Apoptosis and APC in colorectal tumorigenesis.

Tumors result from disruptions in the homeostatic mechanisms that regulate cell birth and cell death. In colon cancer, one of the earliest manifestation of this imbalance is the formation of polyps, caused by somatic and inherited mutations of the adenomatous polyposis coli (APC) tumor suppressor gene in both humans and mice. While the importance of APC in tumorigenesis is well documented, how it functions to prevent tumors remains a mystery. Using a novel inducible expression system, we show that expression of APC in human colorectal cancer cells containing endogenous inactive APC alleles results in a substantial diminution of cell growth. Further evaluation demonstrated that this was due to the induction of cell death through apoptosis. These results suggest that apoptosis plays a role not only in advanced tumors but also at the very earliest stages of neoplasia.

Modulation allostérique du récepteur FP dans le cancer colorectal

Les prostaglandines modulent d’importants rôles physiologiques. Elles sont aussi impliquées dans le développement d’une variété de conditions pathologiques telles l’inflammation, la douleur et le cancer. La prostaglandine PGF2α et son récepteur (récepteur FP) se trouvent impliqué dans la modulation de nombreuses pathologies tels lors de l’accouchement préterme et le cancer colorectal. Récemment, nous avons fait partie d’un groupe de recherche ayant développé des modulateurs allostériques du récepteur FP. Dans une première étude, l’action du PGF2α sur le déclenchement des contractions myométriales a été évaluée, car peu d’information est connue sur la signalisation de cette prostaglandine lors de l’accouchement. Ainsi, nous avons utilisé un peptidomimétique de la deuxième boucle extracellulaire, dénommée PDC113.824. Nos résultats ont démontré que le PDC113.824 permettait de retarder la mise bas chez des souris gestantes, mais agissait de manière différente sur les multiples voies de signalisation de la PGF2α. Ainsi, le PDC113.824 inhibait la voie RhoA-ROCK, dépendante de l’activation de la protéine Gα12 par le. Les protéines RhoA-ROCK sont des acteurs clés dans le remodelage du cytosquelette d’actine et des contractions myométriales lors de l’accouchement. De plus, le PDC113.824 en présence de PGF2α agit comme un modulateur positif sur la voie dépendante de l’activation de la protéine Gαq. Le PDC113.824 serait donc un modulateur allostérique non compétitif possédant des actions à la fois de modulateurs positifs et négatifs sur la signalisation du récepteur FP Dans une seconde étude, des analogues du PDC113.824 ont été conçus et analysés dans un second modèle pathologique, le cancer colorectal. Ce cancer possède de hauts niveaux de récepteur FP. Nous avons donc étudié le rôle du récepteur FP dans le développement et la progression du cancer colorectal et l’effet de modulateurs allostériques. Il est généralement accepté que dans le cancer colorectal, la prostaglandine PGE2 permet la croissance et l’invasion tumorale, ainsi que l’angiogenèse. Toutefois, peu d’informations sont connues sur le rôle du PGF2α dans le cancer colorectal. C’est dans ce contexte que nous avons décidé d’examiner la contribution de ce récepteur dans la progression du cancer colorectal et cherché à déterminer si la modulation des fonctions du récepteur FP a un impact sur la croissance de tumeurs colorectales. Nos recherches ont révélé que l’activation du récepteur FP permet la migration et la prolifération de plusieurs lignées cellulaires humaines et murines d’adénocarcinomes colorectaux. Dans ce contexte, nos expériences ont démontré que la migration des cellules cancéreuses était dépendante de l’activation de la voie Rho. Nos résultats démontrent qu’en effet, l’activation de RhoA, une petite GTPase clé de la voie Gα12, est inhibée de façon sélective par nos composés. De plus, nos molécules allostériques sont également efficaces pour inhiber la voie de signalisation de la ß-caténine, une protéine impliquée dans la genèse du cancer colorectal. In vivo, le traitement de souris avec un des ces modulateurs a permis une inhibition effective de la croissance tumorale. Dans l’ensemble, nos résultats suggèrent donc que les modulateurs allostériques des récepteurs FP pourraient constituer une nouvelle classe de médicaments utilisés pour le traitement du cancer colorectal.

