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PubMed1990

Industrial risk factors for colorectal cancer.

Colorectal cancer is the second most common malignancy in the United States, and its incidence rates have sharply increased recently, especially in males. Industrial exposures, both occupational and environmental, are important colorectal cancer risk factors that are generally unrecognized by clinicians. Migration studies have documented that colorectal cancer is strongly associated with environmental risk factors. The causal role of occupational exposures is evidenced by a substantial literature associating specific work practices with increased colorectal cancer risks. Industrially related environmental exposures, including polluted drinking water and ionizing radiation, have also been associated with excess risks. Currently, there is a tendency to attribute colorectal cancer, largely or exclusively, to dietary and other lifestyle factors, thus neglecting these industrially related effects. Concerted efforts are needed to recognize the causal role of industrial risk factors and to encourage government and industry to reduce carcinogenic exposures. Furthermore, cost-effective screening programs for high-risk population groups are critically needed to further reduce deaths from colorectal cancer.

Colorectal Neoplasms↗

PubMed2002

The role of proteomics in the diagnosis and outcome prediction in colorectal cancer.

Colorectal cancer is the second most frequent cancer in Western countries. Exogenous factors play a major role in the aetiology of sporadic colorectal cancer representing about 90% of all cases, hereditary cancers accounting for about 10% of patients. Thus, in the large majority of cases, cell dysfunction in CRC results from multiple rather than single, gene interactions. Numerous cellular events and environmental influences modify gene expression or post-translational protein modifications. Changes like glycosylation of proteins and lipids which are a common feature in colorectal cancer and influence cancer cell behaviour, cannot be directly detected by genetic studies. Better than genomics studies, functional proteomics studies allow the investigation of environmental factors over time, allowing the monitoring of metabolic responses to various stimuli. However, proteomics studies also have several drawbacks: a) current tools only allow narrow-range analyses, b) identification of proteins of interest remains cumbersome, c) protein studies address multiple compounds of high complexity, d) large amount of proteins are necessary to allow analysis, e) protein research require specific tools, e.g. tagged antibodies, that first have to be developed. Some protein tests are already in application for CRC: a classical prognostic test in colorectal cancer is based on the detection and quantification of a single protein (CEA) in body fluids. Recently, a screening assay based on APC protein truncation test has also been proposed. However, studies linking large protein expression patterns with clinical outcome in colorectal cancer are still in their infancy. To be able to predict occurrence of disease, and treatment outcome, more studies on genotype-phenotype correlations are needed both in sporadic and in hereditary colorectal cancer.

Colorectal Neoplasms↗

PubMed1996

[Advances in the treatment of colorectal cancer].

Colorectal cancer is one of the most serious diseases of our time. Recent progress in its treatment is reviewed in this paper. There are many approaches for treating colorectal cancer; extended surgery to function-preserving surgery. The aim of surgical treatment is to excise the tumor completely, so extended surgery has been performed for curative resection of colorectal cancer. However, the quality of life (QOL) of the patients has been extremely impaired. In recent years, surgical treatments for avoiding colostomy, and urinary and sexual difficulties have been widely carried out, and QOL of the patients could be maintained in the postoperative period. Stage-oriented therapy is accepted as the concept of surgical treatment of colorectal cancer. For further improving the clinical results of colorectal cancer, we advocated "type-oriented therapy" which is based on the biological characteristics of colorectal cancer, by determining i.e., p53 abnormalities of cancer cells, serum p53 antibodies, micrometastasis in the bone marrow and/or sensitivity to anticancer drugs.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2000

Utilization of K-ras mutations identified in stool DNA for the early detection of colorectal cancer.

