Update and latest advances in mechanisms and management of colitis-associated colorectal cancer

Colitis-associated colorectal cancer(CAC)is defined as a specific cluster of colorectal cancers that develop as a result of prolonged colitis in patients with inflammatory bowel disease(IBD).Patients with IBD,including ulcerative colitis and Crohn’s disease,are known to have an increased risk of developing CAC.Although the incidence of CAC has significantly decreased over the past few decades,individuals with CAC have increased mortality compared to individuals with sporadic colorectal cancer,and the incidence of CAC increases with duration.Chronic inflammation is generally recognized as a major contributor to the pathogenesis of CAC.CAC has been shown to progress from colitis to dysplasia and finally to carcinoma.Accumulating evidence suggests that multiple immune-mediated pathways,DNA damage pathways,and pathogens are involved in the pathogenesis of CAC.Over the past decade,there has been an increasing effort to develop clinical approaches that could help improve outcomes for CAC patients.Colonoscopic surveillance plays an important role in reducing the risk of advanced and interval cancers.It is generally recommended that CAC patients undergo endoscopic removal or colectomy.This review summarizes the current understanding of CAC,particularly its epidemiology,mechanisms,and management.It focuses on the mechanisms that contribute to the development of CAC,covering advances in genomics,immunology,and the microbiome;presents evidence for management strategies,including endoscopy and colectomy;and discusses new strategies to interfere with the process and development of CAC.These scientific findings will pave the way for the management of CAC in the near future.

Ulcerative colitis-associated colorectal cancer

The association between ulcerative colitis(UC) and colorectal cancer(CRC) has been acknowledged. One of the most serious and life threatening consequences of UC is the development of CRC(UC-CRC). UC-CRC patients are younger, more frequently have multiple cancerous lesions, and histologically show mucinous or signet ring cell carcinomas. The risk of CRC begins to increase 8 or 10 years after the diagnosis of UC. Risk factors for CRC with UC patients include young age at diagnosis, longer duration, greater anatomical extent of colonic involvement, the degree of inflammation, family history of CRC, and presence of primary sclerosing cholangitis. CRC on the ground of UC develop from non-dysplastic mucosa to indefinite dysplasia, lowgrade dysplasia, high-grade dysplasia and finally to invasive adenocarcinoma. Colonoscopy surveillance programs are recommended to reduce the risk of CRC and mortality in UC. Genetic alterations might play a role in the development of UC-CRC. 5-aminosalicylates might represent a favorable therapeutic option for chemoprevention of CRC.

TNFR1 Deficiency Protects Mice from Colitis-Associated Colorectal Cancer Coupled with a Decreased Level of Oxidative Damage in the Colon: Implications for Anti-TNF Therapy of Unremitting Colitis

It has long been appreciated that there is a direct relationship between the intensity and duration of inflammatory bowel diseases (IBD) and increasing intestinal cancer risk but which elements of the inflammatory response are responsible have not been identified. Anti-TNF drugs have been successful at treating IBD but considering the presumed anti-tumor activity of TNF, it is important to understand whether the treatment impacts on the patients’ intestinal cancer risk. We modeled this relationship by “treating mice lacking TNF receptors with a colon cancer causing combination of azoxymethane followed by repeated dextran sulphate sodium exposures (AOM + DSS regime). TNF receptor type1 gene deficient (TNFR1-/-) and TNFR2-/- mice experienced similar clinical illnesses and colonic inflammation as C57BL/6 wildtype controls during the AOM + DSS regime. Despite the inflammation, TNFR1-/- mice developed significantly fewer colon tumors than the other strains. The reduced tumor incidence was a product of the combined lack of receptor expression on hematopoietic and nonhematopoietic cells, shown using bone marrow cell chimeras of wildtype and TNFR1-/- mice. As oxidative damage is a potent contributing factor to tumorigenesis and inflammatory leukocytes make copious amounts of reactive oxygen radicals, we measured oxidative damage in the animals’ colons. TNFR1-/- mice showed less damage compared to the other strains. We subsequently examined mice deficient in their leukocyte NADPH oxidative pathway (Nox2-/-) for their cancer incidence using the AOM + DSS regime. Nox2-/- mice became inflamed but had fewer tumors than wildtype mice. We conclude that TNF promotes colon cancer including through promoting oxidative processes utilizing TNFR1 in leukocytes. Moreover, the C57BL/6 strain can be used to dissociate mechanisms of colon inflammation from tumorigenic processes. We interpret our results to mean that IBD patients on TNF antagonist therapies will potentially benefit with reduced colon cancer risk even if they do not respond with reduced inflammation.

