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

Lashinger, Laura M.; Harrison, Lauren M.; Rasmussen, Audrey J.; Logsdon, Craig D.; Fischer, Susan M.; McArthur, Mark J.; Hursting, Stephen D.

doi:10.1158/1940-6207.capr-13-0185

Cited by 43 publications

(43 citation statements)

References 27 publications

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“…Both diet-induced obesity and models of genetic obesity show increases in serum leptin, concurrently with increased tumor growth and metastasis in murine models of pancreatic cancer [50][51][52]. Conversely, the progression from intraepithelial lesions to PDAC is delayed in mice administered a prolonged calorie restriction diet in both orthotopic and genetic models of pancreatic cancer [35]. Previous reports, and the current study, suggest that lean mice have slower tumor growth and better survival outcomes than obese mice; furthermore, in the current study, we demonstrate that there is a linear relationship between adiposity and these outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the goal of the current study was to determine if increased adiposity altered tumor growth, survival, and MDSC accumulation and function in a subcutaneous murine model of pancreatic cancer. This model was chosen because obesity exacerbates tumor growth [33,35], and we [36], and others [37], have demonstrated a role for the immune system in controlling Panc.02 tumor growth. An additional goal of this study was to determine if obesity alone (in the absence of tumor) enhanced the accumulation of MDSCs in relevant lymphoid organs.…”

Section: Introductionmentioning

confidence: 99%

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Increased Adiposity Enhances the Accumulation of MDSCs in the Tumor Microenvironment and Adipose Tissue of Pancreatic Tumor-Bearing Mice and in Immune Organs of Tumor-Free Hosts

et al. 2019

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Obesity is associated with increased risk and reduced survival for many types of cancer. Increasing adiposity may affect the balance between immunosuppressive and antitumor mechanisms critical for dictating cancer progression or remission. The goal of the current study was to determine if increased adiposity altered tumor growth, survival, and myeloid-derived suppressor cell (MDSC) accumulation in a subcutaneous murine model of pancreatic cancer. C57BL/6 mice were placed on a 30% kcal calorie-restricted diet, 10% kcal from fat diet fed ad libitum, or 60% kcal from fat diet fed ad libitum for 16 weeks to generate lean, overweight, and obese mice, respectively; followed by subcutaneous injection with 1 × 106 Panc.02 cells. We observed a significant linear relationship between increased adiposity and increased tumor growth and mortality; increased accumulation of Gr-1+CD11b+ MDSCs; and reduced CD8 T cell:MDSC ratio in multiple tissues, including tumor. Increased adiposity also increased the accumulation of MDSCs in the spleen and lymph node of tumor-free mice. These data suggest adiposity induces MDSC accumulation, which may contribute to an immunosuppressive environment promoting tumor growth. Overall, our findings provide a rationale to prevent or reverse increased body weight as a strategy to reduce the accumulation of immunosuppressive cell types.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Increased Adiposity Enhances the Accumulation of MDSCs in the Tumor Microenvironment and Adipose Tissue of Pancreatic Tumor-Bearing Mice and in Immune Organs of Tumor-Free Hosts

et al. 2019

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“…Possible examples include increases in procarcinogenic growth factors such as insulin like growth factors, adipose tissue secreted cytokine imbalances, and a state of chronic inflammation. 21–23 …”

Section: Discussionmentioning

confidence: 99%

Effect of Body Mass Index– and Actual Weight–Based Neoadjuvant Chemotherapy Doses on Pathologic Complete Response in Operable Breast Cancer

Raman

Mott

Schroeder

et al. 2016

Clinical Breast Cancer

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The effect of body mass index (BMI) on pathologic complete response (pCR) accounting for neoadjuvant chemotherapy (NAC) dose reductions remains undefined. In 171 patients with operable breast cancer who received NAC, those with a BMI of ≥25 were less likely to tolerate uncapped taxane doses. Any chemotherapy dose reduction resulted in greater odds of not attaining a pCR in obese patients, independent of known predictors. Introduction The effect of body mass index (BMI) and chemotherapy dose reduction on pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) for locoregional breast cancer remains unclear. Contemporary studies have reported largely on trial populations and used dose-capping. Patients and Methods Patient registries at the University of Iowa were queried to identify patients with operable breast cancer who received NAC. Dose reductions were calculated for taxanes (T), anthracyclines (A) and non–A-T chemotherapy. Clinical-pathologic characteristics, chemotherapy dose reductions, and adverse events were compared between normal (BMI <25) and overweight/obese patients (BMI ≥25). Additionally, the synergistic effect of BMI and chemotherapy dose reduction on pCR was assessed. Results Of 171 eligible patients, 112 were overweight/obese. Chemotherapy dosing was capped in 2 patients; all others initiated full weight-based treatment. Overweight/obese patients required more frequent taxane (44.6% vs. 25.4%; P = .01) and any chemotherapy dose reductions (50.9% vs. 33.9%; P = .03). pCR was attained in 29.2% of patients. In a multivariable model, the interaction term for BMI as a continuous variable and any chemotherapy dose reduction was significant independent of the clinical stage and tumor receptor status (P = .04). For obese patients, any chemotherapy dose reduction was significantly associated with increased odds of not attaining pCR. Conclusion During NAC, overweight/obese patients more often have chemotherapy dose reductions. Chemotherapy dose reduction in obese patients was a powerful predictor of not attaining pCR. This was not seen for normal or overweight patients. Opportunities might exist to improve pCR rates in this higher-risk group.

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“…CaPR has been on the cutting edge of this exciting field in recent years and last year was no exception, including a preclinical vaccine study to prevent the progression of preinvasive lesions in a transgenic murine model of spontaneous basal-type breast cancer (20) and an early-phase clinical trial of a MUC1 vaccine in patients with advanced colorectal adenomas (21). CaPR also published provocative reviews this past year by prominent researchers in this field, e.g., Dhodapkar, who posited that both cancer cells and the immune system represent independent and complex systems with plasticity and adaptive potential and that the cross-talk may determine the evolution of both tumors and the host response (22) We also continue to publish important preclinical discoveries, including a novel combinatorial nanotechnologybased chemopreventive regimen to suppress neoplastic pancreatic lesions (24), studies of energy balance effects on Kras signaling in early pancreatic neoplasia (25,26), novel AMPK-independent preventive effects of metformin in lung tumorigenesis (27), and studies of social isolation, metabolic gene reprogramming and mammary tumors (28). We continue to publish major discoveries in prostaglandin (PG) biology in cancer prevention that began with the first study of PG transporters in neoplasia from the DuBois group in one of the earliest issues of the journal (Holla and colleagues; ref.…”

Section: Greetings Colleaguesmentioning

confidence: 99%

Letter from the Editor

2014

Cancer Prevention Research

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

Cited by 43 publications

References 27 publications

Increased Adiposity Enhances the Accumulation of MDSCs in the Tumor Microenvironment and Adipose Tissue of Pancreatic Tumor-Bearing Mice and in Immune Organs of Tumor-Free Hosts

Increased Adiposity Enhances the Accumulation of MDSCs in the Tumor Microenvironment and Adipose Tissue of Pancreatic Tumor-Bearing Mice and in Immune Organs of Tumor-Free Hosts

Effect of Body Mass Index– and Actual Weight–Based Neoadjuvant Chemotherapy Doses on Pathologic Complete Response in Operable Breast Cancer

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