Colon cancer is the third most common cancer in the United States. However, evidence indicates that a proper diet abundant in fruits and vegetables may be protective against colon cancer development. Bioactive compounds in fruits and vegetables, such as flavonoids and limonoids, have been shown to possess anti-proliferative and antitumorigenic effects in various in vitro and in vivo models of cancer. Since there are few animal studies involving flavonoids and limonoids and colon cancer, this experiment investigated the potentially protective effects of four citrus flavonoids and one limonoid mixture against the promotion stage of chemically-induced colon cancer in rats. Male SD rats (n =60; 10 rats/group) were assigned to receive diets containing 0.1% apigenin, 0.02% naringenin, 0.1% hesperidin, 0.01% nobiletin, 0.035% limonin glucoside/obacunone glucoside mixture, or a control diet (0% flavonoid/limonoid). Rats received the diets for 10 wk and were injected with azoxymethane (15 mg/kg) at wk 3 and 4. The excised colons were evaluated for aberrant crypt foci (ACF) formation, cell proliferation (PCNA assay), apoptosis (TUNEL assay), and iNOS and COX-2 expression. When compared to the control diet, apigenin lowered the number of high multiplicity ACF (> 4 AC/focus) by 57% (P<0.05) and tended to lower the proliferative index (28%; P=0.07), while naringenin lowered both the number of high multiplicity ACF by 51% (P<0.05) and the proliferative index by 32% (P<0.05). Both apigenin and naringenin increased apoptosis of surface colon cells (78% and 97%, respectively; P<0.05) when compared to control diet. Hesperidin, nobiletin, and the limoninglucoside/obacunone glucoside mixture did not have any effects on the above variables measured in this model of colon carcinogenesis. The colonic mucosal protein levels of iNOS or COX-2 were not different among the six diet groups. Evidence suggests that high multiplicity ACF are indicative of future tumor development in both humans and rats. Furthermore, dysregulated proliferation and apoptosis may also lead to tumorigenesis. Therefore, the ability of dietary apigenin and naringenin to reduce high multiplicity ACF, lower proliferation, and increase apoptosis may contribute toward colon cancer prevention. However, their protection is not due to their influence on iNOS and COX-2 protein levels.

We have previously shown that dietary fish oil and fiber, particularly the highly-fermentable pectin, are protective against colon cancer in a rat model of carcinogenesis. Therefore, based upon the current body of literature and our previous experimental findings, we hypothesized that one mechanism by which dietary fish oil+pectin suppress the promotion stage of colon cancer is through butyrate, the fermentation product of fiber, targeting (in particular) the p21Waf1/Cip1 gene and, via targeted histone hyperacetylation, inducing its expression. We found that dietary butyrate supplementation increased the concentration of fecal butyrate (mole %) in the distal colon, and that this increase corresponded to an increase in histone H4 acetylation. Similarly, diets supplemented with butyrate increased p21Waf1/Cip1 expression despite azoxymethane (AOM) treatment, which was not seen in non-butyrate supplemented diets. Furthermore, fish oil+butyrate diets resulted in the highest levels of apoptosis and the lowest levels of ACF, while corn oil+butyrate diets resulted in the lowest levels of apoptosis and the highest levels of ACF. Thus, it appears that the protective effect of fish oil+butyrate is due to the unique properties of fish oil, providing an environment in which butyrate’s enhancement of histone acetylation and p21 expression are pro-apoptotic, thereby diminishing pre-neoplastic ACF development.

No description available.

Colorectal cancer is the second leading cause of death from cancer (men and women combined) in the U.S. and Canada. The mainstay of treatment remains surgical resection and although new agents are constantly emerging to treat colorectal cancer, to date none of the agents have been successful at curing patients with advanced disease. In recent years there has been an increasing interest in the notion that cancers are organized as a hierarchy with the cancer-initiating cell (C-IC or cancer stem cell) existing at the apex. The C-ICs only represent a subset of the total tumour cells; however, research indicates that they are responsible for both the initiation and maintenance of tumour growth. In the studies presented here, we determined that human colon cancers are organized in a hierarchical manner. Furthermore, we prospectively isolated a subset of colon cancer-initiating cells (CC-ICs) based on the expression of the cell surface marker, CD133. The identification of CC-ICs has led to a number of questions concerning the molecular mechanisms driving these cells. Functionally all C-ICs are characterized by their ability to: i) generate a xenograft that histologically resembles the parent tumour from which it was derived, (ii) be serially transplanted in a xenograft assay thereby demonstrating the ability to self-renew and, (iii) generate daughter cells that possess some proliferative capacity but are unable to maintain the cancer because they lack intrinsic regenerative potential. It is becoming evident that cancer cells evolve as a result of their ability to hijack normal self-renewal pathways, a process that can drive malignant transformation. Studying self-renewal in the context of cancer and C-IC maintenance will lead to a better understanding of the mechanisms driving tumour growth. In this work we demonstrate that the inhibitors of differentiation genes (Id1 and Id3) play a central role in driving self-renewal in the CC-IC subset. Furthermore, we demonstrate that this effect is partially mediated through the cdk-inhibitor, p21cip1/waf1.

Colorectal cancer is the second leading cause of death from cancer (men and women combined) in the U.S. and Canada. The mainstay of treatment remains surgical resection and although new agents are constantly emerging to treat colorectal cancer, to date none of the agents have been successful at curing patients with advanced disease. In recent years there has been an increasing interest in the notion that cancers are organized as a hierarchy with the cancer-initiating cell (C-IC or cancer stem cell) existing at the apex. The C-ICs only represent a subset of the total tumour cells; however, research indicates that they are responsible for both the initiation and maintenance of tumour growth. In the studies presented here, we determined that human colon cancers are organized in a hierarchical manner. Furthermore, we prospectively isolated a subset of colon cancer-initiating cells (CC-ICs) based on the expression of the cell surface marker, CD133. The identification of CC-ICs has led to a number of questions concerning the molecular mechanisms driving these cells. Functionally all C-ICs are characterized by their ability to: i) generate a xenograft that histologically resembles the parent tumour from which it was derived, (ii) be serially transplanted in a xenograft assay thereby demonstrating the ability to self-renew and, (iii) generate daughter cells that possess some proliferative capacity but are unable to maintain the cancer because they lack intrinsic regenerative potential. It is becoming evident that cancer cells evolve as a result of their ability to hijack normal self-renewal pathways, a process that can drive malignant transformation. Studying self-renewal in the context of cancer and C-IC maintenance will lead to a better understanding of the mechanisms driving tumour growth. In this work we demonstrate that the inhibitors of differentiation genes (Id1 and Id3) play a central role in driving self-renewal in the CC-IC subset. Furthermore, we demonstrate that this effect is partially mediated through the cdk-inhibitor, p21cip1/waf1.

Includes bibliographical references (leaves 136-156) / 156 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Two novel in vitro preparations were developed from which recordings were made from colonic afferents in the rat and mouse. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 2001

Thesis (Ph. D. in Cancer Biology)--Vanderbilt University, May 2008. / Title from title screen. Includes bibliographical references.

Thesis (M.S.)--Oregon State University, 2008. / Printout. Includes bibliographical references (leaves 75-76). Also available on the World Wide Web.

Thesis (Ph.D.)--Harvard University, 1991. / Includes bibliographical references (p. 259-282).

Thesis (Ph.D.) -- University of Adelaide, Dept. of Medicine, 2000. / Errata pasted onto t.p. verso. Bibliography: leaves 129-148.