Biomarkers for colitis-associated colorectal cancer

Patients with extensive ulcerative colitis(UC) of more than eight years duration have an increased risk of colorectal cancer. Molecular biomarkers for dysplasia and cancer could have a great clinical value in managing cancer risk in these UC patients. Using a wide range of molecular techniques- including cutting-edge OMICS technologies- recent studies have identified clinically relevant biomarker candidates from a variety of biosamples, including colonic biopsies, blood, stool, and urine. While the challenge remains to validate these candidate biomarkers in multi-center studies and with larger patient cohorts, it is certain that accurate biomarkers of colitis-associated neoplasia would improve clinical management of neoplastic risk in UC patients. This review highlights the ongoing avenues of research in biomarker development for colitis-associated colorectal cancer.

Liver transplantation as an alternative for the treatment of non-resectable liver colorectal cancer: Advancing the therapeutic algorithm

Colorectal cancer is a leading cause of cancerrelated mortality,with nearly half of the affected patients developing liver metastases.For three decades,liver resection(LR)has been the primary curative strategy,yet its applicability is limited to about 20%of cases.Liver transplantation(LT)for unresectable metastases was attempted unsuccessfully in the 1990s,with high rates of perioperative death and recurrence.There is now more interest in this strategy due to improvements in systemic therapies and surgical techniques.A significant study conducted by the Oslo group showed that patients receiving liver transplants had a 60%chance of survival after five years.Significantly better results have been achieved by using advanced imaging for risk stratification and further refining selection criteria,especially in the Norvegian SECA trials.This review carefully charts the development and history of LT as a treatment option for colorectal cancer liver metastases.The revolutionary path from the early days of exploratory surgery to the current situation of cautious optimism is traced,highlighting the critical clinical developments and improved patient selection standards that have made LT a potentially curative treatment for such challenging very well selected cases.

Trends in colorectal cancer incidence according to an increase in the number of colonoscopy cases in Korea

BACKGROUND The incidence of colorectal cancer(CRC)and preinvasive CRC(e.g.,early colon cancer and advanced adenoma)is gradually increasing in several countries.AIM To evaluate the trend in incidence of CRC and preinvasive CRC according to the increase in the number of colonoscopies performed in Korea.METHODS This retrospective cohort study enrolled Korean patients from 2002 to 2020 to evaluate the incidence of CRC and preinvasive CRC,and assess the numbers of diagnostic colonoscopies and colonoscopic polypectomies.Colonoscopy-related complications by age group were also determined.RESULTS The incidence of CRC showed a rapid increase,then decreased after 2012 in the 50-75 year-age group.During the study period,the rate of incidence of preinvasive CRC increased at a similar level in patients under 50 and 50-75 years of age.Since 2009,the increase has been rapid,showing a pattern similar to the increase in colonoscopies.The rate of colonoscopic polypectomy in patients aged under 50 was similar to the rate in patients over 75 years of age after 2007.The rate of complications after colonoscopy and related deaths within 3 mo was high for those over 75 years of age.CONCLUSION The diagnosis of preinvasive CRC increased with the increase in the number of colonoscopies performed.As the risk of colonoscopy-related hospitalization and death is high in the elderly,if early lesions at risk of developing CRC are diagnosed and treated under or at the age of 75,colonoscopy-related complications can be reduced for those aged 76 years or over.

