Micronutrients attenuate progression of prostate cancer by elevating the endogenous inhibitor of angiogenesis, platelet factor-4.
BACKGROUND
Longstanding evidence implicates an inadequate diet as a key factor in the onset and progression of prostate cancer. The purpose herein was to discover, validate and characterize functional biomarkers of dietary supplementation capable of suppressing the course of prostate cancer in vivo.


METHODS
The Lady transgenic mouse model that spontaneously develops prostate cancer received a diet supplemented with a micronutrient cocktail of vitamin E, selenium and lycopene ad libitum. A proteomic analysis was conducted to screen for serum biomarkers of this dietary supplementation. Candidate peptides were validated and identified by sequencing and analyzed for their presence within the prostates of all mice by immunohistochemistry.


RESULTS
Dietary supplementation with the combined micronutrients significantly induced the expression of the megakaryocyte-specific inhibitor of angiogenesis, platelet factor-4 (P = 0.0025). This observation was made predominantly in mice lacking tumors and any manifestations associated with progressive disease beyond 37 weeks of life, at which time no survivors remained in the control group (P < 0.0001). While prostates of mice receiving standard chow were enlarged and burdened with poorly differentiated carcinoma, those of mice on the supplemented diet appeared normal. Immunohistochemical analysis revealed marked amplifications of both platelet binding and platelet factor-4 within the blood vessels of prostates from mice receiving micronutrients only.


CONCLUSIONS
We present unprecedented data whereby these combined micronutrients effectively promotes tumor dormancy in early prostate cancer, following initiation mutations that may drive the angiogenesis-dependent response of the tumor, by inducing platelet factor-4 expression and concentrating it at the tumor endothelium through enhanced platelet binding.
1Department of Molecular and Cellular Biology, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5, Canada.
David
D
Cervi
Brian
B
Pak
Natalie A
NA
Venier
Linda M
LM
Sugar
Robert K
RK
Nam
Neil E
NE
Fleshner
Laurence H
LH
Klotz
Vasundara
V
Venkateswaran
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002338:Carotenoids / Q000008:administration & dosage; D019587:Dietary Supplements; D018450:Disease Progression; D007150:Immunohistochemistry; D000077276:Lycopene; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018977:Micronutrients / Q000008:administration & dosage*; D009389:Neovascularization, Pathologic / Q000097:blood / Q000235:genetics / Q000517:prevention & control*; D010973:Platelet Adhesiveness / Q000187:drug effects; D010978:Platelet Factor 4 / Q000097:blood*; D011471:Prostatic Neoplasms / Q000097:blood / Q000098:blood supply / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D040901:Proteomics; D012643:Selenium / Q000008:administration & dosage; D013997:Time Factors; D047368:Tumor Burden; D015854:Up-Regulation; D014810:Vitamin E / Q000008:administration & dosage
D020533:Angiogenesis Inhibitors; D016588:Anticarcinogenic Agents; D018977:Micronutrients; D014810:Vitamin E; D002338:Carotenoids; D010978:Platelet Factor 4; D012643:Selenium; D000077276:Lycopene