Mortality from upper gastrointestinal tumors in colorectal cancer screening patients.

Background and study aims Currently, gastric cancer screening is only cost-effective in countries with high incidence. Integrated screening, in which gastroscopy is performed in conjunction with colonoscopy, could help reduce the gastric cancer screening procedure burden in countries with low or intermediate incidence. However, there is a lack of population-based studies to identify high-risk groups. Methods In this retrospective analysis of a colorectal cancer (CRC) screening program database, we used Cox proportional hazards model to identify an association of high- and low-risk finding (polyps ≥ 10 mm or with high-grade dysplasia) with time to death from upper gastrointestinal cancer (esophageal and gastric). We estimated the 10-year mortality of upper gastrointestinal tumors in different 10-year age groups, stratified by sex and polyp finding at colonoscopy. Results We included 349,856 CRC screening colonoscopies in our study. The median follow-up time was 5.22 years (95% confidence interval [CI] 5.21-5.24 years). Of the participants, 4.5% had polyps ≥ 10 mm or with high-grade dysplasia (HGD). At the end of the study period, 384 deaths from upper gastrointestinal cancer had occurred. Aside from age and sex, we found the presence of high-risk polyps to be significantly associated with upper gastrointestinal cancer death (hazard ratio 1.54, 95% CI 1.06-2.25, P = 0.025). Conclusions CRC screening participants with polyps < 10 mm and no HGD have a lower risk for mortality from upper gastrointestinal cancers compared with participants with polyps > 10 mm and HGD. Future studies will demonstrate whether integrated screening with additional gastroscopy is effective in CRC screening participants with large or highly dysplastic polyps.

Impact of Bowel Preparation Quality on Colonoscopy Findings and Colorectal Cancer Deaths in a Nation-Wide Colorectal Cancer Screening Program.

INTRODUCTION: Adequate bowel preparation is paramount for a high-quality screening colonoscopy. Despite the importance of adequate bowel preparation, there is a lack of large studies that associated the degree of bowel preparation with long-term colorectal cancer outcomes in screening patients. METHODS: In a large population-based screening program database in Austria, quality of bowel preparation was estimated according to the Aronchick Scale by the endoscopist (excellent, good, fair, poor, and inadequate bowel preparation). We used logistic regression to assess the influence of bowel preparation on the detection of different polyp types and the interphysician variation in bowel preparation scoring. Time-to-event analyses were performed to investigate the association of bowel preparation with postcolonoscopy colorectal cancer (PCCRC) death. RESULTS: A total of 335,466 colonoscopies between January 2012 and follow-up until December 2022 were eligible for the analyses. As compared with excellent bowel preparation, adenoma detection was not significantly lower for good bowel preparation (odds ratio 1.01, 95% confidence interval [CI] 0.9971-1.0329, P = 0.1023); however, adenoma detection was significantly lower in fair bowel preparation (odds ratio 0.97, 95% CI 0.9408-0.9939, P = 0.0166). Individuals who had fair or lower bowel preparation at screening colonoscopy had significantly higher hazards for PCCRC death (hazard ratio for fair bowel preparation 2.56, 95% CI 1.67-3.94, P < 0.001). DISCUSSION: Fair bowel preparation on the Aronchick Scale was not only associated with a lower adenoma detection probability but also with increased risk of PCCRC death. Efforts should be made to increase bowel cleansing above fair scores.

Polyp size is associated with colorectal cancer death across histologic polyp subtypes: a retrospective study of a screening colonoscopy registry.