Improving the value of molecular testing:current status and opportunities in colorectal cancer precision medicine

Colorectal cancer(CRC)is the second leading cause of cancer-related deaths worldwide1.Surgical radical resection with adjuvant chemotherapy remains the primary treatment choice for CRC,but the 5-year postoperative survival rate is only approximately 60%,and approximately one-third of patients with CRC experience recurrence within 2 years of surgery2.Fortunately,the transformation of high-throughput sequencing has accelerated the development of precision medicine.For example,KRAS mutations indicate resistance to anti-epidermal growth factor receptor(EGFR)-targeted therapies in CRC3.Furthermore,molecular-guided individualized therapy has brought new promise in major clinical areas and challenges,such as novel biomarkers predicting sensitivity and resistance to immunotherapy for microsatellite stable(MSS)CRC.

Recent clinical trials and optical control as a potential strategy to develop microtubule-targeting drugs in colorectal cancer management

Colorectal cancer(CRC)has remained the second and the third leading cause of cancer-related death worldwide and in the United States,respectively.Although significant improvement in overall survival has been achieved,death in adult populations under the age of 55 appears to have increased in the past decades.Although new classes of therapeutic strategies such as immunotherapy have emerged,their application is very limited in CRC so far.Microtubule(MT)inhibitors such as taxanes,are not generally successful in CRC.There may be some way to make MT inhibitors work effectively in CRC.One potential advantage that we can take to treat CRC may be the combination of optical techniques coupled to an endoscope or other fiber optics-based devices.A combination of optical devices and photo-activatable drugs may allow us to locally target advanced CRC cells with highly potent MT-targeting drugs.In this Editorial review,we would like to discuss the potential of optogenetic approaches in CRC management.

Application of exosomal miRNA mediated macrophage polarization in colorectal cancer:Current progress and challenges

Colorectal cancer(CRC)is a major global health problem with high morbidity and mortality rates.Surgical resection is the main treatment for early-stage CRC,but detecting it early is challenging.Therefore,effective therapeutic targets for advanced patients are still lacking.Exosomes,tiny vesicles in body fluids,play a crucial role in tumor metastasis,immune regulation,and drug resistance.Interestingly,they can even serve as a biomarker for cancer diagnosis and prognosis.Studies have shown that exosomes can carry miRNA,mediate the polarization of M1/M2 macrophages,promote the proliferation and metastasis of cancer cells,and affect the prognosis of CRC.Since the gastrointestinal tract has many macrophages,understanding the mechanism behind exosomal miRNA-mediated macrophage polarization in CRC treatment is crucial.This article summarizes recent advancements in the study of exosomal miRNAs in CRC and their potential as diagnostic and prognostic markers.

Stage at diagnosis of colorectal cancer through diagnostic route:Who should be screened?

BACKGROUND Colorectal cancer(CRC)is a global health concern,with advanced-stage diagnoses contributing to poor prognoses.The efficacy of CRC screening has been well-established;nevertheless,a significant proportion of patients remain unscreened,with>70%of cases diagnosed outside screening.Although identifying specific subgroups for whom CRC screening should be particularly recommended is crucial owing to limited resources,the association between the diagnostic routes and identification of these subgroups has been less appreciated.In the Japanese cancer registry,the diagnostic routes for groups discovered outside of screening are primarily categorized into those with comorbidities found during hospital visits and those with CRC-related symptoms.AIM To clarify the stage at CRC diagnosis based on diagnostic routes.METHODS We conducted a retrospective observational study using a cancer registry of patients with CRC between January 2016 and December 2019 at two hospitals.The diagnostic routes were primarily classified into three groups:Cancer screening,follow-up,and symptomatic.The early-stage was defined as Stages 0 or I.Multivariate and univariate logistic regressions were exploited to determine the odds of early-stage diagnosis in the symptomatic and cancer screening groups,referencing the follow-up group.The adjusted covariates were age,sex,and tumor location.RESULTS Of the 2083 patients,715(34.4%),1064(51.1%),and 304(14.6%)belonged to the follow-up,symptomatic,and cancer screening groups,respectively.Among the 2083 patients,CRCs diagnosed at an early stage were 57.3%(410 of 715),23.9%(254 of 1064),and 59.5%(181 of 304)in the follow-up,symptomatic,and cancer screening groups,respectively.The symptomatic group exhibited a lower likelihood of early-stage diagnosis than the follow-up group[P<0.001,adjusted odds ratio(aOR),0.23;95%confidence interval(95%CI):0.19-0.29].The likelihood of diagnosis at an early stage was similar between the follow-up and cancer screening groups(P=0.493,aOR for early-stage diagnosis in the cancer screening group vs follow-up group=1.11;95%CI=0.82-1.49).CONCLUSION CRCs detected during hospital visits for comorbidities were diagnosed earlier,similar to cancer screening.CRC screening should be recommended,particularly for patients without periodical hospital visits for comorbidities.

