A systematic review of oncosurgical and quality of life outcomes following pelvic exenteration for locally advanced and recurrent rectal cancer.

INTRODUCTION: Pelvic exenteration (PE) is now the standard of care for locally advanced (LARC) and locally recurrent (LRRC) rectal cancer. Reports of the significant short-term morbidity and survival advantage conferred by R0 resection are well established. However, longer-term outcomes are rarely addressed. This systematic review focuses on long-term oncosurgical and quality of life (QoL) outcomes following PE for rectal cancer. METHODS: A systematic review of the PubMed®, Cochrane Library, MEDLINE® and Embase® databases was conducted, in accordance with the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. Studies were included if they reported long-term outcomes following PE for LARC or LRRC. Studies with fewer than 20 patients were excluded. FINDINGS: A total of 25 papers reported outcomes for 5,489 patients. Of these, 4,744 underwent PE for LARC (57.5%) or LRRC (42.5%). R0 resection rates ranged from 23.2% to 98.4% and from 14.9% to 77.8% respectively. The overall morbidity rates were 17.8-87.0%. The median survival ranged from 12.5 to 140.0 months. None of these studies reported functional outcomes and only four studies reported QoL outcomes. Numerous different metrics and timepoints were utilised, with QoL scores frequently returning to baseline by 12 months. CONCLUSIONS: This review demonstrates that PE is safe, with a good prospect of R0 resection and acceptable mortality rates in selected patients. Morbidity rates remain high, highlighting the importance of shared decision making with patients. Longer-term oncological outcomes as well as QoL and functional outcomes need to be addressed in future studies. Development of a core outcomes set would facilitate better reporting in this complex and challenging patient group.

Robotic abdominoperineal resection, posterior vaginectomy and abdomino-lithotomy sacrectomy: technical considerations and case vignette.

When working with patients who have locally advanced rectal cancer (LARC) the ability to undertake minimally invasive procedures becomes more challenging but no less important for patient outcomes. We performed a minimally invasive approach to surgery for LARC invading the posterior vagina and sacrum. The patient was a 75-year-old lady who presented with a locally advanced rectal tumour staged T4N2 with invasion into the posterior wall of the vagina and coccyx/distal sacrum. We introduce a robotic abdominoperineal resection, posterior vaginectomy and abdomino-lithotomy sacrectomy using a purely perineal approach with no robotic adjuncts or intracorporal techniques. Final histology showed moderately differentiated adenocarcinoma invading the vagina and sacrum, ypT4b N0 TRG2 R0 and the patient entered surgical follow-up with no immediate intra- or postoperative complications. A literature review shows the need for more minimally invasive techniques when relating to major pelvic surgery and the benefits of a purely perineal approach include less expensive resource use, fewer training requirements and the ability to utilise this technique in centres that are not robotically equipped.

Open versus Closed technique for administration of heated intraperitoneal chemotherapy (HIPEC): Morbidity and Mortality outcomes from a high-volume centre.

BACKGROUND AND AIMS: Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is an established treatment in selected patients with peritoneal metastases, delivered in the UK in specialist centres. HIPEC can be administered via the open coliseum technique as first described by Sugarbaker (O-HIPEC) or using a closed technique (C-HIPEC). Data comparing the safety and outcomes of these different approaches is limited. This study aims to compare morbidity and mortality rates of O-HIPEC and C-HIPEC following CRS for peritoneal metastases from colorectal cancer and appendiceal tumours. METHODS: Consecutive patients undergoing CRS with open (05/2019-04/2020) and closed (05/2020-04/2021) HIPEC were identified from a prospectively maintained database. Baseline data including primary pathology, HIPEC agent and major operative procedures were analysed using Chi-squared and Fishers exact tests to ensure comparability of groups. Primary outcomes were 30- and 60-day postoperative mortality and morbidity (Common Terminology Criteria for Adverse Events, CTCAE). Secondary outcomes were length of critical care and overall hospital stay. In addition, morbidity and mortality were compared between HIPEC agents (mitomycin and oxaliplatin/5-fluorouracil). RESULTS: 99 patients (39.3%) and 153 patients (60.7%) underwent O-HIPEC, C-HIPEC respectively. Groups were well matched for baseline demographics, pathology, and HIPEC agent. In the O-HIPEC and C-HIPEC groups respectively, the incidence of 60-day complications (CTCAE 1-4) was 40.4% vs 39.3% (chi squared 0.94) and severe complications (CTCAE 3-4) 14% vs 13% (Fisher's exact p = 1) There was no perioperative mortality but one death in each group within the follow up period. There was no difference in morbidity or mortality between those receiving mitomycin or oxaliplatin. CONCLUSION: Closed administration of HIPEC is safe with no difference in post-operative morbidity or mortality compared to open HIPEC administration. Differences in longer term oncological outcomes including overall survival and disease-free survival between open and closed HIPEC techniques are yet to be determined.

