Colorectal cancer is a leading cause of death in the United States. It is now clear that alterations in a number of genes play critical roles in the development of colorectal cancer. In this regard, mutations in ras proto-oncogenes, particularly K-ras mutations, are important genetic alterations which appear to be intimately involved in the pathogenesis of approximately one-half of human colorectal cancers. Recently, our laboratory has reported that K-ras mutations could also be detected in a high percentage of colonic tumors of rats treated with 1,2 dimethylhydrazine (DMH). Moveover, we have shown that certain dietary regimens, involving calcium and vitamin D, can modulate the frequency of K-ras mutations in these tumors. Cellular ras proto-oncogenes encode a family of related, yet distinct, 21 kDA proteins referred to as p21ras, that possess guanine nucleotide binding capacity and GTPase activity and play important roles in membrane signaling events involved in normal cell growth and differentiation. Although highly regulated in normal tissue, the Ras proteins can be constitutively activated by several mechanisms that enhance their transforming ability in colonocytes. Wild type and mutated p21ras interact with signal transduction pathways involving tyrosine kinases and protein kinase C(PKC). These interactions appear to be intimately involved in p21ras-induced colonic malignant transformation. Using the DMH model, we propose to test the hypothesis that colon cancer may involve at least three distinct pathways: 1) K-ras mutated, constitutively activated oncogenic p21ras; 2) K-ras non-mutated, constitutively activated proto-oncogenic (wild type) p21ras, and 3) K-ras independent pathways. Furthermore, we hypothesize that although these pathways may share common components, each is characterized by unique alterations in important signal transduction elements. The present studies will, therefore, address the following specific aims: A) Characterize and compare the signal transduction events which are altered in the presence and absence of constitutively activated p21ras in tumors of rats treated with DMH, with particular emphasis on those events involving PKC and other down-stream effectors of Ras: B) Modulate K-ras mutations in this model, utilizing various experimental manipulations, to establish the causal relationship between activation of mutated p21ras and alterations in signal transduction events identified in Specific Aim A; and C) Begin to systematically define the functional consequences of alterations in the signal transduction pathways found in the DMH model by modulating their expression in CaCo-2 cells, a human colon cancer cell line.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA036745-19
Application #
6375700
Study Section
Special Emphasis Panel (NSS)
Project Start
1983-07-29
Project End
2003-06-30
Budget Start
2001-07-01
Budget End
2003-06-30
Support Year
19
Fiscal Year
2001
Total Cost
$337,833
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
Mustafi, Reba; Dougherty, Urszula; Mustafi, Devkumar et al. (2017) ADAM17 is a Tumor Promoter and Therapeutic Target in Western Diet-associated Colon Cancer. Clin Cancer Res 23:549-561
Hasebe, Takumu; Matsukawa, Jun; Ringus, Daina et al. (2017) Daikenchuto (TU-100) Suppresses Tumor Development in the Azoxymethane and APCmin/+ Mouse Models of Experimental Colon Cancer. Phytother Res 31:90-99
Chen, Nai-Tzu; Souris, Jeffrey S; Cheng, Shih-Hsun et al. (2017) Lectin-functionalized mesoporous silica nanoparticles for endoscopic detection of premalignant colonic lesions. Nanomedicine 13:1941-1952
Mustafi, Devkumar; Ward, Jesse; Dougherty, Urszula et al. (2015) X-ray fluorescence microscopy demonstrates preferential accumulation of a vanadium-based magnetic resonance imaging contrast agent in murine colonic tumors. Mol Imaging 14:
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Dougherty, Urszula; Mustafi, Reba; Sadiq, Farhana et al. (2014) The renin-angiotensin system mediates EGF receptor-vitamin d receptor cross-talk in colitis-associated colon cancer. Clin Cancer Res 20:5848-5859
Wojdyla, Luke; Stone, Amanda L; Sethakorn, Nan et al. (2014) T-oligo as an anticancer agent in colorectal cancer. Biochem Biophys Res Commun 446:596-601
Mustafi, Reba; Dougherty, Urszula; Shah, Hardik et al. (2012) Both stromal cell and colonocyte epidermal growth factor receptors control HCT116 colon cancer cell growth in tumor xenografts. Carcinogenesis 33:1930-9
Chen, Peili; Kartha, Sreedharan; Bissonnette, Marc et al. (2012) AMP-18 facilitates assembly and stabilization of tight junctions to protect the colonic mucosal barrier. Inflamm Bowel Dis 18:1749-59

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