Chemotherapy diminishes lipid storage capacity of adipose tissue in a preclinical model of colon cancer (original) (raw)
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Putative Role of Adipose Tissue in Growth and Metabolism of Colon Cancer Cells
Frontiers in Oncology, 2014
Newly emerging data highlight obesity as an important risk factor for developing certain types of cancer, including colorectal cancer. Although evidence supports a link between the two, the mechanisms responsible for this relationship have not yet been fully elucidated. Hypertrophied and dysfunctional adipose tissue of the obese state is characterized by low-grade inflammation. Adipokines and cytokines secreted from adipocytes, together with the abundant availability of lipids from adipocytes in the tumor microenvironment, promote adhesion, migration, and invasion of tumor cells and support tumor progression and uncontrolled growth. One of the predisposed targets of the deleterious effects exerted by secretions from adipose tissue in obesity is the activities associated with the cellular mitochondria. Mitochondrial oxidative metabolism plays a key role in meeting cells' energetic demands by oxidative phosphorylation (OxPhos). Here we discuss: (a) the dynamic relationship between glycolysis, the tricarboxylic acid cycle, and OxPhos; (b) the evidence for impaired OxPhos (i.e., mitochondrial dysfunction) in colon cancer; (c) the mechanisms by which mitochondrial dysfunction can predispose to cancer. We propose that impaired OxPhos increases susceptibility to colon cancer since OxPhos is sensitive to a large number of factors that are intrinsic to the host (e.g., inflammation). Given that adipocytes are a major source of adipokines and energy for the cancer cell, understanding the mechanisms of metabolic symbiosis between cancer cells and adipocytes should reveal new therapeutic possibilities.
Evidence and Mechanisms of Fat Depletion in Cancer
Nutrients, 2014
The majority of cancer patients experience wasting characterized by muscle loss with or without fat loss. In human and animal models of cancer, body composition assessment and morphological analysis reveals adipose atrophy and presence of smaller adipocytes. Fat loss is associated with reduced quality of life in cancer patients and shorter survival independent of body mass index. Fat loss occurs in both visceral and subcutaneous depots; however, the pattern of loss has been incompletely characterized. Increased lipolysis and fat oxidation, decreased lipogenesis, impaired lipid depositionand adipogenesis, as well as browning of white adipose tissue may underlie adipose atrophy in cancer. Inflammatory cytokines such as interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and interleukin-1 beta (IL-1β) produced by the tumor or adipose tissue may also contribute to adipose depletion. Identifying the mechanisms and time course of fat mass changes in cancer may help identify individuals at risk of adipose depletion and define interventions to circumvent wasting. This review outlines current knowledge of fat mass in cancer and illustrates the need for further studies to assess alterations in visceral and subcutaneous adipose depots and possible mechanisms for loss of fat during cancer progression.
Heterogeneous time-dependent response of adipose tissue during the development of cancer cachexia
Journal of Endocrinology, 2012
Cancer cachexia induces loss of fat mass that accounts for a large part of the dramatic weight loss observed both in humans and in animal models; however, the literature does not provide consistent information regarding the set point of weight loss and how the different visceral adipose tissue depots contribute to this symptom. To evaluate that, 8-week-old male Wistar rats were subcutaneously inoculated with 1 ml (2!10 7 ) of tumour cells (Walker 256). Samples of different visceral white adipose tissue (WAT) depots were collected at days 0, 4, 7 and 14 and stored at K80 8C (seven to ten animals/each day per group). Mesenteric and retroperitoneal depot mass was decreased to the greatest extent on day 14 compared with day 0. Gene and protein expression of PPARg2 (PPARG) fell significantly following tumour implantation in all three adipose tissue depots while C/EBPa (CEBPA) and SREBP-1c (SREBF1) expression decreased over time only in epididymal and retroperitoneal depots. Decreased adipogenic gene expression and morphological disruption of visceral WAT are further supported by the dramatic reduction in mRNA and protein levels of perilipin. Classical markers of inflammation and macrophage infiltration (f4/80, CD68 and MIF-1a) in WAT were significantly increased in the later stage of cachexia (although showing a incremental pattern along the course of cachexia) and presented a depot-specific regulation. These results indicate that impairment in the lipid-storing function of adipose tissue occurs at different times and that the mesenteric adipose tissue is more resistant to the 'fat-reducing effect' than the other visceral depots during cancer cachexia progression.