Consecutive ipsilateral inferior pole patella and superior patella sleeve fractures.

We present a rare, previously undescribed case of a superior patella sleeve fracture in a skeletally immature adolescent male, just 1 month following surgery for an ipsilateral traumatic inferior pole patella fracture. This was initially missed resulting in a delay to surgery. We recommend a high index of suspicion is key in these patients who re-present following subsequent trauma and alternative X-ray views such as a flexed lateral can be extremely beneficial.

Evaluating the potential utility of three-dimensional printed models in preoperative planning and patient consent in gastrointestinal cancer surgery.

INTRODUCTION: The Future of Surgery report from the Royal College of Surgeons of England acknowledges the important role that three-dimensional imaging will play in support of personalised surgical interventions. One component of this is preoperative planning. We investigated surgeons' and patients' perceptions of this evolving technology. MATERIALS AND METHODS: Ethical approval was obtained. From a normal computed tomography scan, three-dimensional models of the stomach, pancreas and rectum were rendered and printed on an Ultimaker™ three-dimensional printer. Semi-structured interviews were performed with surgeons and patients to explore perceived model effectiveness and utility. Likert scales were used to grade responses (1 = strongly disagree; 10 = strongly agree) and qualitative responses recorded. RESULTS: A total of 26 surgeons (9 rectal, 9 oesophagogastric, 8 pancreatic) and 30 patients (median age 62 years, interquartile range, IQR, 68-72 years; 57% male) were recruited. Median surgeon scores were effectiveness for preoperative planning, 6 (IQR 3-7), authenticity, 5 (IQR 3-6), likability, 6 (IQR 4-7), promoting learning, 7 (IQR 5-8), utility, 6 (IQR 5-7) and helping patients, 7 (IQR 5-8). Median patient scores were usefulness to the surgeon, 8 (IQR 7-9), authenticity, 8 (IQR 6-8), likability, 8 (IQR 7-8), helping understanding of condition, 8 (IQR 8-9), helping understanding of surgery, 8 (IQR 7-9) and feeling uncomfortable, 1 (IQR 1-4). Median overall decisional conflict score (0 = no; 100 = high) was 22 (IQR 19-28) and decision effectiveness was 25 (IQR 19-30). DISCUSSION: Overall, patients and surgeons considered that three-dimensional printed models were effective and had potential utility in education and, to a lesser extent, preoperative planning. Patient decisional conflict and effectiveness scores were weighted towards certainty in decision making but had room for improvement, which three-dimensional models may help to facilitate.

Indications and outcomes for repeat cytoreductive surgery and heated intra-peritoneal chemotherapy in peritoneal surface malignancy.

INTRODUCTION: Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) is offered in specialist centres as a treatment for peritoneal surface tumours. Despite its demonstrated efficacy, intra-abdominal recurrence occurs in 31-57% of patients. The aim of this study is to review the early and long-term outcomes in patients who undergo repeat CRS/HIPEC. MATERIALS AND METHODS: A retrospective review of a prospectively maintained database of patients who had undergone repeat CRS/HIPEC for appendiceal neoplasms and colorectal peritoneal metastases (CRPM) from 2003 to 2019 was performed at a single specialist centre. Data pertaining to both short term outcomes and survival were evaluated. RESULTS: Of 1259 patients who had undergone CRS/HIPEC, 84(6.7%) underwent repeat surgery: 45(53.6%) had pseudomyxoma peritonei (PMP) secondary to low grade appendiceal mucinous neoplasms (LAMN), 21(25.0%) had appendix carcinoma and 18(21.4%) had CRPM. Demographics, intra-operative findings and short-term outcomes were comparable across tumour types and between procedures. Median (95% CI) interval between procedures was 22.7(18.9-26.6) months and was comparable between tumour types. Median (95%CI) overall survival was not reached for the cohort overall or for those with PMP, but was 61.0(32.6-89.4) months for those with appendix cancer and 76.9(47.4-106.4) months for CRPM (p=<0.001). Survival was favourable in the PMP group (HR [95%CI] 0.044 [0.008-0.262]; p = 0.000) and unfavourable in the CC2-3 at index CRS procedure group (HR [95%CI] 25.612 [2.703-242.703]; p = 0.005). CONCLUSION: Our findings demonstrate that repeat cytoredutive surgery with HIPEC can result in favourable survival, especially for patients with PMP when complete cytoreduction is achieved at index operation. We recommend that detailed patient assessment is performed through an expert multidisciplinary team meeting (MDT).