Prognostic and predictive role of immune microenvironment in colorectal cancer

Colorectal cancer(CRC)represents a molecularly heterogeneous disease and one of the most frequent causes of cancer-related death worldwide.The traditional classification of CRC is based on pathomorphological and molecular character-istics of tumor cells(mucinous,ring-cell carcinomas,etc.),analysis of mechanisms of carcinogenesis involved(chromosomal instability,microsatellite instability,CpG island methylator phenotype)and mutational statuses of commonly altered genes(KRAS,NRAS,BRAF,APC,etc.),as well as expression signatures(CMS 1-4).It is also suggested that the tumor microenvironment is a key player in tumor progression and metastasis in CRC.According to the latest data,the immune microenvironment can also be predictive of the response to immune checkpoint inhibitors.In this review,we highlight how the immune environment influences CRC prognosis and sensitivity to systemic therapy.

Small nucleolar RNA and its potential role in the oncogenesis and development of colorectal cancer

Small nucleolar RNAs(snoRNAs)represent a class of non-coding RNAs that play pivotal roles in post-transcriptional RNA processing and modification,thereby contributing significantly to the maintenance of cellular functions related to protein synthesis.SnoRNAs have been discovered to possess the ability to influence cell fate and alter disease progression,holding immense potential in controlling human diseases.It is suggested that the dysregulation of snoRNAs in cancer exhibits differential expression across various cancer types,stages,metastasis,treatment response and/or prognosis in patients.On the other hand,colorectal cancer(CRC),a prevalent malignancy of the digestive system,is characterized by high incidence and mortality rates,ranking as the third most common cancer type.Recent research indicates that snoRNA dysregulation is associated with CRC,as snoRNA expression significantly differs between normal and cancerous conditions.Consequently,assessing snoRNA expression level and function holds promise for the prognosis and diagnosis of CRC.Nevertheless,current comprehension of the potential roles of snoRNAs in CRC remains limited.This review offers a comprehensive survey of the aberrant regulation of snoRNAs in CRC,providing valuable insights into the discovery of novel biomarkers,therapeutic targets,and potential tools for the diagnosis and treatment of CRC and furnishing critical cues for advancing research into CRC and the judicious selection of therapeutic targets.

Overcoming geographical and socioeconomic limitations in colorectal cancer screening

Despite colorectal cancer’s(CRC)high global incidence,residents of low-and middle-income countries,as well as low-income minorities in advanced economies have low screening rates.Observational studies demonstrate that in these groups higher incidence of CRC is observed,yet screening rates remain low for consistent reasons.Low income,low educational background,and lack of awareness in combination with inadequate social security of certain population groups impede access and compliance rates to CRC screening.On the other hand,despite the global availability of multiple screening approaches(colonoscopy,sigmoidoscopy,faecal occult blood test,faecal immunochemical test,computed tomography-colonography,etc.)with proven diagnostic validity,many low-income countries still lack established screening programs.The absence of screening guidelines in these countries along with the heterogeneity of guidelines in the rest of the world,demonstrate the need for global measures to tackle this issue comprehensively.An essential step forward is to develop a global approach that will link specific elements of screening with the incidence and available resources in each country,to ensure the achievement of at least a minimum screening program in low-income countries.Utilizing cheaper,cost-effective techniques,which can be carried out by less specialized healthcare providers,might not be equivalent to endoscopy for CRC screening but seems more realistic for areas with fewer resources.Awareness has been highlighted as the most pivotal element for the effective implementation of any screening program concerning CRC.Moreover,multiple studies have demonstrated that outreach strategies and community-based educational programs are associated with encouraging outcomes,yet a centrally coordinated expansion of these programs could provide more consistent results.Additionally,patient navigator programs,wherever implemented,have increased CRC screening and improved follow-up.Therefore,global coordination and patient education seem to be the main areas on which policy making needs to focus.

