Environment-gene interactions in intestinal cancer.
Only 5-10% of all colorectal cancer in the United States can be directly attributed to inheritance of genetic predisposition for tumor development. Thus, the vast majority of colorectal cancer is classified as sporadic, and in these patients environmental factors--particularly the diet--play a major role in determining the probability of tumor formation and its progression. Investigations of how dietary components interact with genetic factors in cancer development have been extremely productive in terms of understanding the subtle and complex mechanisms that maintain homeostasis of the intestinal mucosa, and how perturbations in these mechanisms cause disease. We have found that the cyclin-dependent kinase inhibitor p21(WAF1/cip1) plays a major role in regulating several aspects of mucosal homeostasis and the response to dietary and pharmacologic modulators of tumorigenesis; that disruption of lineages of differentiation of intestinal epithelial cells are intimately involved in tumor formation; and that important pathways that contribute to normal homeostasis and cancer development may be coordinately regulated by mitochondrial function, with the mitochondrial membrane potential playing a key role. Several lines of evidence from our work have also suggested that intestinal epithelial cells have adapted to the environment that they usually encounter. This renders the cells competent to efficiently utilize factors in the intestinal lumen in normal metabolic and signaling pathways that contribute to homeostasis.
Augenlicht
Leonard H
LH
Department of Oncology, Albert Einstein Cancer Center, Montefiore Hospital, 111 East 210th Street, Bronx, NY 10467, USA. augen@aecom.yu.edu
Heerdt
Barbara G
BG
Mariadason
John M
JM
Yang
WanCai
W
Wilson
Andrew J
AJ
Fragale
Alessandra
A
Velcich
Anna
A
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D004032:Diet / Q000009:adverse effects*; D004195:Disease Models, Animal; D004781:Environmental Exposure / Q000009:adverse effects*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D015994:Incidence; D007413:Intestinal Mucosa / Q000473:pathology; D008297:Male; D051379:Mice; D010375:Pedigree; D011379:Prognosis; D012106:Research; D012307:Risk Factors; D015996:Survival Rate