Hartmann's procedure versus intersphincteric abdominoperineal excision (HiP Study): a multicentre prospective cohort study.

AIM: In patients with low rectal cancer it is occasionally necessary to avoid a low coloanal anastomosis due to patient frailty or poor function. In such situations there are two alternative approaches: Hartmann's procedure (HP) or intersphincteric abdominoperineal excision (IAPE). There are few data to guide surgeons as to which of these two procedures is the safest. The aim of this study was to determine the surgical complication rates associated with each procedure. METHOD: This was a multicentre, nonrandomized prospective cohort study of patients undergoing either HP or IAPE. The primary objective was to determine surgical complication rates. Secondary objectives included length of stay, time to adjuvant therapy and quality of life at 90 days. RESULTS: One hundred and seventy nine patients were recruited between April 2016 and June 2019; approximately two thirds of patients underwent HP and one third IAPE. The overall complication rate was high in both groups (54% for the HP group and 52% for the IAPE group). Surgery-specific complication rates were also high, but not significantly different: 43% for HP and 48% for IAPE. The pelvic abscess rate in HP was 11% and was significantly higher in patients with a palpable staple line (15% vs 2%). There was a higher incidence of serious medical complications following IAPE (16% vs 5%), along with a reduction in 90-day quality of life scores. CONCLUSION: This is the largest prospective study to compare HP and IAPE in patients undergoing rectal cancer surgery where primary anastomosis is not deemed appropriate. With similar complication rates, these data support the ongoing use of either HP or IAPE in this patient group.

Sphingolipids and acid ceramidase as therapeutic targets in cancer therapy.

BACKGROUND: Sphingolipids have been shown to play a key part in cancer cell growth and death and have increasingly become the subject of novel anti-cancer therapies. Acid ceramidase, a sphingolipid enzyme, has an important role in the regulation of apoptosis. In this review we aim to assess the current evidence supporting the role of sphingolipids in cancer and the potential role that acid ceramidase may play in cancer treatment. METHODS: A literature search was performed for published full text articles using the PubMed, Cochrane and Scopus databases using the search criteria string "acid ceramidase", "sphingolipid", "cancer". Additional papers were detected by scanning the references of relevant papers. A summary of the evidence for each cancer subgroup was then formed. Given the nature of the data extracted, no meta-analysis was performed. RESULTS: Over expression of acid ceramidase has been demonstrated in a number of human cancers. In vitro data demonstrate that manipulation of acid ceramidase may present a useful therapeutic target. In the clinical setting, a number of drugs have been investigated with the ability to target acid ceramidase, with the most promising of those being small molecular inhibitors, such as LCL521. CONCLUSION: The role of the sphingolipid pathway in cancer is becoming very clearly established by promoting ceramide accumulation in response to cancer or cellular stress. Acid ceramidase is over expressed in a variety of cancers and has a role as a potential target for inhibition by novel specific inhibitors or off-target effects of traditional anti-cancer agents. Further work is required to develop acid ceramidase inhibitors safe for progression to clinical trials.

Awareness of surgical expenditure amongst UK trainees and consultants: A questionnaire study.

INTRODUCTION: Limited knowledge of surgical device and service costs restricts a surgeon's ability to make cost efficient choices and contribute to the efficiency savings required by the NHS to reduce the financial deficit. This study aims to assess how aware surgeons are of surgical equipment and regularly used services. METHODS: A single sided hard copy questionnaire asking for the estimate cost of 24 surgical devices/services was handed out to individuals at two separate UK annual conferences. Items and services which are regularly used and/or clinically significant were selected and, where possible, alternatives to those items were included for comparison. Participants were also asked for their grade and specialty. An estimate was deemed correct if it was within 20% of the actual cost. Planned subgroup analyses for grade and specialty were performed. RESULTS: The 143 participants consisted of 23 (16%) consultants, 39 (27%) registrars, 33 (23%) SHOs and 48 (34%) foundation doctors. Of the 95 participants who were SHO grade or more senior, 67 (71%) work within general surgery. Across all items, only 9.6% of estimates were correct. There was no statistically significant difference between training levels (consultant 11.5%, registrar 10.1%, SHO 8.6%, foundation 8.9%; p = 0.253). Participants were significantly less successful in correctly estimating the cost of high value (>£150 [USD $198; EUR €175]) items (8.5% vs. 11.1%); p = 0.011, and the cost of devices as compared to the cost of services (7.4% vs. 15.0%); p = 0.001. CONCLUSION: Surgeons across all grades and specialties have poor knowledge of device and service costs. It is important that this improves in order to allow surgeons to make a meaningful contribution to NHS efficiency savings by making informed decisions about their use of devices and services.

