Elsevier

Toxicology Letters

Volumes 112–113, 15 March 2000, Pages 395-402
Toxicology Letters

The significance of aberrant crypt foci in understanding the pathogenesis of colon cancer

https://doi.org/10.1016/S0378-4274(99)00261-1Get rights and content

Abstract

Animal models provide a unique opportunity to study the biology of the disease process, and to test hypotheses linking environmental factors in the etiology and prevention of colon cancer. The concept of cancer prevention is to retard, regress or eliminate precancerous lesions. To actuate this concept, it is important to identify and enumerate preneoplastic lesions of various growth dimensions. The study of the precancerous stages in the colon is possible by the identification of aberrant crypt foci (ACF) in rodent colons treated with a carcinogen. The growth, morphological and molecular features of ACF support the contention that ACF are putative preneoplastic lesions. The ACF system is used extensively to identify modulators of colon carcinogenesis. Among the various endpoints being used in cancer research, ACF are the only endpoints which provides a quantitative approach to assess the disease process and the underlying cellular and molecular events as affected by cancer preventive or promoting agents. Many dietary components have been classified as tumor promoters or inhibitors based on their ability to change the tumor outcome. Whether they affect the growth of very early or advanced preneoplastic lesions is not known and can be explored by using ACF system. This information will provide a better understanding of cancer pathogenesis and will lead to the development of different cancer preventive strategies for high-risk individuals and the general population.

Introduction

Studies employing animal models provide the opportunity to test and refine the role of environmental factors in the etiology and prevention of colon cancer. The concept of cancer prevention involves regression, inhibition or elimination of precancerous lesions resulting in the reduction of cancer incidence. There is increasing thrust to actuate this concept in the general population as well as those individuals who are at high risk for developing colon cancer. It is well recognized that carcinogenesis is a multistep process involving the clonal selection and expansion of initiated preneoplastic cells. The clonally expanding cell population is generally termed as a preneoplastic lesion. A girth of information exists regarding the molecular features of the cancer cells. However, very little is known about the biology of the preneoplastic stages. This deficiency led to the identification and quantification of aberrant crypt foci (ACF). Since our first observation (Bird, 1987), knowledge of the biology of ACF and their value in the identification of modulators of colon carcinogenesis has expanded. The use of the ACF system as a tool to study colon carcinogenesis has been reviewed elsewhere (Bird et al., 1989, Bird, 1995, Bird, 1997). This report will provide a brief review of our recent findings that will provide further insight into the use of the ACF system in colon carcinogenesis.

Section snippets

Number and growth characteristics of aberrant crypt foci

The induction and growth characteristics of ACF have been described previously (Bird et al., 1989, Bird, 1995) and are summarized in Table 1, Table 2. Aberrant crypts appear within two weeks after carcinogen injection. Initially they appear as single crypts. They are visualized in the whole mount of colon by topographic examination of the colonic mucosa. A detailed method to visualize ACF has been recently described (Bird, 1998). Aberrant crypts are recognized by their dilated irregular luminal

Value of ACF as a biomarker of colon carcinogenesis

The ACF system is used as biomarker in the study of colon carcinogenesis. There are a number of other indicators currently being proposed as biomarkers including: cell cycle related proteins, quantification and location of proliferating cells in colonic tissue, differentiation markers, enzymatic alterations, expression of specific oncogenes or their products, however, an ‘ideal’ biomarker has yet to be found. The search for biomarkers is mainly to assess risk of developing colon cancer in an

Importance of experimental protocol in the identification of cancer preventive agents

Experimental protocols play an important role in determining the tumor outcome and need to be carefully chosen depending on the question being addressed. Different experimental protocols have been used to identify chemicals capable of affecting initiation as opposed to those that may affect post-initiation stages. Based on our knowledge of cancer development, one can suggest that cancer preventative agents should be classified based on their ability to affect preneoplastic lesions of different

ACF System and the molecular basis of the pathogenesis of colon cancer

The cellular and molecular events taking place during the development of preneoplastic lesions have remained unexplored. Our ability to visualize ACF has opened the opportunity to study the development of these lesions under a variety of growth stimulating and inhibitory environments. We are investigating a number of growth factors and enzymes in ACF varying in crypt multiplicity and histological atypia. We performed immunohistochemistry using a primary antibody against transforming growth

Conclusions

The preceding sections provide findings of selected studies to propose the notion that the ACF system can be used as a valuable tool to study colon specific carcinogens, cancer modulators and the carcinogenic process.

Acknowledgements

The studies described in this manuscript are support by funds received from the American Institute of Cancer Research, the Cancer Research Society Inc. and the Natural Sciences and Engineering Research Council of Canada.

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