BACKGROUND: Surveillance colonoscopy after polyps have been detected at screening aims to reduce the risk for subsequent colorectal cancer, so-called post-colonoscopy colorectal cancer (PCCRC). Inconsistencies exist as to whether the risk should be stratified by histologic subtype. We aimed to compare the risk for PCCRC mortality in screening participants with sessile serrated lesions (SSLs)/traditional serrated adenomas (TSAs), hyperplastic polyps (HPPs), or conventional adenomas. METHODS: Screening colonoscopy registry data were linked to death registry data between 2010 and 2022. We assessed the association of PCCRC death after a diagnosis of SSL/TSA, conventional adenoma, or HPP by Cox regression, and stratified by polyp size ≥10 and <10 mm. RESULTS: 383,801 participants were included in the analysis. There were 1490 HPPs ≥10 mm (2.6%), compared with 1853 SSL/TSAs (19.6%) and 10,960 conventional adenomas (12.9%). When adjusted for polyp location, the association of polyp size ≥10 mm with PCCRC death was of similar magnitude in participants with conventional adenomas (hazard ratio [HR] 3.68, 95%CI 2.49-5.44), SSL/TSAs (HR 2.55, 95%CI 1.13-5.72), and HPPs (HR 5.01, 95%CI 2.45-10.22). Participants with HPPs mostly died of tumors in the distal colon (54.1%; n = 20), while participants with SSL/TSAs more frequently died of proximal tumors (33.3%; n = 3). CONCLUSIONS: Across all histologic types, participants with polyps ≥10 mm had at least a two-fold increase in the likelihood of PCCRC death compared with those with polyps <10 mm. These data suggest that size, rather than histologic subtype, should be a determinant for risk stratification after screening colonoscopy.

Differences between men and women with respect to colorectal cancer mortality despite screening colonoscopy.

BACKGROUND AND AIMS: Women aged 55 to 59 years have a similar prevalence rate and number needed to screen for colorectal adenomas as men at a 10-year younger age. The aim of this study was to determine sex-specific differences in colorectal cancer mortality and estimate the association with adenomas at screening colonoscopy. METHODS: This retrospective study analyzed 323,139 individuals who underwent colonoscopy within a national colorectal cancer screening program in Austria between January 2007 and December 2020. RESULTS: Median patient age was 60 years (interquartile range, 54-67), and the sex distribution in all age groups was nearly identical. Men had significantly higher odds of having an adenoma or serrated polyp, low-risk polyp, high-risk polyp, or colorectal cancer detected at colonoscopy than women (odds ratio [OR] 1.83; 95% confidence interval [CI], 1.80-1.86; OR, 1.46; 95% CI, 1.44-1.49; OR, 1.74; 95% CI, 1.69-1.80; and OR, 1.87; 95% CI, 1.70-2.05, respectively). Strikingly, male sex, when compared with female sex, was associated with an almost 2-fold (hazard ratio, 1.67; 95% CI, 1.05-2.67) increased risk to die from colorectal cancer when an adenoma or serrated polyp was found at the screening colonoscopy and a 4-fold (hazard ratio, 4.14; 95% CI, 2.72-6.3) increased risk when a high-risk polyp was found at the screening colonoscopy. The cumulative incidence for death of colorectal cancer for 60-year-old individuals was 8.5-fold higher in men as compared with women. Markedly, this sex gap narrowed with increasing age, whereas the difference in deaths of other causes remained similar in all age groups. CONCLUSIONS: Our findings strengthen the necessity of sex-specific screening recommendations. Importantly, further prospective studies should focus on sex differences in tumor biology to propose personalized surveillance guidelines.

Detection of high-risk polyps at screening colonoscopy indicates risk for liver and biliary cancer death.

BACKGROUND: Hepatobiliary cancers share risk factors with colorectal cancer (CRC), but there are no combined screening programs for these conditions. AIMS: The aim of this study was to assess whether patients with high-risk colonic polyps are more likely to die from liver related tumors than patients with a negative colonoscopy. METHODS: In this retrospective analysis of mortality data, Austrian screening participants were included. The absolute risk for hepatobiliary cancer death was calculated using the cumulative incidence method. We aimed to identify an association with time to death of hepatobiliary cancer by Cox proportional hazards model. RESULTS: 343,838 colonoscopies performed between 01/2007 and 12/2020 were included in the analysis, of which 17,678 (5.14%) revealed high-risk polyps. Overall hepatobiliary cancer mortality was more than twice as high in patients with high risk polyps (cumulative incidence 0.39%, 95% CI 0.37-0.41%) compared to patients with a negative colonoscopy (cumulative incidence 0.17%, 95% CI 0.17-0.17%). When adjusting for age and sex, having high-risk polyps at screening colonoscopy was significantly associated with hepatobiliary cancer death (HR 1.83, 95% CI 1.29- 2.59, p < 0.001). CONCLUSIONS: Patients with certain colonic polyp characteristics are at increased risk for mortality of liver malignancies. Further studies are needed to determine whether a structured additional screening for liver diseases and consecutive malignancies might be beneficial in these patients.

