts. We addressed the hypothesis that glucocorticoids indirectly affect angiogenesis by altering the release of pro-angiogenic factors from colon cancer-derived myofibroblasts. Our study shows that glucocorticoids reduced prostanoids, urokinase-type plasminogen activator (uPA) and angiopoietin-like protein-2 (ANGPTL2) levels, but increased angiogenin (ANG) in supernatant from human CT5.3hTERT colon cancer-derived myofibroblasts. Conditioned medium from solvent- (CMS) and dexamethasone (Dex)-treated (CMD) myofibroblasts increased human umbilical vein endothelial cell (HUVEC) proliferation, but did not affect expression of pro-angiogenic factors or tube-like structure formation (by HUVECs or human aortic ECs). In a HUVEC scratch assay CMS-induced acceleration of wound healing was blunted by CMD treatment. Moreover, CMS-induced neovessel growth in mouse aortic rings ex vivo was also blunted using CMD. The latter effect could be ascribed to both Dex-driven reduction of secreted factors and potential residual Dex present in CMD (indicated using a dexamethasone-spiked CMS control). A similar control in the scratch assay, however, revealed that altered levels of factors in the CMD, and not potential residual Dex, were responsible for decreased wound closure. In conclusion, our results suggest that glucocorticoids indirectly alter endothelial cell function during tumor development in vivo.

Age and cellular context influence rectal prolapse formation in mice with caecal wall colorectal cancer xenografts.

In patients with rectal prolapse is the prevalence of colorectal cancer increased, suggesting that a colorectal tumor may induce rectal prolapse. Establishment of tumor xenografts in immunodeficient mice after orthotopic inoculations of human colorectal cancer cells into the caecal wall is a widely used approach for the study of human colorectal cancer progression and preclinical evaluation of therapeutics. Remarkably, 70% of young mice carrying a COLO320DM caecal tumor showed symptoms of intussusception of the large bowel associated with intestinal lumen obstruction and rectal prolapse. The quantity of the COLO320DM bioluminescent signal of the first three weeks post-inoculation predicts prolapse in young mice. Rectal prolapse was not observed in adult mice carrying a COLO320DM caecal tumor or young mice carrying a HT29 caecal tumor. In contrast to HT29 tumors, which showed local invasion and metastasis, COLO320DM tumors demonstrated a non-invasive tumor with pushing borders without presence of metastasis. In conclusion, rectal prolapse can be linked to a non-invasive, space-occupying COLO320DM tumor in the gastrointestinal tract of young immunodeficient mice. These data reveal a model that can clarify the association of patients showing rectal prolapse with colorectal cancer.

Selective glucocorticoid receptor-activating adjuvant therapy in cancer treatments.

Although adverse effects and glucocorticoid resistance cripple their chronic use, glucocorticoids form the mainstay therapy for acute and chronic inflammatory disorders, and play an important role in treatment protocols of both lymphoid malignancies and as adjuvant to stimulate therapy tolerability in various solid tumors. Glucocorticoid binding to their designate glucocorticoid receptor (GR), sets off a plethora of cell-specific events including therapeutically desirable effects, such as cell death, as well as undesirable effects, including chemotherapy resistance, systemic side effects and glucocorticoid resistance. In this context, selective GR agonists and modulators (SEGRAMs) with a more restricted GR activity profile have been developed, holding promise for further clinical development in anti-inflammatory and potentially in cancer therapies. Thus far, the research into the prospective benefits of selective GR modulators in cancer therapy limped behind. Our review discusses how selective GR agonists and modulators could improve the therapy regimens for lymphoid malignancies, prostate or breast cancer. We summarize our current knowledge and look forward to where the field should move to in the future. Altogether, our review clarifies novel therapeutic perspectives in cancer modulation via selective GR targeting.