Evaluating unmet needs in patients undergoing surgery for colorectal cancer: a patient reported outcome measures study.

AIM: Patient reported outcome measures (PROMs) are self-reported measures of patients' health status or health-related quality of life at a single point in time. We aimed to evaluate the use of a colorectal PROM and conducted a focus group to further explore this and other unmet needs in our patient population treated surgically for colorectal cancer. METHOD: A multidisciplinary research group consisting of colorectal surgeons, nurse specialists, psychologists, sociologists and patient representatives devised a composite tool of new and existing outcome measures which was piloted in our local population (n = 35). Participants were subsequently invited to attend a semi-structured focus group during which the PROM was reviewed and an unmet needs analysis was performed. Thematic analysis of focus group transcripts was undertaken for emergent themes. RESULTS: Initial consensus was for a tool including the EQ-5D, Functional Assessment of Cancer Therapy - Colorectal (FACT-C), the distress thermometer, a validated measure of stigma, an unmet needs analysis, and questions assessing the psychological impact of cancer. Median and interquartile range values suggested that all metrics were discriminatory with the exception of FACT-C. All participants agreed that the tool was acceptable and reflected the current state of their health and emotions. Thematic analysis of focus group transcripts identified four major themes: physical symptoms, emotional response, information provision and coping mechanisms. CONCLUSION: Through expert consensus, local piloting and patient focus groups we have evaluated a novel PROM for colorectal cancer. Furthermore, through our direct engagement with patients we have identified several unmet needs which we are currently exploring within the clinical service.

Prospective cohort study of surgical trainee experience of access to gastrointestinal endoscopy training in the UK and Ireland.

INTRODUCTION: Surgical trainees are reporting barriers to training in gastrointestinal (GI) endoscopy. This snapshot survey aimed to gather data on variation in access to quality GI endoscopy training for Colorectal and Upper Gastrointestinal (GI) surgical trainees across the UK and Ireland. MATERIALS AND METHODS: An online 20-point survey was designed and distributed nationally to surgical trainee members of the Association of Surgeons in Training (ASiT), Dukes and The Roux Group (formerly Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland Trainees). The survey was designed in collaboration with The Roux Group for Upper GI trainees and the Dukes' Club for Colorectal trainees. RESULTS: 218 responses were received, most with a Colorectal or Upper GI sub-specialty interest (colorectal 56.0%; upper GI surgery 25.7%). Only 28.6% of trainees attended a dedicated training endoscopy list at least once a week with 28.1% not attending any at all. Less than half of trainees reported having endoscopy formally timetabled on rotas (36.9%). Most trainees (88.0%) encountered difficulties in gaining endoscopy training including lack of available lists (77.2%), conflicting operative commitments (59.4%), preferential allocation of lists to gastroenterology trainees (57.9%) and resistance from endoscopy departmental leads (38.6%). Regarding JAG accreditation, 77.1% respondents felt it should be mandatory prior to CCT with 80.3% believing this would lead to better access to dedicated endoscopy training equivalent to gastroenterology trainees. 93.1% trainees felt that attaining JAG accreditation by surgical trainees was important to patient care. DISCUSSION: This study demonstrates significant barriers in accessing GI endoscopy training for general surgical trainees which urgently needs to be improved. In order to meet JAG training requirements for surgical trainees, a multifaceted collaborative approach from surgical and gastroenterology training bodies, local JAG trainers and the General Surgery SAC and JCST is required. This is to ensure that endoscopy is promoted and a robust model of training is successfully designed and delivered to general surgery trainees.

Early anastomotic complications in colorectal surgery: a systematic review of techniques for endoscopic salvage.