Colorectal Cancer and Precursor Lesion Prevalence in Adults Younger Than 50 Years Without Symptoms.

Importance: Incidence of colorectal cancer (CRC) is increasing among younger adults. However, data on precursor lesions in patients who are asymptomatic, especially those aged younger than 50 years, are lacking. Objective: To analyze the prevalence and number needed to screen (NNS) for adenomas, advanced adenomas, and serrated lesions, as well as the incidence of CRC in patients older than age 20 years. Design, Setting, and Participants: This cohort study was conducted among 296 170 patients who received a screening colonoscopy within a national screening colonoscopy registry from 2012 to 2018 in Austria, including 11 103 patients aged younger than 50 years. CRC incidence was analyzed using data from Statistic Austria from 1988 to 2018. Data were analyzed in September 2021. Main Outcome and Measures: The prevalence of adenomas and other lesions and the incidence of CRC in individuals aged 20 years or older were assessed. Results: Among 296 170 patients included in the study (median [IQR] age, 60 [54-68] years; 150 813 females [50.9%]), 11 103 patients (3.7%) were aged younger than 50 years and 285 067 patients (96.3%) were aged 50 years or older. Among patients younger than age 50 years, 1166 individuals (10.5%; NNS = 9) had adenomas and 389 individuals (3.9%; NNS = 26) had at least 1 advanced adenoma, while among those aged 50 years or older, 62 384 individuals (21.9%; NNS = 5) had adenomas and 19 680 individuals (6.9%; NNS = 15) had at least 1 advanced adenoma. Among 1128 males aged 40 to 44 years, 160 individuals (14.2%; NNS = 7) had at least 1 adenoma, and among 1398 females aged 40 to 44 years, 114 individuals (8.1%; NNS = 12) had at least 1 adenoma. The prevalence of adenomas for individuals aged 45 to 49 years vs 50 to 54 years was 490 of 2879 males (17.1%; NNS = 6) vs 8269 of 40 935 males (20.2%; NNS = 5) and 284 of 2792 females (10.2%; NNS = 10) vs 4997 of 40 303 females (12.4%; NNS = 8), respectively. Prevalence of adenomas changed from 61 of 498 individuals (12.4%) in 2008 to 150 of 1064 individuals (14.1%) in 2018 among those younger than 50 years and from 2646 of 12 166 individuals (21.8%) to 10 673 of 37 922 individuals (28.2%) among those aged 50 years and older. The prevalence of advanced adenomas changed from 20 individuals (4.0%) in 2008 to 55 individuals (5.2%) in 2018 in individuals younger than 50 years and from 888 individuals (7.3%) in 2008 to 2578 individuals (6.8%) in 2018 among those aged 50 years and older. Among individuals younger than age 50 years, CRC incidence per 100 000 individuals changed from 9.1 incidents in 1988 to 10.2 incidents in 2018 among males (average annual percentage change [AAPC], 0.5%; 95% CI, 0.1% to 1.0%) and from 9.7 incidents in 1988 to 7.7 incidents in 2018 among females, with a nonsignificant AAPC (-0.2%; 95% CI, -0.7% to 0.3%). Among individuals aged 50 years or older, CRC incidence per 100 000 individuals changed from 168 incidents in 1988 to 97 incidents in 2018 among females (AAPC, -1.8%; 95% CI, -1.9% to -1.6%), and 217 incidents in 1988 to 143 incidents in 2018 among males (AAPC, -1.2%; 95% CI, -1.3% to -1.1%). Conclusion: In this study, CRC incidence decreased after 1988 in Austria among individuals older than 50 years, while among patients younger than 50 years, incidence increased among males but decreased among females. Prevalence of adenomas increased in all age groups, while advanced adenoma prevalence increased among patients younger than 50 years but decreased in patients aged 50 years and older.

Gas6 in chronic liver disease-a novel blood-based biomarker for liver fibrosis.

