IGF1 dependence of dietary energy balance effects on murine Met1 mammary tumor progression, epithelial-to-mesenchymal transition, and chemokine expression

Abstract

Luminal breast tumors with little or no estrogen receptor a expression confer poor prognosis. Using the Met1 murine model of luminal breast cancer, we characterized the IGF1-dependency of diet-induced obesity (DIO) and calorie restriction (CR) effects on tumor growth, growth factor signaling, epithelial-to-mesenchymal transition (EMT), and chemokine expression. Liver-specific IGF1-deficient (LID) and littermate control (LC) mice were administered control, DIO, or 30% CR diets for 3 months before orthotopic injection of Met1 cells. Tumors grew for 1 month and then were assessed for Akt pathway activation and mRNA expression of chemokine and EMT constituents. LID mice, regardless of diet, displayed reduced Met1 tumor growth and downregulated Akt, EMT, and chemokine pathways. CR, relative to control, reduced serum IGF1 and Met1 tumor growth in LC (but not LID) mice. DIO, relative to control, increased Met1 tumor growth and chemokine expression in LID mice, and had no effect on serum IGF1 or pAkt or cyclin D1 expression in either genotype. Thus, circulating IGF1 (in association with Akt, EMT, and chemokines) regulated Met1 tumor growth. While the anticancer effects of CR were largely IGF1-dependent, the procancer effects of DIO manifested only when circulating IGF1 levels were low. Thus, in a murine model of luminal breast cancer, IGF1 and its downstream signaling pathway, EMT, and chemokines present possible mechanistic regulatory targets. Transplanted MMTV1 Wnt1 mammary tumor growth was also reduced in LID mice, relative to LC mice, suggesting that the IGF1 effects on mammary tumor growth are not limited to Met1 tumors.

Dietary Energy Balance Modulation of Kras- and Ink4a/Arf+/−-Driven Pancreatic Cancer: The Role of Insulin-like Growth Factor-I

“…The LID mice were then injected with NB508 PDAC cells derived from a spontaneous tumor of a Kras Ink4a +/- mouse. Previously, we used this model to establish that the effects of CR and obesity on tumor suppression or progression, respectively, were largely dependent upon modulation of circulating IGF-1 (15). In the LID mice, CR did not reduce mammary tumor growth or circulating levels of IGF-1 relative to the control diet.…”

“…In the LID mice, CR did not reduce mammary tumor growth or circulating levels of IGF-1 relative to the control diet. Although DIO LID mice displayed some IGF-independent effects, these were not able to overcome the prevailing impact of low circulating IGF-1 on tumor growth (15). Consistent with a causal relationship between IGF-1 and PDAC, LID mice, relative to WT mice, had significantly reduced serum IGF-1 levels, PDAC growth, tumoral proliferation (as assessed by Ki-67 staining), and tumoral Akt/mTOR signaling; each of which was rescued by IGF-1 infusion.…”

“…We and others have shown in preclinical models that diet-induced obesity (DIO) enhances the development and progression of several cancer types in association with increased insulin-like growth factor (IGF)-1 and activation of the Akt/mammalian target of rapamycin (mTOR) pathway (12-15). However, to our knowledge, the effects of DIO have not yet been reported in a preclinical model of spontaneous PDAC.…”

Calorie Restriction Decreases Murine and Human Pancreatic Tumor Cell Growth, Nuclear Factor-κB Activation, and Inflammation-Related Gene Expression in an Insulin-like Growth Factor-1−Dependent Manner

“…Levels of protein expression were analyzed using the Lincoplex bead-based cytokine/chemokine panel (Millipore Corporation, Billerica, MS) on a BioRad Bioplex 200 analyzer (BioRad) according to manufacturer's directions. Choice of concentration (400 ng/mL) was based on physiologically relevant levels of circulating IGF-1 observed in mice fed the same control diet used in the present study [35], [36], [37]. Supernatants were collected from three separate experiments.…”

Interacting Inflammatory and Growth Factor Signals Underlie the Obesity-Cancer Link

“…Elevated IGF-1 has been identified as a risk factor in many cancer types (18). In a genetically engineered mouse model of liver-specific IGF-1 deficiency, circulating IGF-1 was reduced by ;75%, causing a significant decrease (relative to a wild-type control) in either tumor multiplicity or volume in mouse models of colon (26), mammary (27), or pancreatic (28) cancer. Liver-specific IGF-1 deficiency mice, relative to wild-type mice, also show reduced serum cytokine concentrations, and this has been linked to an IGF-1/NF-kB interaction (26).…”