Association of diet-induced hyperinsulinemia with accelerated growth of prostate cancer (LNCaP) xenografts.
BACKGROUND
Prior research suggested that energy balance and fat intake influence prostate cancer progression, but the influence of dietary carbohydrate on prostate cancer progression has not been well characterized. We hypothesized that hyperinsulinemia resulting from high intake of refined carbohydrates would lead to more rapid growth of tumors in the murine LNCaP xenograft model of prostate cancer.


METHODS
Athymic mice were injected subcutaneously with LNCaP human prostate cancer cells and, when tumors were palpable, were randomly assigned (n = 20 per group) to high carbohydrate-high fat or low carbohydrate-high fat diets. Body weight and tumor volume were measured weekly. After 9 weeks, serum levels of insulin and insulin-like growth factor 1 (IGF-1) were measured by enzyme immunoassay. AKT activation and the levels of the insulin receptor in tumor cells were determined by immunoblotting. The in vitro growth response of LNCaP cells to serum from mice in the two treatment groups was measured based on tetrazolium compound reduction. All statistical tests were two-sided.


RESULTS
After 9 weeks on the experimental diets, mice on the high carbohydrate-high fat diet were heavier (mean body weight of mice on the high carbohydrate-high fat diet = 34 g versus 29.1 g on the low carbohydrate-high fat diet, difference = 4.9 g, 95% CI = 3.8 to 6.0 g; P = .003), experienced increased tumor growth (mean tumor volume in mice on high carbohydrate-high fat diet = 1695 versus 980 mm3 on low carbohydrate-high fat diet, difference = 715 mm3, 95% CI = 608 to 822 mm3; P<.001), and experienced a statistically significant increase in serum insulin and IGF-1 levels. Tumors from mice on the high carbohydrate-high fat diet had higher levels of activated AKT and modestly higher insulin receptor levels than tumors from mice on the low carbohydrate-high fat diet. Serum from mice on the high carbohydrate-high fat diet was more mitogenic for LNCaP cells in vitro than serum from mice fed the low carbohydrate-high fat diet.


CONCLUSIONS
A diet high in refined carbohydrates is associated with increased tumor growth and with activation of signaling pathways distal to the insulin receptor in a murine model of prostate cancer.
Venkateswaran
Vasundara
V
Division of Urology, S-118B, Sunnybrook Health Sciences Centre, 2075 Bayview Ave, Toronto, ON M4N3M5, Canada. vasundara.venkateswaran@sunnybrook.ca
Haddad
Ahmed Q
AQ
Fleshner
Neil E
NE
Fan
Rong
R
Sugar
Linda M
LM
Nam
Rob
R
Klotz
Laurence H
LH
Pollak
Michael
M
D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D001835:Body Weight; D015986:Confounding Factors, Epidemiologic; D004040:Dietary Carbohydrates / Q000008:administration & dosage / Q000009:adverse effects*; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects*; D004044:Dietary Proteins / Q000008:administration & dosage; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D006946:Hyperinsulinism / Q000097:blood / Q000150:complications* / Q000209:etiology*; D015151:Immunoblotting; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000097:blood / Q000209:etiology* / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011897:Random Allocation; D014183:Transplantation, Heterologous
D014408:Biomarkers, Tumor; D004040:Dietary Carbohydrates; D004041:Dietary Fats; D004044:Dietary Proteins; D007328:Insulin; D019394:Ki-67 Antigen; D007334:Insulin-Like Growth Factor I; D051057:Proto-Oncogene Proteins c-akt