The expression of the receptor tyrosine kinase Axl and its cleavage product soluble Axl (sAxl) is increased in liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). In this multicenter study, we evaluated the diagnostic value of Gas6, the high-affinity ligand of Axl, in patients with chronic liver disease. Levels of sAxl and Gas6, and their albumin (alb) ratios were analyzed in serum samples of patients with biopsy-proven liver fibrosis, end-stage liver disease, HCC, and healthy controls, and were compared to Fibrosis-4 (FIB-4), enhanced liver fibrosis (ELF™) test, Child-Pugh score (CPS), model of end-stage liver disease (MELD) score, hepatic venous pressure gradient, and α-fetoprotein, respectively. A total of 1111 patients (median age 57.8 y, 67.3% male) was analyzed. Gas6/alb showed high diagnostic accuracy for the detection of significant (≥F2: AUC 0.805) to advanced fibrosis (≥F3: AUC 0.818), and was superior to Fib-4 for the detection of cirrhosis (F4: AUC 0.897 vs. 0.878). In addition, Gas6/alb was highly predictive of liver disease severity (Odds ratios for CPS B/C, MELD ≥ 15, and clinically significant portal hypertension (CSPH) were 16.534, 10.258, and 12.115), and was associated with transplant-free survival (Hazard ratio 1.031). Although Gas6 and Gas6/alb showed high diagnostic accuracy for the detection of HCC in comparison to chronic liver disease patients without cirrhosis (AUC 0.852, 0.868), they failed to discriminate between HCC in cirrhosis versus cirrhosis only. In conclusion, Gas6/alb shows a high accuracy to detect significant to advanced fibrosis and cirrhosis, and predicts severity of liver disease including CSPH.

Non-Canonical Activin A Signaling Stimulates Context-Dependent and Cellular-Specific Outcomes in CRC to Promote Tumor Cell Migration and Immune Tolerance.

We have shown that activin A (activin), a TGF-ß superfamily member, has pro-metastatic effects in colorectal cancer (CRC). In lung cancer, activin activates pro-metastatic pathways to enhance tumor cell survival and migration while augmenting CD4+ to CD8+ communications to promote cytotoxicity. Here, we hypothesized that activin exerts cell-specific effects in the tumor microenvironment (TME) of CRC to promote anti-tumoral activity of immune cells and the pro-metastatic behavior of tumor cells in a cell-specific and context-dependent manner. We generated an Smad4 epithelial cell specific knockout (Smad4-/-) which was crossed with TS4-Cre mice to identify SMAD-specific changes in CRC. We also performed IHC and digital spatial profiling (DSP) of tissue microarrays (TMAs) obtained from 1055 stage II and III CRC patients in the QUASAR 2 clinical trial. We transfected the CRC cells to reduce their activin production and injected them into mice with intermittent tumor measurements to determine how cancer-derived activin alters tumor growth in vivo. In vivo, Smad4-/- mice displayed elevated colonic activin and pAKT expression and increased mortality. IHC analysis of the TMA samples revealed increased activin was required for TGF-ß-associated improved outcomes in CRC. DSP analysis identified that activin co-localization in the stroma was coupled with increases in T-cell exhaustion markers, activation markers of antigen presenting cells (APCs), and effectors of the PI3K/AKT pathway. Activin-stimulated PI3K-dependent CRC transwell migration, and the in vivo loss of activin lead to smaller CRC tumors. Taken together, activin is a targetable, highly context-dependent molecule with effects on CRC growth, migration, and TME immune plasticity.

Gastrointestinal endoscopy devices and the European Union Medical Device Regulation: European Society of Gastrointestinal Endoscopy (ESGE) Position Statement.

Gastrointestinal endoscopy is largely dependent on medical devices. The European Union (EU) has recently introduced stricter rules and regulations for the approval of medical devices. This has consequences both for endoscopists and for patients. The new regulations increase the need for clinical trials and observational studies for new and current devices used in endoscopy to ensure clinical benefit and reduce patient harm. European endoscopy environments should facilitate industry-sponsored clinical trials and registry studies to meet the demand for robust data on endoscopic devices as required in the new legislation. The European Society of Gastrointestinal Endoscopy (ESGE) will play an active role in the establishment of the new system.The EU is establishing independent expert panels for device regulation in gastroenterology and hepatology, including endoscopy, that are charged with assessing the requirements for device testing. The ESGE encourages endoscopists with expertise in the technical and clinical performance of endoscopy devices to apply for expert panel membership. The ESGE has provided information for interested endoscopists on the ESGE website. Private European companies called "notified bodies" are entitled to conduct device approval for the EU. The ESGE will actively engage with these notified bodies for topics related to the new endoscopy device approval process to ensure continued access to high quality endoscopy devices for endoscopists in Europe.