Unraveling colorectal cancer prevention:The vitamin D-gut flora-immune system nexus

Colorectal cancer(CRC)is one of the most common cancers diagnosed in the world.Although environmental and genetic factors play a major role in the pathogenesis of CRC,extensive research has suggested that vitamin D may play a pivotal role in the development of CRC.Vitamin D,primarily obtained through sunlight exposure,dietary sources,and supplements,has long been recognized for its essential functions in maintaining health,including immune regulation.This article delves into the intricate relationship between vitamin D,the immune system,gut flora,and the prevention of CRC.It presents a synthesis of epidemiological data,experimental studies,and clinical trials,highlighting the mechanisms by which vitamin D influences immune cell function,cytokine production,and inflammation.By enhancing the immune system’s surveillance and antitumor activity,vitamin D may offer a promising avenue for CRC prevention.Furthermore,this comprehensive review delves into the prospective clinical applications of vitamin D supplementation and delineates the forthcoming avenues of research in this dynamic domain.Additionally,the paper tentatively outlines a spectrum of prophylactic impacts of vitamin D on CRC,emphasizing its significant potential in reducing CRC risk through shedding light on its mechanisms,encompassing antineoplastic mechanisms,influences on the immune system,and modulation of the gut microbiome.

Microbiota in colorectal cancer related to liver metastasis

The prevalence of colorectal cancer(CRC) is increasing annually and metastasis is the principal cause of death in patients with CRC, with the liver being the most frequently affected site. Many studies have shown a strong interplay between the gut flora, particularly Fusobacterium nucleatum(F. nucleatum), Escherichia coli, and Bacteroides fragilis, and the development of gut tumors. Some strains can induce gut inflammation and produce toxins that directly harm gut epithelial cells, ultimately accelerating the onset and progression of CRC. However,little clinical evidence exists on the specific interplay between the gut microflora and colorectal cancer liver metastasis(CRLM). Some research showed the existence of viable F. nucleatum in distant metastasis of CRC.Subsequently, gut microbiota products, such as lipopolysaccharides, sodium butyrate, and protein cathepsin K, were also found to affect the development of CRC. This article summarizes the mechanism and research status of the interplay between gut microflora and CRLM, discusses the importance of gut microflora in the treatment of CRLM, and proposes a new approach to understanding the mechanism of CRLM and potential treatments for the microbiome. It is anticipated that the gut microbiota will be a formidable therapeutic and prophylactic tool for treating and preventing CRLM.

Colorectal cancer screening:A review of current knowledge and progress in research

Colorectal cancer(CRC)is one of the most prevalent malignancies worldwide,being the third most commonly diagnosed malignancy and the second leading cause of cancer-related deaths globally.Despite the progress in screening,early diagnosis,and treatment,approximately 20%-25%of CRC patients still present with metastatic disease at the time of their initial diagnosis.Furthermore,the burden of disease is still expected to increase,especially in individuals younger than 50 years old,among whom early-onset CRC incidence has been increasing.Screening and early detection are pivotal to improve CRC-related outcomes.It is well established that CRC screening not only reduces incidence,but also decreases deaths from CRC.Diverse screening strategies have proven effective in decreasing both CRC incidence and mortality,though variations in efficacy have been reported across the literature.However,uncertainties persist regarding the optimal screening method,age intervals and periodicity.Moreover,adherence to CRC screening remains globally low.In recent years,emerging technologies,notably artificial intelligence,and non-invasive biomarkers,have been developed to overcome these barriers.However,controversy exists over the actual impact of some of the new discoveries on CRC-related outcomes and how to effectively integrate them into daily practice.In this review,we aim to cover the current evidence surrounding CRC screening.We will further critically assess novel approaches under investigation,in an effort to differentiate promising inno-vations from mere novelties.