Whole‐body and adipose tissue metabolic phenotype in cancer patients
Journal of Cachexia, Sarcopenia and Muscle, 2022
Background Altered adipose tissue (AT) metabolism in cancer-associated weight loss via inflammation, lipolysis, and white adipose tissue (WAT) browning is primarily implicated from rodent models; their contribution to AT wasting in cancer patients is unclear. Methods Energy expenditure (EE), plasma, and abdominal subcutaneous WAT were obtained from men (aged 65 ± 8 years) with cancer, with (CWL, n = 27) or without (CWS, n = 47) weight loss, and weight-stable non-cancer patients (CON, n = 26). Clinical images were assessed for adipose and muscle area while plasma and WAT were assessed for inflammatory, lipolytic, and browning markers. Results CWL displayed smaller subcutaneous AT (SAT; P = 0.05) and visceral AT (VAT; P = 0.034) than CWS, and displayed higher circulating interleukin (IL)-6 (P = 0.01) and WAT transcript levels of IL-6 (P = 0.029), IL-1β (P = 0.042), adipose triglyceride lipase (P = 0.026), and browning markers (Dio2, P = 0.03; PGC-1a, P = 0.016) than CWS and CON. There was no difference across groups in absolute REE (P = 0.061), %predicted REE (P = 0.18), circulating free fatty acids (FFA, P = 0.13) or parathyroid hormone-related peptide (PTHrP; P = 0.88), or WAT protein expression of inflammation (IL-6, P = 0.51; IL-1β, P = 0.29; monocyte chemoattractant protein-1, P = 0.23) or WAT protein or gene expression of browning (uncoupling protein-1, UCP-1; P = 0.13, UCP-1, P = 0.14). In patients with cancer, FFA was moderately correlated with WAT hormone-sensitive lipase transcript (r = 0.38, P = 0.018, n = 39); circulating cytokines were not correlated with expression of WAT inflammatory markers and circulating PTHrP was not correlated with expression of WAT browning markers. In multivariate regression using cancer patients only, body mass index (BMI) directly predicted SAT (N = 25, R 2 = 0.72, P < 0.001), VAT (N = 28, R 2 = 0.64, P < 0.001), and absolute REE (N = 22, R 2 = 0.43, P = 0.001), while BMI and WAT UCP-1 protein were indirectly associated with %predicted REE (N = 22, R 2 = 0.45, P = 0.02), and FFA was indirectly associated with RQ (N = 22, R 2 = 0.52, P < 0.001). Conclusions Cancer-related weight loss was associated with elevated circulating IL-6 and elevations in some WAT inflammatory, lipolytic and browning marker transcripts. BMI, not weight loss, was associated with increased energy expenditure. The contribution of inflammation and lipolysis, and lack thereof for WAT browning, will need to be clarified in other tumour types to increase generalizability. Future studies should consider variability in fat mass when exploring the relationship between cancer and adipose metabolism and should observe the trajectory of lipolysis and energy expenditure over time to establish the clinical significance of these associations and to inform more mechanistic interpretation of causation.
Oncotarget, 2017
Morbidly obese patients who accomplish substantial weight loss often display a long-term decline in their resting metabolism, causing even relatively restrained caloric intake to trigger a relapse to the obese state. Paradoxically, we observed that morbidly obese mice receiving chemotherapy for cancer experienced spontaneous weight reduction despite unabated ingestion of their high fat diet (HFD). This response to chemotherapy could also be achieved in morbidly obese mice without cancer. Optimally dosed methotrexate (MTX) or cyclophosphamide (CY) enabled the mice to completely and safely normalize their body weight despite continued consumption of obesogenic quantities of HFD. Weight reduction was not attributable to decreased HFD intake, enhanced energy expenditure or malabsorption. MTX or CY dosing significantly depleted both adipose tissue and preadipocyte progenitors. Remarkably, however, despite continued high fat feeding, a compensatory increase in hepatocyte lipid storage was...
Morphological and Functional Changes in the Peritumoral Adipose Tissue of Colorectal Cancer Patients
Obesity (Silver Spring, Md.), 2017
The role of peritumoral adipose tissue (AT) has not been extensively studied in colorectal cancer (CRC). This study was conducted in 20 male subjects undergoing elective surgery for CRC. The differences between the peritumoral visceral adipose tissue (P-VAT), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) of the patients were described via immunohistochemistry and molecular biology analyses. The interactions between adipocytes and a colon cancer cell line were also investigated by using an in vitro coculture system. The analyses revealed that adipocytes near the tumor were significantly smaller than the adipocytes from other sites. The P-VAT was preferentially infiltrated by a CD68+/CD163+/IDO- macrophage subset with a prevalent reparative inflammatory response, while the macrophages identified in VAT and SAT mainly presented inflammatory features. Furthermore, the P-VAT presented a higher expression of adiponectin compared with other sites. Morphological analy...
Alteration of liver fat metabolism following irinotecan plus 5-fluorouracil treatment
2011
This study determined how chemotherapy treatment for colorectal cancer alters hepatic fat metabolism. Livers were isolated from tumor-bearing animals after one and two cycles of chemotherapy consisting of irinotecan plus 5-fluorouracil. Fatty acid amounts and composition within triglycerides (TG) and phospholipids (PL) as well as gene expression were assessed. Total TG did not change and total PL were higher after 7 days following treatment. Docosahexaenoic acid became undetectable after the treatment at 5 and 7 days, respectively. Following one cycle, the alterations appeared temporary. After second cycle, total TG were lower and n-3 fatty acids were also lower causing n-6/n-3 ratio to be higher. Chemotherapy altered 13 genes of 44, however not all genes within a single pathway were affected. The alterations in gene expression did not necessarily parallel the observations in fatty acids. This study is important to develop identify target pathways to circumvent negative effects of chemotherapy-associated steatohepatitis.
