Energy balance, metabolism and cancer prevention: mechanistic insights from transdisciplinary studies

Stephen D Hursting is with the Department of Nutritional Sciences, The University of Texas at Austin and Department of Molecular Carcinogenesis, the University of Texas MD Anderson Cancer Center, USAThe prevalence of obesity, an established risk factor for many cancers, has risen steadily for the past several decades in the US and many other countries. Unfortunately, the mechanisms underlying the obesity and cancer connection are not well understood, and new targets and strategies for offsetting the impact of obesity on cancer risk and/or progression are urgently needed.Nutritional Science

Obesity and Cancer Metabolism: A Perspective on Interacting Tumor–Intrinsic and Extrinsic Factors

Obesity is associated with increased risk and poor prognosis of many types of cancers. Several obesity-related host factors involved in systemic metabolism can influence tumor initiation, progression, and/or response to therapy, and these have been implicated as key contributors to the complex effects of obesity on cancer incidence and outcomes. Such host factors include systemic metabolic regulators including insulin, insulin-like growth factor 1, adipokines, inflammation-related molecules, and steroid hormones, as well as the cellular and structural components of the tumor microenvironment, particularly adipose tissue. These secreted and structural host factors are extrinsic to, and interact with, the intrinsic metabolic characteristics of cancer cells to influence their growth and spread. This review will focus on the interplay of these tumor cell–intrinsic and extrinsic factors in the context of energy balance, with the objective of identifying new intervention targets for preventing obesity-associated cancer

Reducing the burden of obesity-associated cancers with anti-inflammatory long-chain omega-3 polyunsaturated fatty acids

Today’s world population has an unprecedented risk of dying from the consequences of being overweight and obese. Chronic diseases such as cardiovascular disease, type 2 diabetes, and cancer are often accelerated because of excessive adiposity. Various biological mechanisms are implicated in the obesity-cancer link, particularly local and systemic inflammation as well as altered growth factor signaling pathways. In order to combat obesity-induced inflammation and the resulting increases in cancer risk and progression, the identification of safe and effective mechanism-based interventions is imperative. Notably, long chain omega-3 polyunsaturated fatty acids (PUFAs) modulate the secretion of pro-inflammatory cytokines, prostaglandins and other inflammatory mediators, restore insulin sensitivity, and can prevent or delay tumorigenesis. Delineating the precise mechanisms by which omega-3 PUFAs suppress obesity-induced inflammation will help identify promising key mechanistic targets and intervention strategies to break the obesity-cancer link

Tumor-Associated Macrophage-Mediated Targeted Therapy of Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer. TNBC is often infiltrated with a large number of macrophages, which in turn promote tumor growth and metastasis. In this study, tumor-associated macrophages (TAMs) were exploited as a target to deliver doxorubicin (DOX), a chemotherapeutic agent, to TNBC using nanoparticles surface-functionalized by i) acid-sensitive sheddable PEGylation and ii) modifying with mannose (i.e. DOX-AS-M-PLGA-NPs). In mice with orthotopic M-Wnt triple-negative mammary tumors, a single intravenous injection of DOX-AS-M-PLGA-NPs significantly reduced macrophage population in tumors within 2 days, and the density of the macrophages recovered slowly. Repeated injections of DOX-AS-M-PLGA-NPs can help maintain the population of the macrophages at a lower level. In M-Wnt tumor-bearing mice that were pre-treated with zoledronic acid to non-selectively deplete macrophages, the TAM-targeting DOX-AS-M-PLGA-NPs were not more effective than the DOX-AS-PLGA-NPs that were not surface-modified with mannose, and thus do not target TAMs, in controlling tumor growth. However, in M-Wnt tumor-bearing mice that were not pre-treated with zoledronic acid, the TAM-targeting DOX-AS-M-PLGA-NPs were significantly more effective than the non-targeting DOX-AS-PLGA-NPs in controlling the tumor growth. The AS-M-PLGA-NPs or other nanoparticles surface-functionalized similarly, when loaded with chemotherapeutic agents commonly used in adjuvant therapy of TNBC, may be developed into targeted therapy of TNBC

Differential Effects of Calorie Restriction and Exercise on the Adipose Transcriptome in Diet-Induced Obese Mice