Colorectal cancer is one of the most common malignancies in the western world. About 60,000 Americans die of colorectal cancer each year. The annual incidence rate in Israel is 40 per 100,000 persons, namely a total of 2,000 new cases each year. An important step in the progression of colorectal cancer includes induction of activating mutations in the proto-oncogene K-ras. The mutations in K-ras appear early during tumorigenesis, at the intermediate adenoma stage, and thus can be used as a biomarker for early detection in about 40% of colonic tumors. A large yet unknown number of mutated cells are shed from the developing tumor during its progression. Indeed, K-ras mutations were detected in DNA isolated from stool obtained from symptomatic and asymptomatic patients with colorectal cancer, suggesting a novel approach for a noninvasive screening procedure. However, severe difficulties in obtaining reproducible yields of amplifiable DNA from stool, and usage of nonquantitative, time-consuming procedures, hampered further progress in the utilization of K-ras mutations for the early detection of colorectal cancer. Apparently a novel protocol is required that provides reproducible output of amplifiable DNA from small amounts of stool, detects if K-ras mutated DNA is present, and determines the quantity of K-ras mutated cells in the stool sample. In addition, this protocol should be simple, robotics compatible, and thus suitable for cost-effective, large-scale mutation screening. Molecular assays for detecting K-ras mutations and additional biomarkers in stool DNA promise to be highly sensitive, specific, and cost-effective. As such they should be very effective when used in chemoprevention studies and screening protocols for colorectal cancer.

Biomarkers, Tumor↗

PubMed2006

Implications of CEA and p53 overexpression in the poor prognosis of colorectal cancer.

Colorectal cancer (CRC) is one of the most frequent and aggressive types of cancer. Several clinicopathologic features have been studied to identify the prognostic factors that can provide information concerning the favorable or the poor outcome of colorectal cancer. In the present study, the relationship between serum CEA, p53 expression, and DNA index to the different clinicopathological characteristics of colorectal cancer patients was sought. Fifty patients with CRC were included in this study. p53 protein was detected immunohistochemically using specific monoclonal antibodies. Samples were investigated for DNA index using flow cytometry. In addition, the serum CEA was determined using ELISA. The results showed that 27/50 (54%) were positive for p53. Concerning CEA reactivity, it was found that 35/50 (70%) were reactive for CEA. These results indicate that CEA is more sensitive than p53 to detect colorectal cancer. There was a statistically significant difference between the recurrent and nonrecurrent groups in the CRC Duke's stages, survival time, serum CEA (p = 0.001, 0.016, < 0.001, respectively). Kaplan-Meier method and log-rank test showed that the mean survival time for cases positive for both p53 and CEA is significantly different from cases positive for CEA only, positive for p53 only, and negative for both p53 and CEA (p = 0.0002). Survival time was statistically significant with respect to sex, p53, CEA, and Duke's stages (p = 0.006, 0.024, 0.001, 0.017, respectively). Cox regression model showed that the prognosis of colorectal cancer is influenced by sex, p53, CEA reactivity, and CRC Duke's stages (p = 0.014, 0.006, 0.019, 0.014, respectively). In conclusion, the use of more than one tumor marker may successfully aid in the prediction of colorectal cancer prognosis.

Adult↗

PubMed1998

Infrequent inactivation of DCC gene in replication error-positive colorectal cancers.

Colorectal cancers with and without the replication error (RER) exhibit fundamental differences in genotype and phenotype. While alterations in APC, p53, and K-ras genes have been characterized between RER+ and RER- colorectal cancers, the status of deleted in colorectal carcinomas (DCC) gene has not been yet. Alterations of DCC gene were analyzed in stage-matched two panels of 30 RER+ and 30 RER- colorectal cancers using semiquantitative reverse transcription-PCR and PCR-LOH analyses. Loss or reduction of DCC mRNA expression and allelic loss at the DCC locus were significantly less frequent in RER+ cancers than in RER- cancers. Interestingly, reduced DCC mRNA expression was observed in all 5 RER- cancers with liver metastasis. Our results support the concept that RER+ and RER- colorectal cancers represent different pathways of carcinogenesis and may give a hint for clarifying the specific mechanism of DCC inactivation in RER- colorectal cancers.

Colorectal Neoplasms↗

PubMed2002

Review article: genetic testing and counselling for hereditary colorectal cancer.