Polyp characteristics at screening colonoscopy and post-colonoscopy colorectal cancer mortality: a retrospective cohort study.

BACKGROUND AND AIMS: Polyp size and high-grade dysplasia in polyps at screening colonoscopy are considered risk factors for post-colonoscopy colorectal cancer (PCCRC) development and death, which might be averted by surveillance colonoscopy. However, robust evidence backing these risk factors is lacking. We aimed to investigate whether polyp size or dysplasia grade is associated with PCCRC mortality. METHODS: This was a retrospective study including individuals of the Austrian Quality Certificate for Screening Colonoscopy who underwent a colonoscopy between January 2007 and December 2020. We investigated the association of polyp size and dysplasia in polyps with PCCRC mortality according to Cox regression analysis. In addition, whether patients with certain polyp characteristics had similar risk for CRC death compared with the Austrian population was assessed by calculating standardized mortality ratios (SMRs). RESULTS: A total of 316,001 individuals were included. After a median follow-up time of 5.27 years (95% confidence interval [CI], 5.25-5.29), a significant association of polyps 10 to 20 mm (hazard ratio, 4.00; 95% CI, 2.46-6.50; P < .001) as well as high-grade dysplasia (hazard ratio, 6.61; 95% CI, 3.31-13.2; P < .001) with PCCRC death was observed. PCCRC mortality was significantly lower than the expected CRC mortality in the general population in patients with polyps <10 mm and without high-grade dysplasia (SMR, .27; 95% CI, .21-.33; P < .001), which was not observed for patients with polyps ≥10 mm or with high-grade dysplasia (SMR, 2.05; 95% CI, 1.64-2.57; P < .001). CONCLUSIONS: Polyp size ≥10 mm and high-grade dysplasia are associated with PCCRC mortality in screening patients. The data suggest that these patients might benefit most from surveillance colonoscopy.

Comparison of adenoma detection rate and proximal serrated polyp detection rate and their effect on post-colonoscopy colorectal cancer mortality in screening patients.

BACKGROUND: Patients with serrated polyps are at increased risk for post-colonoscopy colorectal cancer (PCCRC); however, evidence for a dedicated serrated polyp detection rate is lacking. The aim of this study was to investigate the association of the proximal serrated polyp detection rate (PSDR) and adenoma detection rate (ADR) with PCCRC death. METHODS: This was a retrospective analysis within the Austrian quality assurance program for screening colonoscopy. Spearman's rank coefficient was calculated for the assessment of association between ADR and PSDR. Whether ADR or PSDR were associated with colorectal cancer mortality was assessed by Cox proportional hazards model. RESULTS: 229/729 screening colonoscopies performed by 308 endoscopists were analyzed. The ADR (hazard ratio [HR] per 1 percentage point increase 0.98, 95 %CI 0.96-0.99) as well as the PSDR (HR per 1 percentage point increase 0.97, 95 %CI 0.94-0.99) were significantly associated with PCCRC death. The correlation coefficient of the ADR and PSDR calculated at every colonoscopy was 0.70 (95 %CI 0.70-0.71), and the corresponding PSDR value for an ADR performance standard of 25 % was 11.1 %. At the end of the study period, 86 endoscopists (27.9 %) reached an ADR of > 25 % and a PSDR of > 11.1 %. CONCLUSIONS: The ADR as well as the PSDR were associated with PCCRC death. Striving for a high PSDR in addition to a high ADR might reduce the risk for PCCRC mortality in patients undergoing screening colonoscopy.

[Quality Assurance of Screening Colonoscopy in Austria and Europe]. / Qualitätssicherung in der Vorsorgekoloskopie in Österreich und europaweit.

Screening colonoscopy, an efficient tool for reducing the incidence and mortality of colorectal cancer, is only effective if it is performed under high quality standards. The European Society for Gastrointestinal Endoscopy has identified the following key performance measures for screening: adenoma detection rate, cecal intubation rate, and adequate bowel preparation rate. The Quality Certificate for Colorectal Cancer Screening-which was launched as a quality assurance program on a voluntary basis by the Austrian Society of Gastroenterology and Hepatology together with the umbrella organization of Austrian social insurance carriers and the Austrian Cancer Aid for endoscopists throughout Austria-monitors these quality parameters. The aim is to achieve the highest standards of colorectal cancer screening in order to achieve the best outcomes for patients. Interest in quality-assured screening colonoscopy is also high throughout Europe: many countries, e.g., the Netherlands, Norway, and the United Kingdom, have programs to monitor and improve the quality of screening.

