Colorectal cancer stem cells

Colorectal cancer (CRC) is one of the most commonly diagnosed and lethal cancers worldwide. It is a multistep process that requires the accumulation of genetic/epigenetic aberrations. There are several issues concerning colorectal carcinogenesis that remain unanswered, such as the cell of origin and the type of cells that propagate the tumor after its initiation. There are two models of carcinogenesis: the stochastic and the cancer stem cell (CSC) model. According to the stochastic model, any kind of cell is capable of initiating and promoting cancer development, whereas the CSC model suggests that tumors are hierarchically organized and only CSCs possess cancer-promoting potential. Moreover, various molecular pathways, such as Wingless/Int (Wnt) and Notch, as well as the complex crosstalk network between microenvironment and CSCs, are involved in CRC. Identification of CSCs remains controversial due to the lack of widely accepted specific molecular markers. CSCs are responsible for tumor relapse, because conventional drugs fail to eliminate the CSC reservoir. Therefore, the design of CSC-targeted interventions is a rational target, which will enhance responsiveness to traditional therapeutic strategies and reduce local recurrence and metastasis. This review discusses the implications of the newly introduced CSC model in CRC, the markers used up to now for CSC identification, and its potential implications in the design of novel therapeutic approaches.     

结直肠息肉和结直肠癌

与结直肠癌相关的癌前病变包括结直肠腺瘤、非腺瘤性结直肠息肉病和炎症性肠病,认识这些癌前病变对于结直肠癌的预防、结直肠癌的危险性评估以及结直肠癌的诊断均具有重要意义。新的WHO结直肠癌定义的明确阐述提出了许多必须面对的新问题。     

Colorectal cancer vaccines in clinical trials

This article elucidates current strategies of active immunotherapy for colorectal cancer patients with a focus on T-cell mediated immunotherapy. Poor prognosis of especially stage III and IV colorectal cancer patients emphasizes the need for advanced therapeutic intervention. Here, we refer to clinical trials using either tumor cell-derived vaccines or tumor antigen vaccines with a special interest on safety, induced immune responses, clinical benefit and efforts to improve the clinical impact of these vaccines in the context of colorectal cancer treatment.     

Colorectal cancer in young black patients

A higher percentage of young black patients are discovered with a more advanced stage of colorectal cancer than is reported for white patients. To evalute this phenomenon, various prognostic factors in young colorectal cancer patients at Howard University Hospital were studied.     

Colorectal cancer pathology reporting: a regional audit.

AIMS: To audit the information content of pathology reports of colorectal cancer specimens in one National Health Service region. METHODS: All reports of colorectal cancer resection specimens from the 17 NHS histopathology laboratories in Wales during 1993 were evaluated against: (a) standards previously agreed as desirable by pathologists in Wales; and (b) standards considered to be the minimum required for informed patient management. RESULTS: 1242 reports were audited. There was notable variation in the performance of different laboratories and in the completeness of reporting of individual items of information. While many items were generally well reported, only 51.5% (640/ 1242) of rectal cancer reports contained a statement on the completeness of excision at the circumferential resection margin and only 30% (373/1242) of all reports stated the number of involved lymph nodes. All of the previously agreed items were contained in only 11.3% (140/1242) of reports on colonic tumours and 4.0% (40/1242) of reports on rectal tumours. Seventy eight per cent (969/1242) of colonic carcinoma reports and 46.6% (579/ 1242) of rectal carcinoma reports met the minimum standards. CONCLUSIONS: The informational content of many routine pathology reports on colorectal cancer resection specimens is inadequate for quality patient management, for ensuring a clinically effective cancer service through audit, and for cancer registration. Template proforma reporting using nationally agreed standards is recommended as a remedy for this, along with improved education, review of laboratory practices in the light of current knowledge, and further motivation of pathologists through their involvement in multidisciplinary cancer management teams.     

Colorectal cancer and the CHEK2 1100delC mutation

The CHEK2 1100delC mutation was recently identified as a low-penetrance breast cancer susceptibility allele. The mutation occurred more frequently in families with clustering of breast and colorectal cancers (CRCs) than in families with clustering of breast cancer only. Hence, the 1100delC mutation could also be a low-penetrance CRC susceptibility allele. To test this hypothesis, we examined the mutation in 629 unselected CRC cases, 230 controls, and 105 selected CRCs diagnosed in patients before age 50. The mutation was observed in 1.6% of unselected patients and in 0.3% of controls (Not significant (NS)). After stratifying unselected patients according to defined genetic risk (on the basis of age at diagnosis and family history of colorectal and endometrial cancer), the highest frequency was observed in high-risk patients (12.5%), followed by moderate-risk patients (3.3%), and was lowest in low-risk patients (1.0%, P(trend) 0.014). In selected patients, 1.6% carried the mutation (NS). Subgroup analyses for tumor localization, gender, and age at diagnosis did not reveal an association with the 1100delC genotype. In addition, a pooled analysis, combining data of one published study in unselected CRC cases and our study, also did not reveal an association. In conclusion, the frequency of the 1100delC genotype was neither significantly increased in unselected CRC patients nor in selected CRC patients diagnosed before age 50. However, after stratifying unselected CRC patients according to defined genetic risk, a significant trend of increasing frequency was observed. Together, the results are consistent with a low-penetrance effect (OR 1.5-2.0) of the CHEK2 1100delC on CRC risk. Large case-control studies are required to clarify the exact role of the CHEK2 1100delC mutation in CRC.     

