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Schematic overview of the mechanisms linking obesity, adipose tissue, and pancreatic cancer as discussed in the main text. During obesity, inflamed (visceral) adipose tissue (adipocytes and resident/recruited immune cells) releases a variety of adipokines (e.g., increase in leptin, lipocalin 2, Wnt5a, and decrease in adiponectin) and adipose-derived inflammatory cytokines (e.g., IL-6 and TNF-α) that may promote proliferation of transformed pancreatic epithelial cells. Obesity-associated gut dysbiosis may lead to metabolic endotoxemia (elevated LPS) that plays a role in adipose tissue inflammation and has direct effects on pancreatic cells. Obesity-associated changes of the gut microbiome may also induce or alter the pancreatic microbiome, which promotes cancer growth. Obesity-associated systemic hyperinsulinemia (and elevated IGF-1) as well as elevated intrapancreatic insulin levels (from pancreatic β-cells) can act as potent growth stimulatory factors for transformed (pre-)neoplastic pancreatic cells. Intrapancreatic adipocytes, either through differentiation of adipose-derived stem cells and/or transdifferentiation of acinar (or pancreatic stellate) cells, may also have a robust impact on pancreatic cancer cell proliferation and changes of the tumor microenvironment. Downstream of oncogenic Kras, the decrease in FGF21 (in transformed pancreatic cells) may render the pancreas susceptible to the pro-tumorigenic effects of obesity. Blue and purple cells within the adipose tissue illustrate various immune cells (e.g., neutrophils (purple) and macrophages (blue)). Yellow circles within the adipose tissue represent adipocytes. Partly created with Servier Medical Art.
Source publication
The prevalence of obesity in adults and children has dramatically increased over the past decades. Obesity has been declared a chronic progressive disease and is a risk factor for a number of metabolic, inflammatory, and neoplastic diseases. There is clear epidemiologic and preclinical evidence that obesity is a risk factor for pancreatic cancer. A...
Contexts in source publication
Context 1
... mechanisms are generally discussed that underlie the obesity-PDAC connection. A central role is clearly played by adipose tissue and obesity-associated adipose tissue inflammation (Figure 2). ...
Context 2
... may be achieved by interventions aimed at inhibiting or reducing obesity-associated adipose tissue inflammation in general or by targeting specific factors that mechanistically initiate and sustain the link between adipose tissue and pancreatic neoplastic cells. Figure 2. Schematic overview of the mechanisms linking obesity, adipose tissue, and pancreatic cancer as discussed in the main text. ...
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Citations
... It is recognized that activating KRAS mutations drives tumor initiation and progression in the vast majority of human PDAC [1,2]; this process also requires a second major stimulus, such as inflammation [3]. Epidemiologic data strongly implicated diet-induced obesity (DIO) as a risk factor in human PDAC [4]. Our previous studies demonstrated that DIO accelerates PDAC tumorigenesis in genetically engineered mouse models [5]. ...
Simple Summary
Epidemiologic evidence and previous research have established obesity, diabetes and the metabolic syndrome as risk factors for pancreatic cancer in humans, while the precise mechanisms remain incompletely characterized. The concept that these metabolic diseases may be driven by diet implies that many cancers could be prevented or delayed through lifestyle modifications. By design, genetically engineered mouse models expressing oncogenic mutants of KRAS protein within the epithelial cells of the pancreas closely recapitulate the human disease. Research on diet-induced obesity in such mice implies the involvement of diverse factors including elevated insulin/insulin-like growth factors, inflammation, and genetic/epigenetic alterations and has revealed dramatic acceleration of cancer incidence that was more marked in males than females. The present research uses proteomic and phosphoproteomic analysis as a foundation to assess differentially expressed proteins and associated signal transduction pathways, yielding further novel mechanistic insights into the influence of tumor microenvironment on diet-induced obesity-associated pancreatic cancer.