Colorectal cancer is the second leading cause of cancer death, after lung cancer, in the USA. The great majority (80%) of patients with colorectal cancer have sporadic disease with no evidence of having inherited the disorder. In the remaining 20%, a potentially definable genetic component exists. With the discovery of gene mutations related to hereditary colorectal cancer, risk assessment based on genetic test results is now feasible. The following review focuses on the two well-described colorectal cancer genetic syndromes-familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer, the process of genetic counselling, currently available genetic tests, and indications for their use.

Adenomatous Polyposis Coli↗

PubMedDate not supplied

Primary and secondary prevention of colorectal cancer.

Colorectal cancer is the third leading cause of cancer deaths in the United States. Because of the nature and the progression of the disease, it is highly preventable and suitable for screening. Yet the American Cancer Society estimates included over 100,000 cases of new occurrence of colorectal cancer and over 50,000 deaths in the year 2002. The continued high colorectal cancer mortality rate is due to the under utilization of screening tests. This review will explore the barriers to low screening test use. Implications for healthcare professionals on how to increase the general populations' awareness of colorectal cancer and ways to increase adherence to screening by integrating theories of the Health Belief Model will be discussed. The current research and literature about primary prevention focused on modifiable risk factors and chemoprevention will be examined. Secondary prevention, however, will be the key to help reduce the mortality and morbidity of colorectal cancer. The current screening guidelines will be reviewed as well. It is possible to increase screening rate by modifying and influencing patients' perceived cancer risk, and by educating and training healthcare providers.

Colonoscopy↗

PubMed1996

Genetic heterogeneity and unmapped genes for colorectal cancer.

Colorectal cancer (CRC) has a strong familial component. Candidate genes for colorectal cancer have been identified through mutations in four mismatch repair genes (hMSH2, hMLH1, hPMS1, and hPMS2) and genes that are deleted or mutated in tumors (DCC, APC, and p53). Linkage analysis of candidate loci/regions was performed in 10 kindreds ascertained for common colorectal cancer from the Utah Population Database. Evidence for linkage to candidate genes was assessed using two- or three-point logarithm of the odds ratio scores with markers spanning the region of localization. One kindred is linked to hMSH2 and also fits the criteria for hereditary nonpolyposis colorectal cancer, having early age of onset and high penetrance for CRC. The remaining nine kindreds are unlinked to the candidate genes tested. These kindreds have a later age of onset and a lower penetrance than hereditary nonpolyposis colorectal cancer kindreds. these results indicate that further unmapped susceptibility loci may be responsible for much of the familial aggregation of CRC.

Adult↗

PubMed2001

The molecular basis for prevention of colorectal cancer.

Colorectal cancer is the second leading cause of cancer death in the United States. Despite aggressive treatment and early screening strategies, the prognosis for patients with advanced disease remains poor. Extensive research examining familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC), two common forms of inherited colorectal cancer, have provided invaluable insights into some of the molecular mechanisms underlying both familial, as well as nonfamilial, colorectal cancer. The molecules involved in these pathways may provide effective targets for prevention and/or treatment of colorectal cancer. These targets include cyclooxygenase-2 (COX-2), peroxisome proliferator-activated receptor (PPAR)-delta, PPAR-gamma, transforming growth factor-beta receptor type II, epidermal growth factor receptor, and inducible-nitrous oxide synthase.

Colorectal Neoplasms↗

PubMed2004

Review article: chemoprevention of colorectal cancer.

Colorectal cancer is a disease with a high mortality at present, due to the late stage at which many cases present. Attention is therefore focusing on preventative strategies for colorectal cancer given that polyps appear to be identifiable and treatable precursor lesions of this disease. Endoscopic polypectomy has been shown to reduce the incidence of colorectal cancer and there is a good case for endoscopic screening of the general population. However, this will require a large amount of manpower and resources and its success will also depend on the overall compliance of the population. Epidemiological studies have shown that individuals reporting a regular intake of aspirin and other non-steroidal anti-inflammatory drugs have a reduced risk of developing colorectal polyps and cancer. Similarly, a number of natural substances, such as calcium and folate, when supplemented regularly in the diet, have also been linked to a possible decreased incidence of colorectal cancer. This has led to the concept of using such agents to reduce the number of cases of colorectal cancer. In this article, we review the current evidence for the use of these and other agents for the chemoprevention of colorectal cancer, together with theories as to their possible mechanisms of action.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2005

Global fibrinolytic capacity increased exponentially in metastatic colorectal cancer.