ESMO consensus guidelines for the management of patients with metastatic colorectal cancer

Colorectal cancer (CRC) is one of the most common malignancies in Western countries. Over the last 20 years, and the last decade in particular, the clinical outcome for patients with metastatic CRC (mCRC) has improved greatly due not only to an increase in the number of patients being referred for and undergoing surgical resection of their localised metastatic disease but also to a more strategic approach to the delivery of systemic therapy and an expansion in the use of ablative techniques. This reflects the increase in the number of patients that are being managed within a multidisciplinary team environment and specialist cancer centres, and the emergence over the same time period not only of improved imaging techniques but also prognostic and predictive molecular markers. Treatment decisions for patients with mCRC must be evidence-based. Thus, these ESMO consensus guidelines have been developed based on the current available evidence to provide a series of evidence-based recommendations to assist in the treatment and management of patients with mCRC in this rapidly evolving treatment setting.

Compartmentalized expression of kallikrein 4 (KLK4/hK4) isoforms in prostate cancer: nuclear, cytoplasmic and secreted forms

The prostate-specific antigen-related serine protease gene, kallikrein 4 (KLK4), is expressed in the prostate and, more importantly, overexpressed in prostate cancer. Several KLK4 mRNA splice variants have been reported, but it is still not clear which of these is most relevant to prostate cancer. Here we report that, in addition to the full-length KLK4 (KLK4-254) transcript, the exon 1 deleted KLK4 transcripts, in particular, the 5'-truncated KLK4-205 transcript, is expressed in prostate cancer. Using V5/His6 and green fluorescent protein (GFP) carboxy terminal tagged expression constructs and immunocytochemical approaches, we found that hK4-254 is cytoplasmically localized, while the N-terminal truncated hK4-205 is in the nucleus of transfected PC-3 prostate cancer cells. At the protein level, using anti-hK4 peptide antibodies specific to different regions of hK4-254 (N-terminal and C-terminal), we also demonstrated that endogenous hK4-254 (detected with the N-terminal antibody) is more intensely stained in malignant cells than in benign prostate cells, and is secreted into seminal fluid. In contrast, for the endogenous nuclear-localized N-terminal truncated hK4-205 form, there was less difference in staining intensity between benign and cancer glands. Thus, KLK4-254/hK4-254 may have utility as an immunohistochemical marker for prostate cancer. Our studies also indicate that the expression levels of the truncated KLK4 transcripts, but not KLK4-254, are regulated by androgens in LNCaP cells. Thus, these data demonstrate that there are two major isoforms of hK4 (KLK4-254/hK4-254 and KLK4-205/hK4-205) expressed in prostate cancer with different regulatory and expression profiles that imply both secreted and novel nuclear roles.

Dimensions of quality of life and psychosocial variables most salient to colorectal cancer patients

Colorectal cancer is one of the most common invasive cancers, and is responsible for considerable physical and psychosocial morbidity. Understanding the quality of life experienced by colorectal cancer patients is essential for evaluating the full impact of the disease on individuals, their families and their communities. Patient perspective is essential in establishing a proper understanding of the quality of life of colorectal cancer patients. Despite this, few studies have employed a qualitative methodology to explore quality of life issues for colorectal cancer patients. A review of the literature identified only seven qualitative studies pertaining to quality of life issues for colorectal cancer patients, a surprising finding given the prevalence of this cancer. Accordingly, this study sought to build on the findings of previous qualitative research by providing descriptive data on the quality of life and psychosocial variables most salient to colorectal cancer patients. Six core themes emerged from interview and focus group data: Satisfaction with diagnosis and treatment; support (including information provision); quality of life; benefits of diagnosis; making sense of the cancer experience; and coping strategies. The information derived from this study will help inform the development of supportive care services to address the needs of the increasing number of people diagnosed with colorectal cancer. Copyright (c) 2005 John Wiley & Sons, Ltd.

Measurement of community beliefs about colorectal cancer

Few educational campaigns have focused on bowel cancer, though studies have indicated that members of the community need and want current information about relevant issues. In order to facilitate research in this area, reliable and valid measures of community attitudes are needed. Content validity of a survey instrument was obtained through use of a Delphi process with Directors of Education from the Australia Cancer Council and focus group discussions with informed members of the public. The subsequent survey of community perceptions about colorectal cancer included a broad range of content areas related to the risk of bowel cancer, preventing and coping with bowel cancer and beliefs about susceptibility and severity. The construct validity of these content areas was investigated by use of a factor analysis and confirmation of an association with related predictor variables. Two measures related to personal influence and anticipated coping responses showed favourable psychometric properties, including moderate to high levels of internal consistency and test-retest reliability. A test of the concurrent validity of these measures requires further development of instruments related to colorectal cancer or adaptation of measures from other areas of health research. (C) 2000 Elsevier Science Ltd. All rights reserved.