Early colorectal cancer screening–no time to lose

In this editorial,we comment on the article entitled“Stage at diagnosis of colorectal cancer through diagnostic route:Who should be screened?”by Agatsuma et al.Colorectal cancer(CRC)is emerging as an important health issue as its incidence continues to rise globally,adversely affecting the quality of life.Although the public has become more aware of CRC prevention,most patients lack screening awareness.Some poor lifestyle practices can lead to CRC and symptoms can appear in the early stages of CRC.However,due to the lack of awareness of the disease,most of the CRC patients are diagnosed already at an advanced stage and have a poor prognosis.

Association of tumor budding with clinicopathological features and prognostic value in stage III-IV colorectal cancer

BACKGROUND Tumor budding(TB)has emerged as a promising independent prognostic biomarker in colorectal cancer(CRC).The prognostic role of TB has been extensively studied and currently affects clinical decision making in patients with stage I and II CRC.However,existing prognostic studies on TB in stage III CRC have been confined to small retrospective cohort studies.Consequently,this study investigated the correlation among TB categories,clinicopathological features,and prognosis in stage III-IV CRC to further enhance the precision and individualization of treatment through refined prognostic risk stratification.AIM To analyze the relationship between TB categories and clinicopathological characteristics and assess their prognostic value in stage III-IV CRC to further refine the prognostic risk stratification of stage III-IV CRC.METHODS The clinical data of 547 CRC patients were collected for this retrospective study.Infiltration at the front edge of the tumor buds was counted according to the 2016 International Tumor Budding Consensus Conference guidelines.RESULTS Multivariate Cox proportional hazards regression analysis demonstrated that chemotherapy(P=0.004),clinical stage IV(P<0.001),≥4 regional lymph node metastases(P=0.004),left-sided colonic cancer(P=0.040),and Bd 2-3(P=0.002)were independent prognostic factors in patients with stage III-IV CRC.Moreover,the density of tumor infiltrating lymphocytes was higher in Bd 1 than in Bd 2-3,both in the tumor stroma and its invasive margin.CONCLUSION TB has an independent predictive prognostic value in patients with stage III-IV CRC.It is recommended to complete the TB report of stage III-IV CRC cases in the standardized pathological report to further refine risk stratification.

Evaluating combined bevacizumab and XELOX in advanced colorectal cancer: Serum markers carcinoembryonic antigen, carbohydrate antigen 125, carbohydrate antigen 199 analysis

BACKGROUND Colorectal cancer ranks third and second among common and fatal cancers.The treatment of metastatic colorectal cancer(mCRC)is generally based on XELOX in clinical practice,which includes capecitabine(CAP)and oxaliplatin.Serum tumor markers carcinoembryonic antigen(CEA),carbohydrate antigen(CA)125 and CA199 are prognostic factors for various tumors.AIM To investigate evaluating combined bevacizumab(BEV)and XELOX in advanced colorectal cancer:Serum markers CEA,CA125,CA199 analysis.METHODS In this retrospective study,a total of 94 elderly patients diagnosed with mCRC were recruited and subsequently categorized into two groups based on the distinct treatment modalities they received.The control group was treated with XELOX plus CAP(n=47),while the observation group was treated with XELOX plus CAP and BEV(n=47).Several indexes were assessed in both groups,including disease control rate(DCR),incidence of adverse effects,serum marker levels(CEA,CA125,and CA19)and progression-free survival(PFS).RESULTS After 9 wk of treatment,the serum levels of CEA,CA199 and CA125 in the observation group were significantly lower than those in the control group(P<0.05).Moreover,the PFS of the observation group(9.12±0.90 mo)was significantly longer than that of the control group(6.49±0.64 mo).Meanwhile,there was no statistically significant difference in the incidence of adverse reactions and DCR between the two groups during maintenance therapy(P>0.05).CONCLUSION On the basis of XELOX treatment,the combination of BEV and CAP can reduce serum tumor marker levels and prolong PFS in patients with mCRC.