Colorectal cancers are one of the most common malignancies associated with coagulation abnormalities ranging from asymptomatic laboratory changes to massive thromboembolism or hemorrhage. It was previously shown that global fibrinolytic was increased in non-metastatic colorectal cancer. In this study global fibrinolytic capacity was measured in patients with colorectal cancer and metastatic liver disease, which always more commonly displays various coagulation disorders. Nineteen patients with biopsy-proven colorectal cancer, 30 patients with metastatic colorectal cancer, and 20 healthy control subjects were involved into the study. Using standart silicated fibrin pellets and tissue plasminogen activator, fibrinolytic capacity of the plasmas was detected with the amount of d-dimer produced before the reaction was stopped by adding aprotinin to the medium. Mean global fibrinolytic capacity (GFC) was increased to higher levels in patients with metastatic disease compared to levels in non-metastatic disease (p<0.05). Fibrinogen/GFC ratio correlated to the increase of d-dimer levels. Global fibrinolytic capacity was much higher in metastatic disease, reflecting a progression to overt disseminated intravascular coagulation.

Colorectal Neoplasms↗

PubMed1999

Screening and surveillance for colorectal cancer.

Colorectal cancer is the second most common cause of cancer death among American men and woman. Currently available screening and surveillance techniques are effective in detecting early-stage colorectal cancer and its premalignant precursor lesion, the adenomatous polyp (adenoma). Removal of adenomas by colonoscopic polypectomy significantly reduces the incidence of colorectal cancer. Appropriate screening and surveillance recommendations should be based on the individual's colorectal cancer risk stratification. High-risk groups, such as patients with hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP), should be offered genetic counseling and specialized screening recommendations for colorectal and associated extracolonic malignancies.

Colorectal Neoplasms↗

PubMed2003

[Primary and secondary prevention of colorectal cancer].

Colorectal cancer is really a public health problem. The authors review the literature about the environmental factors leading to colorectal cancer. Chemoprevention of colorectal cancer is also discussed, particularly by aspirin and non steroidal anti-inflammatory drugs. Development of specific cyclooxygenase-2 inhibitors constitutes a promising research's field. Secondary prevention by coloscopy and polypectomy must lead to a lower rate of colorectal cancer disease and improvement of mortality.

Colonoscopy↗

PubMed2005

An overview of apoptosis and the prevention of colorectal cancer.

Colorectal cancer arises as a result of the accumulation of genetic errors many of which affect the control of apoptosis. Effective chemoprevention strategies for colorectal cancer must rectify these genetic defects. Mutation of apc is often the initiating genetic lesion in colorectal cancers that develop along the chromosomal instability pathway. Depending on the cellular context, loss of apc activates the Wnt signalling pathway causing immediate widespread apoptosis of colorectal epithelial cells and defects in differentiation and cell migration. Only cells that are inherently resistant to apoptosis survive this initial wave of apoptosis. These surviving cells constitute the epithelial population that develop into adenomas. Two gene targets of the Wnt signalling pathway are of particular relevance to apoptosis. Although controversial, survivin may function to inhibit apoptosis. MYC has two outputs in normal cells, the induction of apoptosis and proliferation. These opposing functions work so that MYC can only induce cell proliferation in cells if apoptosis is disabled. p53 couples apoptosis to mitogenic signals and survival pathways. Under some circumstances, NF-kappaB can act as an inhibitor of apoptosis possibly through increased expression of bcl-x(L). Tumours that evolve by the microsatellite instability pathway often have mutations in the proapoptotic gene bax. Colonic adenomas express cyclo-oxygenase-2 (COX-2) and may be targets of chemoprevention before the development of malignancy. However, the recent discovery that coxibs increase the risk of serious cardiovascular events limits their use as chemopreventive agents. Nevertheless, aspirin remains a drug of great interest as it is already known to reduce the risk of colorectal cancer by up to 50%. The balance of evidence shows that high vegetable fibre diets can prevent colorectal cancer, probably via the fermentation of butyrate enhancing the apoptotic response to DNA damage.