A pre-post test evaluation of the impact of the PELICAN MDT-TME development programme on the working lives of colorectal cancer team members

Background - The PELICAN Multidisciplinary Team Total Mesorectal Excision (MDT-TME) Development Programme aimed to improve clinical outcomes for rectal cancer by educating colorectal cancer teams in precision surgery and related aspects of multidisciplinary care. The Programme reached almost all colorectal cancer teams across England. We took the opportunity to assess the impact of participating in this novel team-based Development Programme on the working lives of colorectal cancer team members. Methods - The impact of participating in the programme on team members' self-reported job stress, job satisfaction and team performance was assessed in a pre-post course study. 333/568 (59%) team members, from the 75 multidisciplinary teams who attended the final year of the Programme, completed questionnaires pre-course, and 6-8 weeks post-course. Results - Across all team members, the main sources of job satisfaction related to working in multidisciplinary teams; whilst feeling overloaded was the main source of job stress. Surgeons and clinical nurse specialists reported higher levels of job satisfaction than team members who do not provide direct patient care, whilst MDT coordinators reported the lowest levels of job satisfaction and job stress. Both job stress and satisfaction decreased after participating in the Programme for all team members. There was a small improvement in team performance. Conclusions - Participation in the Development Programme had a mixed impact on the working lives of team members in the immediate aftermath of attending. The decrease in team members' job stress may reflect the improved knowledge and skills conferred by the Programme. The decrease in job satisfaction may be the consequence of being unable to apply these skills immediately in clinical practice because of a lack of required infrastructure and/or equipment. In addition, whilst the Programme raised awareness of the challenges of teamworking, a greater focus on tackling these issues may have improved working lives further.

Identification of aspirin analogues that repress NF-κB signalling and demonstrate anti-proliferative activity towards colorectal cancer in vitro and in vivo

Substantial evidence indicates that aspirin and related non-steroidal anti-inflammatory drugs (NSAIDs) have potential as chemopreventative/therapeutic agents. However, these agents cannot be universally recommended for prevention purposes due to their potential side-effect profiles. Here, we compared the growth inhibitory and mechanistic activity of aspirin to two novel analogues, diaspirin (DiA) and fumaryl diaspirin (F-DiA). We found that the aspirin analogues inhibited cell proliferation and induced apoptosis of colorectal cancer cells at significantly lower doses than aspirin. Similar to aspirin, we found that an early response to the analogues was a reduction in levels of cyclin D1 and stimulation of the NF-κB pathway. This stimulation was associated with a significant reduction in basal levels of NF-κB transcriptional activity, in keeping with previous data for aspirin. However, in contrast to aspirin, DiA and F-DiA activity was not associated with nucleolar accumulation of RelA. For all assays, F-DiA had a more rapid and significant effect than DiA, identifying this agent as particularly active against colorectal cancer. Using a syngeneic colorectal tumour model in mice, we found that, while both agents significantly inhibited tumour growth in vivo, this effect was particularly pronounced for F-DiA. These data identify two compounds that are active against colorectal cancer in vitro and in vivo. They also identify a potential mechanism of action of these agents and shed light on the chemical structures that may be important for the antitumour effects of aspirin.

The feasibility and acceptability of trial procedures for a pragmatic randomised controlled trial of a structured physical activity intervention for people diagnosed with colorectal cancer : findings from a pilot trial of cardiac rehabilitation versus usual care (no rehabilitation) with an embedded qualitative study

Funding This work is supported by the National Institute for Health Research—Health Service and Development Research, Project reference number: NIHR—HS&DR Project:12/5001/09.

Acceptance of relapse fears in breast cancer patients: effects of an act-based abridged intervention