Adipose tissue lipolysis and energy metabolism in early cancer cachexia in mice
Cancer Biology & Therapy, 2014
Cancer cachexia is a progressive metabolic disorder that results in depletion of adipose tissue and skeletal muscle. A growing body of literature suggests that maintaining adipose tissue mass in cachexia may improve quality-of-life and survival outcomes. Studies of lipid metabolism in cachexia, however, have generally focused on later stages of the disorder when severe loss of adipose tissue has already occurred. Here, we investigated lipid metabolism in adipose, liver and muscle tissues during early stage cachexiabefore severe fat lossin the colon-26 murine model of cachexia. White adipose tissue mass in cachectic mice was moderately reduced (34-42%) and weight loss was less than 10% of initial body weight in this study of early cachexia. In white adipose depots of cachectic mice, we found evidence of enhanced protein kinase A-activated lipolysis which coincided with elevated total energy expenditure and increased expression of markers of brown (but not white) adipose tissue thermogenesis and the acute phase response. Total lipids in liver and muscle were unchanged in early cachexia while markers of fatty oxidation were increased. Many of these initial metabolic responses contrast with reports of lipid metabolism in later stages of cachexia. Our observations suggest intervention studies to preserve fat mass in cachexia should be tailored to the stage of cachexia. Our observations also highlight a need for studies that delineate the contribution of cachexia stage and animal model to altered lipid metabolism in cancer cachexia and identify those that most closely mimic the human condition.
Adipose tissue fatty acid composition and colon cancer: a case–control study
Purpose An increased dietary intake of fat, particularly polyunsaturated fatty acids (PUFAs), has been related to an increased risk of breast, prostate and colon cancers. Patients with and without colon cancer were tested for differences in their fatty stores composition. Methods The fatty acid levels were determined by gas– liquid chromatography in adipose tissue samples, subcu-taneous and visceral, obtained intra-operatively from 52 colon cancer and 50 nonneoplastic abdominal disease patients. Statistical analysis was performed using one-way ANOVA, SNK test and Dunnet test. Differences in the composition of saturated, monounsaturated and polyun-saturated fatty acids, in visceral and in subcutaneous samples of colon cancer and nonneoplastic patients, were assessed. Results The sum of saturated and monounsaturated fatty acids, respectively, in visceral and in subcutaneous samples , was higher in neoplastic patients (p \ 0.001). The sum of some n-6 polyunsaturated fatty acids (PUFAs), the dietary precursor linoleic acid (LA-18:2n-6), and their metabolites, gammalinolenic acid (GLA-18:3n-6) ? di-homogammalinolenic acid (DGLA-20:3n-6) ? arachi-donic acid (AA-22:4n-6), was higher in subcutaneous fat of controls (p \ 0.05). The samples from these patients had a fatty acid composition, both subcutaneous and visceral, with a higher content of alphalinolenic acid (ALA-18:3n-3) and stearidonic acid (SDA-18:4n-3) compared to neoplastic patients (p \ 0.001). These had subcutaneous and visceral fat stores statistically higher in GLA, DGLA and AA (p \ 0.001). Colon cancer patients had subcutaneous adi-pose stores higher in ALA and LA than visceral sites (p \ 0.001). Conclusions Fatty acids may be involved in colon car-cinogenesis and there is a depot-specific impact on this process by visceral fat.
Oncology Letters, 2017
The development and progression of cancer is a complex and multifactorial process and the global prevalence of obesity is markedly increasing. A number of studies have made an association between obesity and increased rates of epithelial tumors. Obesity is associated with altered adipokine levels, potentially contributing to the process of tumor development and metastasis. In the current study, the associations between circulating adipokines and measures of adiposity and tumor characteristics among patients diagnosed with solid malignancies were examined at the time of presentation, and following the administration of chemotherapy. A total of 30 patients with cancer and matched healthy controls were enrolled in the present study. Plasma adipokine levels of hepatocyte growth factor (HGF), adiponectin and leptin were determined using commercially available ELISA kits. At baseline, plasma HGF, adiponectin and leptin levels were not significantly different between patients with cancer and the healthy controls. Circulating HGF levels were significantly associated with the stage of cancer at diagnosis (P=0.044), but lacked a significant association with lymph node status (P=0.194). Plasma adiponectin and leptin levels were not significantly associated with tumor characteristics at the time of diagnosis. Only leptin was positively correlated with the body mass index of patients with cancer (P<0.001). No significant correlations were detected between the evaluated adipokines and measures of visceral obesity, as determined by waist circumference and the waist-hip ratio at presentation. Following administration of chemotherapy, adiponectin was the only adipokine evaluated in the current study that exhibited a significant difference, when compared with baseline plasma levels (P= 0.013), and a significant positive correlation between baseline and follow-up circulating levels (P=0.002) among patients with cancer. In addition, there were no significant inter-correlations between circulating adipokines at baseline level and during follow-up in patients with cancer. Collectively, the findings of the current study suggest a lack of diagnostic roles for the adipokines investigated and no significant association with measures of adiposity. Adiponectin may be a potential adipokine to measure in patients with cancer, in order to further assess its prognostic and predictive potential.