Abstract
Diet-induced obesity (DIO) promotes pancreatic ductal adenocarcinoma (PDAC) in mice expressing KRasG12D in the pancreas (KC mice), but the precise mechanisms remain unclear. Here, we performed multiplex quantitative proteomic and phosphoproteomic analysis by liquid chromatography–tandem mass spectrometry and further bioinformatic and spatial analysis of pancreas tissues from control-fed versus DIO KC mice after 3, 6, and 9 months. Normal pancreatic parenchyma and associated proteins were steadily eliminated and the novel proteins, phosphoproteins, and signaling pathways associated with PDAC tumorigenesis increased until 6 months, when most males exhibited cancer, but females did not. Differentially expressed proteins and phosphoproteins induced by DIO revealed the crucial functional role of matrisomal proteins, which implies the roles of upstream regulation by TGFβ, extracellular matrix-receptor signaling to downstream PI3K-Akt-mTOR-, MAPK-, and Yap/Taz activation, and crucial effects in the tumor microenvironment such as metabolic alterations and signaling crosstalk between immune cells, cancer-associated fibroblasts (CAFs), and tumor cells. Staining tissues from KC mice localized the expression of several prognostic PDAC biomarkers and elucidated tumorigenic features, such as robust macrophage infiltration, acinar–ductal metaplasia, mucinous PanIN, distinct nonmucinous atypical flat lesions (AFLs) surrounded by smooth muscle actin-positive CAFs, invasive tumors with epithelial–mesenchymal transition arising close to AFLs, and expanding deserted areas by 9 months. We next used Nanostring GeoMX to characterize the early spatial distribution of specific immune cell subtypes in distinct normal, stromal, and PanIN areas. Taken together, these data richly contextualize DIO promotion of Kras-driven PDAC tumorigenesis and provide many novel insights into the signaling pathways and processes involved.
... Pancreas [144][145][146][147][148][149] Chronic inflammation and hyperinsulinemia. ...
Background
The link between excess adiposity and carcinogenesis has been well established for multiple malignancies, and cancer is one of the main contributors to obesity-related mortality. The potential role of different weight-loss interventions on cancer risk modification has been assessed, however, its clinical implications remain to be determined. In this clinical review, we present the data assessing the effect of weight loss interventions on cancer risk.
Methods
In this clinical review, we conducted a comprehensive search of relevant literature using MEDLINE, Embase, Web of Science, and Google Scholar databases for relevant studies from inception to January 20, 2024. In this clinical review, we present systematic reviews and meta-analysis, randomized clinical trials, and prospective and retrospective observational studies that address the effect of different treatment modalities for obesity in cancer risk. In addition, we incorporate the opinions from experts in the field of obesity medicine and oncology regarding the potential of weight loss as a preventative intervention for cancer.
Results
Intentional weight loss achieved through different modalities has been associated with a reduced cancer incidence. To date, the effect of weight loss on the postmenopausal women population has been more widely studied, with multiple reports indicating a protective effect of weight loss on hormone-dependent malignancies. The effect of bariatric interventions as a protective intervention for cancer has been studied extensively, showing a significant reduction in cancer incidence and mortality, however, data for the effect of bariatric surgery on certain specific types of cancer is conflicting or limited.
Conclusion
Medical nutrition therapy, exercise, antiobesity medication, and bariatric interventions, might lead to a reduction in cancer risk through weight loss-dependent and independent factors. Further evidence is needed to better determine which population might benefit the most, and the amount of weight loss required to provide a clinically significant preventative effect.
... The connection between obesity and cancer is multifactorial [6], encompassing alterations in hormonal profiles, chronic low-grade inflammation, and the intricate interplay of various metabolic pathways. This nexus is not confined to a single type of cancer; instead, it spans a broad spectrum, including but not limited to colorectal [7], pancreatic [8], liver [9], endometrial, ovarian, adenocarcinoma of the esophagus, gastric cardia, gallbladder, renal cell carcinoma, thyroid cancers, as well as meningioma and multiple myeloma [10] and, last but not least, postmenopausal breast cancer (BC) [10,11]. ...
Simple Summary
Obesity is a global health challenge closely linked to breast cancer (BC). Recognizing this intricate relationship, our research explores the multifaceted connections between obesity and BC. The aim of this narrative review was to underline the key role of a personalized rehabilitation approach targeting the connection between obesity and BC. By comprehending these links, we aim to enhance risk assessment, improve survivorship care, and contribute valuable insights to the broader field of cancer rehabilitation. Moreover, tailored and technology-driven methods show potential insight into enhancing the effectiveness of rehabilitation in cancer patients with obesity. Through this research, we seek to pave the way for effective strategies addressing the challenges faced by obese individuals with BC.