Objective: Relapse fear is a common psychological scar in cancer survivors. The aim of this study is to assess the effects of an abridged version of Acceptance and Commitment Therapy (ACT) in breast cancer patients.Method: An open trial was developed with 12 non-metastatic breast cancer patients assigned to 2 conditions, ACT and waiting list. Interventions were applied in just one session and focused on the acceptance of relapse fears through a ‘defusion’ exercise. Interference and intensity of fear measured through subjective scales were collected after each intervention and again 3 months later. Distress, hypochondria and ‘anxious preocupation’ were also evaluated through standardized questionnaires.Results: The analysis revealed that ‘defusion’ contributed to decrease the interference of the fear of recurrence, and these changes were maintained three months after intervention in most subjects. 87% of participants showed clinically significant decreases in interference at follow-up sessions whereas no patient in the waiting list showed such changes. Statistical analysis revealed that the changes in interference were significant when comparing pre, post and follow-up treatment, and also when comparing ACT and waiting list groups. Changes in intensity of fear, distress, anxious preoccupation and hypochondria were also observed.Conclusions: Exposure through ‘defusion’ techniques might be considered a useful option for treatment of persistent fears in cancer patients. This study provides evidence for therapies focusing on psychological acceptance in cancer patients through short, simple and feasible therapeutic methods.

NOD2 mutations and colorectal cancer - Where do we stand?

Due to the overwhelming burden of colorectal cancer (CRC), great effort has been placed on identifying genetic mutations that contribute to disease development and progression. One of the most studied polymorphisms that could potentially increase susceptibility to CRC involves the nucleotide-binding and oligomerization-domain containing 2 (NOD2) gene. There is growing evidence that the biological activity of NOD2 is far greater than previously thought and a link with intestinal microbiota and mucosal immunity is increasingly sought after. In fact, microbial composition may be an important contributor not only to inflammatory bowel diseases (IBD) but also to CRC. Recent studies have showed that deficient NOD2 function confers a communicable risk of colitis and CRC. Despite the evidence from experimental models, population-based studies that tried to link certain NOD2 polymorphisms and an increase in CRC risk have been described as conflicting. Significant geographic discrepancies in the frequency of such polymorphisms and different interpretations of the results may have limited the conclusions of those studies. Since being first associated to IBD and CRC, our understanding of the role of this gene has come a long way, and it is tempting to postulate that it may contribute to identify individuals with susceptible genetic background that may benefit from early CRC screening programs or in predicting response to current therapeutic tools. The aim of this review is to clarify the status quo of NOD2 mutations as genetic risk factors to chronic inflammation and ultimately to CRC. The use of NOD2 as a predictor of certain phenotypic characteristics of the disease will be analyzed as well.

Mesenchymal stromal cells (MSCs) and colorectal cancer - a troublesome twosome for the anti-tumour immune response?

The tumour microenvironment (TME) is an important factor in determining the growth and metastasis of colorectal cancer, and can aid tumours by both establishing an immunosuppressive milieu, allowing the tumour avoid immune clearance, and by hampering the efficacy of various therapeutic regimens. The tumour microenvironment is composed of many cell types including tumour, stromal, endothelial and immune cell populations. It is widely accepted that cells present in the TME acquire distinct functional phenotypes that promote tumorigenesis. One such cell type is the mesenchymal stromal cell (MSC). Evidence suggests that MSCs exert effects in the colorectal tumour microenvironment including the promotion of angiogenesis, invasion and metastasis. MSCs immunomodulatory capacity may represent another largely unexplored central feature of MSCs tumour promoting capacity. There is considerable evidence to suggest that MSCs and their secreted factors can influence the innate and adaptive immune responses. MSC-immune cell interactions can skew the proliferation and functional activity of T-cells, dendritic cells, natural killer cells and macrophages, which could favour tumour growth and enable tumours to evade immune cell clearance. A better understanding of the interactions between the malignant cancer cell and stromal components of the TME is key to the development of more specific and efficacious therapies for colorectal cancer. Here, we review and explore MSC- mediated mechanisms of suppressing anti-tumour immune responses in the colon tumour microenvironment. Elucidation of the precise mechanism of immunomodulation exerted by tumour-educated MSCs is critical to inhibiting immunosuppression and immune evasion established by the TME, thus providing an opportunity for targeted and efficacious immunotherapy for colorectal cancer growth and metastasis.