Colorectal cancer registration: the central importance of pathology

BACKGROUND: Changes in cancer care have increased the importance of cancer registries in monitoring trends and outcomes. Registries are increasingly using computerised systems, such as patient administration and histopathology, as data sources. Omissions by registries can cause interpretation errors, but use of multiple data sources can overcome this. METHODS: Registrations of new colorectal cancers in Cornwall were compared with cases identified from primary sources over one year. RESULTS: Two hundred and thirty cases were identified locally, 93% in documentary records, 89.6% via histopathology, and 81.3% in the clinical data capture module of the patient administration system. Two hundred and forty four cases were known to the regional registry, but after eliminating wrongly assigned and unconfirmed cases only 201 remained. Twenty nine cases identified locally, particularly cases of advanced disease, were unknown to the registry. CONCLUSIONS: District registers based on histopathology augmented from other sources would provide more accurate and less biased information than existing regionally based methods.     

Colorectal cancer susceptibility loci as predictive markers of rectal cancer prognosis after surgery

To understand the molecular mechanism of rectal cancer and develop markers for disease prognostication, we generated and explored a dataset from 243 rectal cancer patients by gene expression microarray analysis of cancer samples and matched controls, and SNP‐arrays of germline DNA. We found that two of the loci most strongly linked with colorectal cancer (CRC) risk, 8q24 (upstream of MYC) and 18q21 (in the intron of SMAD7), as well as 20q13 (in the intron of LAMA5), are tightly associated with the prognosis of rectal cancer patients. For SNPs on 18q21 (rs12953717 and rs4464148) and 20q13 (rs4925386), alleles that correlate with higher risk for the development of CRC are associated with shorter disease free survival (DFS). However, for rs6983267 on 8q24, the low risk allele is associated with a higher risk for recurrence and metastasis after surgery, and importantly, is strongly correlated with the resistance of CRC cell lines to chemoradiotherapy (CRT). We also found that although MYC expression is dramatically increased in cancer, patients with higher levels of MYC have a better prognosis. The expression of SMAD7 is weakly correlated with DFS. Notably, the presence of the 8q24 and 18q21 SNP alleles is not correlated with expression levels of MYC and SMAD7. rs4464148, and probably rs6983267 and rs4925386, are linked with overall survival time of patients. In conclusion, we show that several CRC risk SNPs detect subpopulations of rectal cancer patients with poor prognosis, and that rs6983267 probably affects prognosis through interfering with the resistance of cancer cells to CRT.     

Colorectal cancer: surgical management of recurrent and metastatic disease

The surgeon''s responsibility to patients with colorectal cancer does not end with resection of the primary locoregional disease. The surgeon has a role to play in (1) designing and implementing strategies aimed at preventing recurrence, (2) early detection of recurrent disease, and (3) resective therapy of recurrent disease in selected instances, either with curative intent or for palliation. To perform these roles, the surgeon must have a thorough knowledge of catheter techniques for regional drug delivery, resective techniques for metastatic or locally recurrent disease, and combined surgical and radiotherapy approaches.     

Colorectal cancer: lessons for genetic counselling and care for families

Cancers of the colon and the rectum are the second leading cause of malignacy in European countries with similar incidence rates for men and women and, therefore, one of the major health concerns. Emphasis is placed on the early detection of a developing neoplasm in order to improve the life expectancy of patients and their quality of life. Colorectal cancer (CRC) is an excellent model for studying the etiology and pathogenesis of a common malignancy and the complex multistage process of carcinogenesis. Abundant clinical and pathological evidence suggests that CRC arises from benign adenomas that proceed through a series of steps to metastatic carcinomas. Following the discovery of oncogenes and, more importantly tumor suppressor genes, Fearon & Vogelstein (1990) proposed a scheme of genetic events which are associated with colorectal tumorigenesis. Genetic linkage studies have recently identified another type of gene for colon cancer susceptibility that seems to act by destabilising the genome.     

Colorectal cancer with and without microsatellite instability involves different genes.

There is evidence supporting a multistep genetic model for colorectal tumorigenesis. In familial adenomatosis polyposis (FAP), the inherited defect is a mutation in the APC gene. The vast majority of all sporadic colorectal cancers also show mutations in the APC gene, and the tumorigenesis in sporadic colorectal cancer and FAP is assumed to involve the same genes. Hereditary nonpolyposis colorectal cancer (HNPCC) is associated with germline mutations in DNA mismatch repair genes and, as a result of defective mismatch repair, microsatellite instability (MSI) is frequently seen. Tumorigenesis in HNPCC was first thought to involve mutations in the same genes as in FAP and sporadic colorectal cancer. Recently, however, an alternative pathway to development of colorectal cancer has been suggested in colorectal tumors with MSI, compared to those tumors without the MSI phenotype. We used a consecutive series of 191 sporadic colorectal cancers to find out if there were any differences between the two groups of tumors regarding the prevalence of mutations in the APC, KRAS, TP53, and TGFbetaR2 genes. As expected, 86% (19/22) of MSI-positive tumors showed a mutation in TGFbetaR2, while only one of 164 (0.6%) MSI-negative tumors did. A highly statistically significant negative association was found between MSI and alterations in APC and TP53. The MSI-positive tumors were screened for mutations in exon 3 of beta-catenin, which has been suggested to substitute for the APC mutation in the genesis of colorectal cancer, without finding mutations in any of the 22 MSI-positive tumors. The number of mutations found in KRAS was lower in MSI-positive than in MSI-negative tumors but the difference was not statistically significant. Our results strongly support the idea that carcinogenesis in MSI-positive and MSI-negative colorectal cancer develops through different pathways.