We tested the hypothesis that obesity reversal by calorie restriction (CR) versus treadmill exercise (EX) differentially modulates adipose gene expression using 48 female C57BL/6 mice administered a diet-induced obesity (DIO) regimen for 8 weeks, then randomized to receive for 8 weeks either: (1) a control (AIN-76A) diet, fed ad libitum (DIO control); (2) a 30% CR regimen; (3) a treadmill EX regimen (with AIN-76A diet fed ad libitum); or (4) continuation of the DIO diet. Relative to the DIO controls, both CR and EX reduced adiposity by 35–40% and serum leptin levels by 80%, but only CR increased adiponectin and insulin sensitivity. Gene expression microarray analysis of visceral white adipose tissue revealed 209 genes responsive to both CR and EX, relative to the DIO group. However, CR uniquely altered expression of an additional 496 genes, whereas only 20 were uniquely affected by EX. Of the genes distinctly responsive to CR, 17 related to carbohydrate metabolism and glucose transport, including glucose transporter (GLUT) 4. Chromatin immunoprecipitation assays of the Glut4 promoter revealed that, relative to the DIO controls, CR significantly increased histone 4 acetylation, suggesting epigenetic regulation may underlie some of the differential effects of CR versus EX on the adipose transcriptome

Metabolic Reprogramming by Folate Restriction Leads to a Less Aggressive Cancer Phenotype

Folate coenzymes are involved in biochemical reactions of one-carbon transfer, and deficiency of this vitamin impairs cellular proliferation, migration and survival in many cell types. Here the effect of folate restriction on mammary cancer was evaluated using three distinct breast cancer subtypes differing in their aggressiveness and metastatic potential: non-invasive basal-like (E-Wnt), invasive but minimally metastatic claudin-low (M-Wnt), and highly metastatic claudin-low (metM-Wntliver) cell lines, each derived from the same pool of MMTV-Wnt-1 transgenic mouse mammary tumors. NMR-based metabolomics was used to quantitate 41 major metabolites in cells grown in folate-free medium versus standard medium. Each cell line demonstrated metabolic reprogramming when grown in folate-free medium. In E-Wnt, M-Wnt and metM-Wntliver cells 12, 29, and 25 metabolites, respectively, were significantly different (p<0.05 and at least 1.5-fold change). The levels of eight metabolites (aspartate, ATP, creatine, creatine phosphate, formate, serine, taurine and β-alanine) were changed in each folate-restricted cell line. Increased glucose, decreased lactate, and inhibition of glycolysis, cellular proliferation, migration and invasion occurred in M-Wnt and metM-Wntliver cells (but not E-Wnt cells) grown in folate-free versus standard medium. These effects were accompanied by altered levels of several folate-metabolizing enzymes, indicating that the observed metabolic reprogramming may result from both decreased folate availability and altered folate metabolism. These findings reveal that folate restriction results in metabolic and bioenergetic changes and a less aggressive cancer cell phenotype

You complete me: tumor cell-myeloid cell nuclear fusion as a facilitator of organ-specific metastasis

Every cancer genome is unique, resulting in potentially near infinite cancer cell phenotypes and an inability to predict clinical outcomes in most cases. Despite this profound genomic heterogeneity, many cancer types and subtypes display a non-random distribution of metastasis to distant organs, a phenomenon known as organotropism. Proposed factors in metastatic organotropism include hematogenous versus lymphatic dissemination, the circulation pattern of the tissue of origin, tumor-intrinsic factors, compatibility with established organ-specific niches, long-range induction of premetastatic niche formation, and so-called “prometastatic niches” that facilitate successful colonization of the secondary site following extravasation. To successfully complete the steps required for distant metastasis, cancer cells must evade immunosurveillance and survive in multiple new and hostile environments. Despite substantial advances in our understanding of the biology underlying malignancy, many of the mechanisms used by cancer cells to survive the metastatic journey remain a mystery. This review synthesizes the rapidly growing body of literature demonstrating the relevance of an unusual cell type known as “fusion hybrid” cells to many of the hallmarks of cancer, including tumor heterogeneity, metastatic conversion, survival in circulation, and metastatic organotropism. Whereas the concept of fusion between tumor cells and blood cells was initially proposed over a century ago, only recently have technological advancements allowed for detection of cells containing components of both immune and neoplastic cells within primary and metastatic lesions as well as among circulating malignant cells. Specifically, heterotypic fusion of cancer cells with monocytes and macrophages results in a highly heterogeneous population of hybrid daughter cells with enhanced malignant potential. Proposed mechanisms behind these findings include rapid, massive genome rearrangement during nuclear fusion and/or acquisition of monocyte/macrophage features such as migratory and invasive capability, immune privilege, immune cell trafficking and homing, and others. Rapid acquisition of these cellular traits may increase the likelihood of both escape from the primary tumor site and extravasation of hybrid cells at a secondary location that is amenable to colonization by that particular hybrid phenotype, providing a partial explanation for the patterns observed in some cancers with regard to sites of distant metastases