Anastomotic strictures in colorectal surgery: treatment with endoscopic balloon dilation

The incidence of anastomotic stricture following colorectal surgery has increased in recent years. This complication is observed in 2-5% of all operated patients and is probably due to the greater number of low anastomoses performed with surgical staplers. We observed 31 patients with postoperative stricture, arising from one to nine months post-surgery. All patients had been treated for colorectal cancer and underwent endoscopy either during routine follow-up or for symptoms of stenosis. In 16 patients (group A) the stricture diameter was less than 4 mm and the patients had symptoms attributable to partial bowel obstruction. In the remaining 15 patients (group B), who had difficult bowel movements, the stricture diameter ranged from 4 to 8 mm. All patients were treated with endoscopic dilation using achalasia balloons. The results were considered good when the post-dilation anastomosis diameter achieved was at least 13 mm, fair when it was 9-12 mm and poor when it was less than 9 mm. The short term results (3 weeks) were good in 27 patients (87.2%), fair in 3 patients (9.6%), and poor in 1 patient (3.2%). After several unsuccessful dilations, the latter was treated by surgery. Follow-up at 3-4 months of the remaining 30 patients revealed good results in 20 (66.6%), fair in 6 (20%), and poor in 4 (13.3%). In 1 of these 4 patients, cancer recurrence was observed and a new surgical resection was performed. In 2 patients a self–expandable metal stent was inserted for 4-6 weeks, with satisfactory results. In 1 patient a biodegradable polydioxanone stent was inserted with good results after 6 months. Follow-up at 3-4 months showed good results in 25 patients. After 38 months, cancer recurrence in the area of the anastomosis was observed in 1 patient, who was treated surgically. Endoscopic dilatation should be considered the first therapeutic approach in case of anastomotic strictures, as it is immediately effective, repeatable, and does not preclude surgery if this should become necessary. .

NOD2 mutations and colorectal cancer - Where do we stand?

Due to the overwhelming burden of colorectal cancer (CRC), great effort has been placed on identifying genetic mutations that contribute to disease development and progression. One of the most studied polymorphisms that could potentially increase susceptibility to CRC involves the nucleotide-binding and oligomerization-domain containing 2 (NOD2) gene. There is growing evidence that the biological activity of NOD2 is far greater than previously thought and a link with intestinal microbiota and mucosal immunity is increasingly sought after. In fact, microbial composition may be an important contributor not only to inflammatory bowel diseases (IBD) but also to CRC. Recent studies have showed that deficient NOD2 function confers a communicable risk of colitis and CRC. Despite the evidence from experimental models, population-based studies that tried to link certain NOD2 polymorphisms and an increase in CRC risk have been described as conflicting. Significant geographic discrepancies in the frequency of such polymorphisms and different interpretations of the results may have limited the conclusions of those studies. Since being first associated to IBD and CRC, our understanding of the role of this gene has come a long way, and it is tempting to postulate that it may contribute to identify individuals with susceptible genetic background that may benefit from early CRC screening programs or in predicting response to current therapeutic tools. The aim of this review is to clarify the status quo of NOD2 mutations as genetic risk factors to chronic inflammation and ultimately to CRC. The use of NOD2 as a predictor of certain phenotypic characteristics of the disease will be analyzed as well.

The relationship between health literacy and indicators of informed decision making for colorectal cancer screening among African Americans

African Americans are disproportionately affected by colorectal cancer (CRC) incidence and mortality. CRC early detection leads to better treatment outcomes and, depending on the screening test, can prevent the development of CRC. African Americans, however, are screened less often than Whites. Aspects of decision making (e.g., decisional conflict, decision self-efficacy) can impact decision making outcomes and may be influenced by social determinants of health, including health literacy. However the relationship between social determinants of health and indicators of decision making in this population is not fully understood. Additionally, individuals have a choice between different CRC screening tests and an individual’s desire to use a particular screening test may be associated with social determinants of health such as health literacy. This study aimed to examine the relationship between social determinants of health and indicators of decision making for CRC screening among African Americans. A total of 111 participants completed a baseline and 14-month follow-up survey assessing decisional conflict, decision self-efficacy, decisional preference (shared versus informed decision making), and CRC test preference. Health literacy was negatively associated with decisional conflict and positively associated with decision self-efficacy (ps < .05). Individuals who were unemployed or working part-time had significantly greater decisional conflict than individuals working full-time (ps < .05). Individuals with a first-degree family history of CRC had significantly lower decision self-efficacy than individuals without a family history (p < .05). Women were significantly more likely to prefer making a shared decision rather than an informed decision compared to men (p < .05). Lastly, previous CRC screening behavior was significantly associated with CRC test preference (e.g., individuals previously screened using colonoscopy were significantly more likely to prefer colonoscopy for their next screening test; ps < .05). These findings begin to identify social determinants of health (e.g., health literacy, employment) that are related to indicators of decision making for CRC among African Americans. Furthermore, these findings suggest further research is needed to better understand these relationships to help with the future development and improvement of interventions targeting decision making outcomes for CRC screening in this population.