Expression and significance of pigment epithelium-derived factor and vascular endothelial growth factor in colorectal adenoma and cancer

BACKGROUND The incidence and mortality of colorectal cancer(CRC)are among the highest in the world,and its occurrence and development are closely related to tumor neovascularization.When the balance between pigment epithelium-derived factors(PEDF)that inhibit angiogenesis and vascular endothelial growth factors(VEGF)that stimulate angiogenesis is broken,angiogenesis is out of control,resulting in tumor development.Therefore,it is very necessary to find more therapeutic targets for CRC for early intervention and later treatment.AIM To investigate the expression and significance of PEDF,VEGF,and CD31-stained microvessel density values(CD31-MVD)in normal colorectal mucosa,adenoma,and CRC.METHODS In this case-control study,we collected archived wax blocks of specimens from the Digestive Endoscopy Center and the General Surgery Department of Chengdu Second People's Hospital from April 2022 to October 2022.Fifty cases of specimen wax blocks were selected as normal intestinal mucosa confirmed by electronic colonoscopy and concurrent biopsy(normal control group),50 cases of specimen wax blocks were selected as colorectal adenoma confirmed by electronic colonoscopy and pathological biopsy(adenoma group),and 50 cases of specimen wax blocks were selected as CRC confirmed by postoperative pathological biopsy after inpatient operation of general surgery(CRC group).An immunohistochemical staining experiment was carried out to detect PEDF and VEGF expression in three groups of specimens,analyze their differences,study the relationship between the two and clinicopathological factors in CRC group,record CD31-MVD in the three groups,and analyze the correlation of PEDF,VEGF,and CD31-MVD in the colorectal adenoma group and the CRC group.The F test or adjusted F test is used to analyze measurement data statistically.Kruskal-Wallis rank sum test was used between groups for ranked data.The chi-square test,adjusted chi-square test,or Fisher's exact test were used to compare the rates between groups.All differences between groups were compared using the Bonferroni method for multiple comparisons.Spearman correlation analysis was used to test the correlation of the data.The test level(α)was 0.05,and a two-sided P<0.05 was considered statistically significant.RESULTS The positive expression rate and expression intensity of PEDF were gradually decreased in the normal control group,adenoma group,and CRC group(100%vs 78%vs 50%,χ^(2)=34.430,P<0.001;++~++vs+~++vs-~+,H=94.059,P<0.001),while VEGF increased gradually(0%vs 68%vs 96%,χ^(2)=98.35,P<0.001;-vs-~+vs++~+++,H=107.734,P<0.001).In the CRC group,the positive expression rate of PEDF decreased with the increase of differen-tiation degree,invasion depth,lymph node metastasis,distant metastasis,and TNM stage(χ^(2)=20.513,4.160,5.128,6.349,5.128,P<0.05);the high expression rate of VEGF was the opposite(χ^(2)=10.317,13.134,17.643,21.844,17.643,P<0.05).In the colorectal adenoma group,the expression intensity of PEDF correlated negatively with CD31-MVD(r=-0.601,P<0.001),whereas VEGF was not significantly different(r=0.258,P=0.07).In the CRC group,the expression intensity of PEDF correlated negatively with the expression intensity of CD31-MVD and VEGF(r=-0.297,P<0.05;r=-0.548,P<0.05),while VEGF expression intensity was positively related to CD31-MVD(r=0.421,P=0.002).CONCLUSION It is possible that PEDF can be used as a new treatment and prevention target for CRC by upregulating the expression of PEDF while inhibiting the expression of VEGF.