Abstract P4-04-16: Obesity-associated systemic interleukin-6 promotes pre-adipocyte aromatase expression via increased breast cancer cell prostaglandin E2 production

Obesity is associated with a worse breast cancer prognosis, particularly in estrogen receptor alpha (ERα) positive, postmenopausal patients. We hypothesized that this is mediated in part by an elevation in breast cancer cell cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production that results in greater local pre-adipocyte aromatase expression. We utilized an in vitro model of the obese patient's tumor microenvironment in which cultured MCF-7 breast cancer cells and pre-adipocytes were exposed to pooled serum from obese (OB; BMI ≥ 30.0 kg/m2) or normal weight (N; BMI 18.5–24.9 kg/m2) postmenopausal women. Exposure to OB versus N sera significantly increased MCF-7 cell COX-2 expression and PGE2 production. Pre-adipocyte aromatase expression was 89 % greater following culture in conditioned media (CM) from MCF-7 cells exposed to OB versus N sera (OB-CM and N-CM, respectively), a difference nullified by MCF-7 cell treatment with the COX-2 inhibitor celecoxib. Previous analysis of the sera revealed significantly higher interleukin-6 (IL-6) concentrations in the OB versus N samples. Depletion of IL-6 from the sera neutralized the difference in pre-adipocyte aromatase expression stimulated by OB-CM versus N-CM. Finally, CM from pre-adipocyte/MCF-7 cell co-cultures exposed to OB sera stimulated greater MCF-7 and T47D breast cancer cell ERα activity and proliferation in comparison to N sera. This study indicates that obesity-associated systemic IL-6 indirectly enhances pre-adipocyte aromatase expression via increased breast cancer cell PGE2 production. Investigation regarding the efficacy of a COX-2 inhibitor/aromatase inhibitor combination therapy in the obese postmenopausal patient population is warranted

Increased Ammonium Toxicity in Response to Exogenous Glutamine in Metastatic Breast Cancer Cells

Several cancers, including breast cancers, show dependence on glutamine metabolism. The purpose of the present study was to determine the mechanistic basis and impact of differential glutamine metabolism in nonmetastatic and metastatic murine mammary cancer cells. Universally labeled 13C5-glutamine metabolic tracing, qRT-PCR, measures of reductive–oxidative balance, and exogenous ammonium chloride treatment were used to assess glutamine reprogramming. Results show that 4 mM media concentration of glutamine, compared with 2 mM, reduced viability only in metastatic cells, and that this decrease in viability was accompanied by increased incorporation of glutamine-derived carbon into the tricarboxylic acid (TCA) cycle. While increased glutamine metabolism in metastatic cells occurred in tandem with a decrease in the reduced/oxidized glutathione ratio, treatment with the antioxidant molecule N-acetylcysteine did not rescue cell viability. However, the viability of metastatic cells was more sensitive to ammonium chloride treatment compared with nonmetastatic cells, suggesting a role of metabolic reprogramming in averting nitrogen cytotoxicity in nonmetastatic cells. Overall, these results demonstrate the ability of nonmetastatic cancer cells to reprogram glutamine metabolism and that this ability may be lost in metastatic cells

The Role of the Insulin/IGF System in Cancer: Lessons Learned from Clinical Trials and the Energy Balance-Cancer Link

Numerous epidemiological and pre-clinical studies have demonstrated that the insulin/insulin-like growth factor (IGF) system plays a key role in the development and progression of several types of cancer. Insulin/IGF signaling, in cooperation with chronic low-grade inflammation, is also an important contributor to the cancer-promoting effects of obesity. However, clinical trials for drugs targeting different components of this system have produced largely disappointing results, possibly due to the lack of predictive biomarker use and problems with the design of combination therapy regimens. With careful attention to the identification of likely patient responders and optimal drug combinations, the outcome of future trials may be improved. Given that insulin/IGF signaling is known to contribute to obesity-associated cancer, further investigation regarding the efficacy of drugs targeting this system and its downstream effectors in the obese patient population is warranted