Animals↗

PubMedDate not supplied

CT colonography: surveillance in patients with a history of colorectal cancer.

Colorectal cancer is a leading cause of morbidity and mortality in the United States. It is also a disease that is preventable if precursor adenomatous polys are removed. Once a diagnosis of colorectal cancer is made, surgical resection is the only means of cure. The ability to resect colorectal cancer for cure is largely dependent upon the stage of tumor at presentation. Once a patient has been treated for colorectal cancer with surgery and in some cases neo-adjuvant or adjuvant therapy, they will present for follow-up. Surveillance is performed on these patients in order to detect local recurrence that if detected early can be surgically resected for cure. Surveillance also allows detection of distant metastatic disease that may in some cases also be cured with resection. Finally, surveillance of the remaining colon is important to detect the development of new or metachronous adenomatoid polyps that if left in place could develop into new colon cancers. Imaging can play a part in patient surveillance to detect recurrent disease at extracolonic sites as well as the development of new colonic lesions. CT colonography is a promising tool for surveillance in patients with a history of colorectal cancer.

Colonic Polyps↗

PubMed1999

Racial and ethnic factors in the genetic pathogenesis of colorectal cancer.

Colorectal cancer can develop by two distinct pathogenic mechanisms: one involving chromosomal breakage and aneuploidy (called chromosomal instability) and one involving mutations at DNA micro-satellite sequences (termed micro-satellite instability). Relatively few reports consider these mechanisms of colorectal cancer development across racial or ethnic groups. Available data indicate a moderate increase in colorectal cancer risk among Ashkenazi Jews who have a mutational polymorphism at codon 1307 in the APC gene. In American blacks, there is evidence for a higher prevalence of right-sided colonic tumors and an earlier age of onset of colorectal cancer. In addition, blacks have the highest colon cancer incidence in the United States among ethnic groups and have poorer 5-year survival rates compared with whites. While some differences may be attributed to health care access and socioeconomic differences, these do not completely explain all the variances. In the chromosomal instability pathway, there are polymorphisms within the P53 gene that are more prevalent in blacks, but the significance of these polymorphisms is not fully known. Blacks are more likely to demonstrate micro-satellite instability in their tumors; however, the mechanism for this phenomenon in blacks is unexplored. Differences in diet among racial and ethnic groups and polymorphic variations in drug metabolizing or acetylation genes have not been adequately cataloged. Identification of genetic and environmental factors among racial and ethnic groups should offer some insights into the observed epidemiologic data and advance opportunities to better understand the control and development of colorectal cancer.

Adenoma↗

PubMed2004

A review of oxaliplatin and its clinical use in colorectal cancer.

Colorectal cancer is one of the leading causes of death from malignant diseases in the Western world. Worldwide, approximately 50% of patients who present with colorectal cancer will develop metastatic disease and eventually die from this malignancy. Recently, significant advances have been made in the medical treatment of advanced colorectal cancer with the introduction of novel cytotoxic drugs, such as irinotecan and oxaliplatin. Based on the results of recent Phase III trials, combination regimens of infusional 5-fluorouracil/leucovorin and oxaliplatin (FOLFOX) have emerged as a new standard of care in the palliative and adjuvant treatment of colorectal cancer. The addition of biological agents targeting angiogenesis or oncogenes such as epidermal growth factor receptor (EGFR) to FOLFOX will conceivably further enhance the activity of treatment regimens. Making use of all available active therapeutic options in the course of disease has significantly improved median overall survival of metastatic colorectal cancer into a chronic disease, with implications for treatment strategies and pharmacoeconomic considerations.

Animals↗