BACKGROUND: Anastomotic complications following colorectal surgery are associated with significant morbidity and mortality. For patients in whom systemic sepsis is absent or well controlled, minimal access techniques, such as endoscopic therapies, are being increasingly employed to reduce the morbidity of surgical re-intervention. In this review, we aim to assess the utility of endoscopic management in the acute setting of colorectal anastomotic complications, focusing on anastomotic leak. METHOD: A literature search was performed for published full text articles using the PubMed, Cochrane and Scopus databases using the search criteria string "colorectal anastomotic ("leak" OR "bleed"), "endoscopy", endoscopic management". Additional papers were detected by scanning the references of relevant papers. Data were extracted from each study by two authors onto a dedicated pro-forma. Given the nature of the data extracted, no meta-analysis was performed. RESULTS: A total of 89 papers were identified, 16 of which were included in this review; an additional 14 papers were obtained from reference searches. In patients who are not physiologically compromised, there are promising data regarding the salvage rate of stents, over-the-scope endoscopic clips, vacuum therapy and fibrin glue in the early management of colorectal anastomotic leak. There is no consensus regarding the optimal approach, and data to assist the physician in patient selection are lacking. Whilst data on salvage (i.e. healing and avoidance of surgery) are well understood, no data on functional outcomes are reported. CONCLUSION: Endoscopic therapy in the management of stable patients with colorectal anastomotic leaks appears safe and in selected patients is associated with high rates of technical success. Challenges remain in selecting the most appropriate strategy, patient selection, and understanding the functional and long-term sequelae of this approach. Further evidence from large prospective cohort studies are needed to further evaluate the role of these novel strategies.

Proteomic profiling of rectal cancer reveals acid ceramidase is implicated in radiation response.

BACKGROUND: Neoadjuvant chemoradiotherapy (CRT) is used in locally advanced rectal cancer when tumours threaten the circumferential resection margin, with varying response to treatment. This experimental study aimed to identify significantly differentially expressed proteins between patients responding and not responding to CRT, and to validate any proteins of interest. METHODS: Mass spectrometry (with isobaric tagging for relative quantification) analysis of rectal cancers pre- and post-CRT, and at resection. Validation of proteins of interest was performed by assessing tissue microarray (TMA) immunohistochemistry expression in a further 111 patients with rectal cancer. RESULTS: Proteomic data are available via ProteomeXchange with identifier PXD008436. Reduced abundance of contributing peptide ions for acid ceramidase (AC) (log fold change -1.526, p = 1.17E-02) was observed in CRT responders. Differential expression of AC was confirmed upon analysis of the TMAs. Cancer site expression of AC in stromal cells from post-CRT resection specimens was observed to be relatively low in pathological complete response (p = 0.003), and relatively high with no response to CRT (p = 0.017). CONCLUSION: AC may be implicated in the response of rectal cancer to CRT. We propose its further assessment as a novel potential biomarker and therapeutic target. SIGNIFICANCE: There is a need for biomarkers to guide the use of chemoradiotherapy in rectal cancer, as none are in routine clinical use. We have determined acid ceramidase may have a role in radiation response, based on novel proteomic profiling and validation in a wider dataset using tissue microarrays. The ability to predict or improve response would positively select those patients who will derive benefit, prevent delays in the local and systemic management of disease in non-responders, and reduce morbidity associated with chemoradiotherapy.

Exome sequencing of synchronously resected primary colorectal tumours and colorectal liver metastases to inform oncosurgical management.

BACKGROUND: Next generation sequencing technology has facilitated mapping of the colorectal cancer genotype and furthered our understanding of metastogenesis. The aim of this study was to investigate for conserved and different mutations in the exomes of synchronously resected primary colorectal tumour and liver metastases. This information could potentially be utilised to guide the treatment of advanced disease with the help of biological information from the primary tumour. METHODS: We performed exome sequencing of synchronously resected primary colorectal cancer and colorectal liver metastases as well as normal colonic mucosa and liver parenchyma, from four patients who had received neo-adjuvant chemotherapy, at a depth of 50X using the Ion Proton platform. Raw data was mapped to the reference genome prior to variant calling, annotation and downstream analysis. RESULTS: Exome sequencing identified 585 non-synonymous missense single nucleotide variants (SNVs), of which 215 (36.8%) were unique to the primary tumour, 226 (38.6%) unique to the metastasis and 81 (13.8%) present in patient matched pairs. SNVs identified in the ErbB pathway appear to be concordant between primary and metastatic tumours. CONCLUSION: Only 13.8% of the metastatic exome can be predicted by the genotype of the primary tumour. We have demonstrated concordance of a number of SNVs in the ErbB pathway, which may inform selection of therapeutic agents in advanced colorectal cancer.

