An energy-dense diet high in fat, refined sugar and providing excess calories relative to energy expenditure that is typical of Western diets has been associated with an increased risk of prostate cancer (CaP). Increased intake of lycopene-rich foods, such as cooked tomatoes, is associated with a decreased risk of CaP. Insulin-like growth factor-I (IGF-I) is a potent mitogen that has been implicated as a critical factor in the development of CaP. The pro-oncogenic role of IGF-1 has been extensively demonstrated in both in vitro studies and in animal models of cancer as well as in human epidemiological cohorts. Serum IGF-I is regulated by caloric intake in both human and animal models and it has been proposed that certain nutrients that may prevent CaP, in particular lycopene, also modulate IGF-I levels. Our preliminary data suggest that men at high risk for CaP who adopt a very low fat, high fiber diet under residential conditions, have reduced serum IGF-1 levels and their sera have decreased mitogenicity for CaP cells in vitro. We have also demonstrated that in CaP xenograft-bearing SCID mice, a low-fat diet reduces serum IGF-I and leads to decreased mitogenicity of sera as well as to a marked reduction of tumor size and increased tumor apoptosis, when compared to mice fed a high fat, isocaloric diet. In addition, we studied TRAMP mice, a transgenic model of CaP (transgenic for SV40T antigen with a probasin promoter), and showed that decreasing caloric intake by 20% lowered serum IGF-I levels and decreased tumor incidence and severity. IGF-I infusion to these diet-restricted TRAMP mice restored serum IGF-I to ad-lib levels and caused an increase in tumor incidence similar to that seen in the ad-lib group. These studies led us to theorize that IGF-I is an important oncogenic circulating molecule, whose levels can be modulated by dietary composition. We hypothesize that that bioavailable IGF-I within the microenvironment of prostate epithelial cells in vitro is a major determinant of CaP development and progression. Therefore, modulation of IGF-I levels by nutritional factors may be an important potential therapeutic target for determination of CaP risk and progression. Our proposed studies will determine if dietary fat and/or lycopene regulate serum-bioavailable IGF-I in a manner that determine the development of CaP.
Our specific aims are to: 1) Establish the effects of modulating dietary fat content from 42 to 12% on serum IGF-I and the concurrent progression of CaP in TRAMP mice and determine whether infusion of IGF-I is capable of reversing any reduction of tumor progression in the low-fat-fed group. 2) Examine the effects of genetically lowered serum IGF-I on the progression of CaP in LID mice, in which the liver IGF-I gene has been selectively deleted using Cre-Lox technology and in whom circulating IGF-I levels are 25% of normal, mated with TRAMP mice. 3) Determine if a high-fat diet modulates CaP progression and/or serum IGF-I in the LID-TRAMP model to assess the linkage between serum IGF-I, dietary fat and CaP. 4) Examine the relationships of dietary lycopene and fat in modulating CaP progression and/or serum IGF-I in the TRAMP and LID/TRAMP models. We will determine the relative importance of free (bioavailable) IGF-I as compared to total IGF-I (which is bound to IGFBPs) in the development of CaP by developing new, specific assays for mouse free and total IGF-I, IGFBP-3 and IGFBP-1 Our studies will provide definitive information regarding the role of IGF-I as an important nutritionally regulated serum marker for CaP risk and progression and will allow the design of logical strategies to determine of the efficacy of dietary interventions in CaP prevention and treatment in humans.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100938-03
Application #
6896901
Study Section
Special Emphasis Panel (ZCA1-SRRB-U (J1))
Program Officer
Kim, Young Shin
Project Start
2003-06-13
Project End
2008-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
3
Fiscal Year
2005
Total Cost
$339,300
Indirect Cost
Name
University of California Los Angeles
Department
Pediatrics
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Vidal, Adriana C; Howard, Lauren E; de Hoedt, Amanda et al. (2018) Neutrophil, lymphocyte and platelet counts, and risk of prostate cancer outcomes in white and black men: results from the SEARCH database. Cancer Causes Control 29:581-588
Vidal, Adriana C; Howard, Lauren E; de Hoedt, Amanda et al. (2018) Obese patients with castration-resistant prostate cancer may be at a lower risk of all-cause mortality: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. BJU Int 122:76-82
Freedland, Stephen J; Vidal, Adriana C; Howard, Lauren E et al. (2017) Race and risk of metastases and survival after radical prostatectomy: Results from the SEARCH database. Cancer 123:4199-4206
Skove, Stephanie L; Howard, Lauren E; Aronson, William J et al. (2017) Timing of Prostate-specific Antigen Nadir After Radical Prostatectomy and Risk of Biochemical Recurrence. Urology 108:129-134
Moreira, Daniel M; Howard, Lauren E; Sourbeer, Katharine N et al. (2017) Predicting Time From Metastasis to Overall Survival in Castration-Resistant Prostate Cancer: Results From SEARCH. Clin Genitourin Cancer 15:60-66.e2
Leapman, Michael S; Freedland, Stephen J; Aronson, William J et al. (2016) Pathological and Biochemical Outcomes among African-American and Caucasian Men with Low Risk Prostate Cancer in the SEARCH Database: Implications for Active Surveillance Candidacy. J Urol 196:1408-1414
Moreira, Daniel M; Howard, Lauren E; Sourbeer, Katharine N et al. (2016) Predictors of Time to Metastasis in Castration-resistant Prostate Cancer. Urology 96:171-176
Klaassen, Zachary; Howard, Lauren; Terris, Martha K et al. (2015) Does larger tumor volume explain the higher prostate specific antigen levels in black men with prostate cancer--Results from the SEARCH database. Cancer Epidemiol 39:1066-70
Klaassen, Zachary; Singh, Abhay A; Howard, Lauren E et al. (2015) Is clinical stage T2c prostate cancer an intermediate- or high-risk disease? Cancer 121:1414-21
Moreira, D M; Howard, L E; Sourbeer, K N et al. (2015) Predicting bone scan positivity in non-metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis 18:333-7

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