Ultrasound-Guided Injections at the Lateral Femoral Cutaneous Nerve: The Inguinal Ligament as a Barrier.

BACKGROUND: Ultrasound-guided perineural injections at the lateral femoral cutaneous nerve (LFCN) may confirm the correct diagnosis and provide symptom relief in meralgia paresthetica. Although correct visualization of the nerve is generally described as feasible, failure rates of the procedure may be as high as 30%. OBJECTIVES: This study investigated the spread of injected fluids in ultrasound-guided perineural injections at the LFCN. The aim of the study was to evaluate whether the inguinal ligament impedes the distribution of injected fluids along the course of the LFCN. STUDY DESIGN: We used a descriptive research design. SETTING: Research was conducted at an anatomical research facility. METHODS: In fresh, nonembalmed cadavers, 2 mL of ink were injected with ultrasound-guidance at the LFCN below the inguinal ligament. The course of the nerve was then dissected to show the extent of nerve staining. RESULTS: Spread of the injected ink proximal to the inguinal ligament was found in 67.65% of specimens, while the ink did not pass the inguinal ligament in 32.35%. Concerning proximal spread, specimen body mass index was not of any relevance. LIMITATIONS: This cadaver study is only a simulation of the real clinical setting and does not allow any insight into the efficacy of the injection in living patients. CONCLUSIONS: The inguinal ligament is a barrier in the distribution of injected fluids in about one-third of specimens. This might be a major cause of failure in ultrasound-guided injections. The results from our study are in line with previously published failure rates and our findings might provide the anatomic basis to advance injection techniques. KEY WORDS: Cadaver study; injection; lateral femoral cutaneous nerve; LFCN; meralgia paresthetica; nerve entrapment; sonography; ultrasound.

Author Correction: Increased stiffness of the tumor microenvironment in colon cancer stimulates cancer associated fibroblast-mediated prometastatic activin A signaling.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Increased stiffness of the tumor microenvironment in colon cancer stimulates cancer associated fibroblast-mediated prometastatic activin A signaling.

Colorectal cancer (CRC) is the second deadliest cancer in the US due to its propensity to metastasize. Stromal cells and especially cancer-associated fibroblasts (CAF) play a critical biophysical role in cancer progression, but the precise pro-metastatic mechanisms are not clear. Activin A, a TGF-ß family member, is a strong pro-metastatic cytokine in the context of CRC. Here, we assessed the link between biophysical forces and pro-metastatic signaling by testing the hypothesis that CAF-generated mechanical forces lead to activin A release and associated downstream effects. Consistent with our hypothesis, we first determined that stromal activin A secretion increased with increasing substrate stiffness. Then we found that stromally-secreted activin A induced ligand-dependent CRC epithelial cell migration and epithelial to mesenchymal transition (EMT). In addition, serum activin A levels are significantly increased in metastatic (stage IV) CRC patients (1.558 ng/ml versus 0.4179 ng/ml, p < 0.05). We propose that increased tumor microenvironment stiffness leads to stromal cell-mediated TGF-ß family signaling relying on the induction and utilization of activin A signaling.

TGFß and activin A in the tumor microenvironment in colorectal cancer.

Although overall survival in colorectal cancer (CRC) is increasing steadily due to progress in screening, therapeutic options and precise diagnostic tools remain scarce. As the understanding of CRC as a complex and multifactorial condition moves forward, the tumor microenvironment has come into focus as a source of diagnostic markers and potential therapeutic targets. The role of TGFß in shifting the epithelial cancer compartment towards invasiveness and a pro-migratory phenotype via stromal signaling has been widely investigated. Accordingly, recent studies have proposed that CRC patients could be stratified into distinct subtypes and have identified one poor prognosis subset of CRC that is characterized by high stromal activity and elevated levels of TGFß. The TGFß superfamily member activin A is crucial for the pro-metastatic properties of the TGFß pathway, yet it has been under-researched in CRC carcinogenesis. In this review, we will elucidate the signaling network and interdependency of both ligands in the context of the tumor microenvironment in CRC.