Attributes of excellent surgical trainers: An analysis of outstanding trainers.

Excellent surgical trainers play a key role in teaching, mentoring and inspiring the next generation of trainee surgeons. Although there are differences in approach, personality and technique among trainers, common themes exist for those that truly shine as examples of good training. The good surgical trainer has long been the "unsung hero" of patient safety, inspiring and imparting wisdom and skill in trainee surgeons, and instilling a sense of confidence and compassion. In order to recognise exceptional trainers, the Association of Surgeons in Training (ASiT) introduced the Silver Scalpel Award in 2000. The award acknowledges talented trainers who go the "extra mile" for their trainees, and the selection process includes both written nominations and structured interviews with the nominees. We wished to identify what makes the best trainers excellent, to see if these attributes could be used to develop recommendations on how to train and how to support trainers. Here we present an outline of key attributes of an excellent surgical trainer, based on qualitative synthesis of the interview sheets from Silver Scalpel interviews. These results clearly highlight that good trainers are first and foremost good doctors, and that good training goes hand-in-hand with excellent patient care. This symbiotic relationship between training and patient outcomes should be acknowledged, and trainers should be supported by their employers to empower them to carry out their dual roles of training and patient care to the best of their ability. Trainers are key role models to inspire the next generation of surgeons and exceptional trainers should be celebrated.

Post-operative C-reactive protein profile following abdominal wall reconstruction with transversus abdominis posterior components separation.

INTRODUCTION: Abdominal wall reconstruction using posterior component separation with transversus abdominis release (AWTAR) produces a unique post-operative CRP profile, when compared to routine elective colorectal operations. Therefore, we aim to establish the normal post-operative C-reactive protein (poCRP) profile following AWRTAR and reduce the unnecessary invasive interventions in patients already at greater risk of septic complications. METHODS: A retrospective analysis of daily poCRP levels was performed both for patients who underwent uncomplicated AWRTAR (n=12), and a comparator group of uncomplicated open right hemicolectomies (RH) matched for age and sex (n=24). All operations in both groups were performed by a single surgeon from 2013 to 2015. RESULTS: The median (IQR) age was 62 (16) and 67 (16) years respectively, with a higher proportion of males to females in both groups (10:2 vs. 17:7). The poCRP profile follows an initial steep rise, peaking at day 2 followed by a gradual washout phase. The poCRP peak is significantly greater in the AWRTAR group compared to the RH group (274 [95%CI ±25] vs. 160 [95%CI±27]; p=0.0001), with a positive correlation between day 2 CRP levels and operative length (r=0.56). CONCLUSIONS: We have demonstrated that uncomplicated AWRTAR provokes a significantly greater poCRP rise (>200) compared to that well described in the literature for uncomplicated open colectomy. As poCRP is an important marker of post-operative recovery with abnormally high levels associated with septic complications, these data should help clinicians interpret the post-operative clinical course after AWRTAR.

MUC13 protects colorectal cancer cells from death by activating the NF-κB pathway and is a potential therapeutic target.

MUC13 is a transmembrane mucin glycoprotein that is over produced by many cancers, although its functions are not fully understood. Nuclear factor-κB (NF-κB) is a key transcription factor promoting cancer cell survival, but therapeutically targeting this pathway has proved difficult because NF-κB has pleiotropic functions. Here, we report that MUC13 prevents colorectal cancer cell death by promoting two distinct pathways of NF-kB activation, consequently upregulating BCL-XL. MUC13 promoted tumor necrosis factor (TNF)-induced NF-κB activation by interacting with TNFR1 and the E3 ligase, cIAP1, to increase ubiquitination of RIPK1. MUC13 also promoted genotoxin-induced NF-κB activation by increasing phosphorylation of ATM and SUMOylation of NF-κB essential modulator. Moreover, elevated expression of cytoplasmic MUC13 and NF-κB correlated with colorectal cancer progression and metastases. Our demonstration that MUC13 enhances NF-κB signaling in response to both TNF and DNA-damaging agents provides a new molecular target for specific inhibition of NF-κB activation. As proof of principle, silencing MUC13 sensitized colorectal cancer cells to killing by cytotoxic drugs and inflammatory signals and abolished chemotherapy-induced enrichment of CD133+ CD44+ cancer stem cells, slowed xenograft growth in mice, and synergized with 5-fluourouracil to induce tumor regression. Therefore, these data indicate that combining chemotherapy and MUC13 antagonism could improve the treatment of metastatic cancers.