Abstract
Obesity is a global health challenge with increasing prevalence, and its intricate relationship with cancer has become a critical concern in cancer care. As a result, understanding the multifactorial connections between obesity and breast cancer is imperative for risk stratification, tailored screening, and rehabilitation treatment planning to address long-term survivorship issues. The review follows the SANRA quality criteria and includes an extensive literature search conducted in PubMed/Medline, Web of Science, and Scopus. The biological basis linking obesity and cancer involves complex interactions in adipose tissue and the tumor microenvironment. Various mechanisms, such as hormonal alterations, chronic inflammation, immune system modulation, and mitochondrial dysfunction, contribute to cancer development. The review underlines the importance of comprehensive oncologic rehabilitation, including physical, psychological, and nutritional aspects. Cancer rehabilitation plays a crucial role in managing obesity-related symptoms, offering interventions for physical impairments, pain management, and lymphatic disorders, and improving both physical and psychological well-being. Personalized and technology-driven approaches hold promise for optimizing rehabilitation effectiveness and improving long-term outcomes for obese cancer patients. The comprehensive insights provided in this review contribute to the evolving landscape of cancer care, emphasizing the importance of tailored rehabilitation in optimizing the well-being of obese cancer patients.
... However, the implications of obesity extend beyond diabetes, as compelling evidence consistently demonstrates a signifcant correlation between obesity and numerous cardiovascular diseases [3]. Furthermore, the incidence of obesity exhibits a close relationship with various neoplastic pathologies [4], including breast [5], colorectal [6], kidney [7], and pancreatic [8] cancers, thus emphasizing the urgent need to address this global health crisis. In addition to its ramifcations on physical health, obesity profoundly afects mental well-being [9]. ...
Obesity, characterized by excessive adipose tissue accumulation, has emerged as a crucial determinant for a wide range of chronic medical conditions. The identification of effective interventions for obesity is of utmost importance. Widely researched antiobesity agents focus on pancreatic lipase, a significant therapeutic target. This study presented the evaluation of ten flavonoid compounds in terms of their inhibitory activities against pancreatic lipase, utilizing both in vitro and in silico approaches. The results indicated that all tested compounds demonstrated modest and weaker inhibitory activities compared to the reference compound, orlistat. Among the compounds investigated, F01 exhibited the highest potency, with an IC50 value of 17.68 ± 1.43 µM. The enzymatic inhibition kinetic analysis revealed that F01 operated through a competitive inhibition mechanism with a determined K i of 7.16 μM. This value suggested a moderate binding affinity for the pancreatic lipase enzyme. Furthermore, the associated V max value was quantified at 0.03272 ΔA·min−1. In silico studies revealed that F01 displayed a binding mode similar to that of orlistat, despite lacking an active functional group capable of forming a covalent bond with Ser152 of the catalytic triad. However, F01 formed a hydrogen bond with this crucial amino acid. Furthermore, F01 interacted with other significant residues at the enzyme’s active site, particularly those within the lid domain. Based on these findings, F01 demonstrates substantial potential as a candidate for further investigations.
... 40,41 For example, high BMI increases oxidative stress, which may damage mitochondria and genetic materials; obesity is also associated with systemic inflammatory responses, promoting the secretion of pro-inflammatory factors and chemokines and reinforcing the local invasion and cancer cell proliferation. 42 Also, obesity alters the microenvironment of the intestinal flora, increases the metabolism and secretion of short-chain fatty acids and endotoxins, and increases intestinal permeability, contributing to a systemic proinflammatory state. 43 Compared to nondiabetic patients, diabetic patients treated surgically for pancreatic cancer have poorer survival, which can be attributed to insulin resistance, hyperinsulinemia, and an altered cellular metabolic environment creating a favorable environment for tumor growth and metastasis. ...
Background
Benefiting from increased life expectancy and improved perioperative management, more elderly patients with pancreatic head cancer (PHC) underwent pancreaticoduodenectomy (PD). However, individualized predictive models for the safety and efficacy of PD is still lacking. this study aimed to developed three safety‐ and efficacy‐related risk calculators for elderly (> = 65 years) PHC patients.
Methods
This study was designed with two research cohorts, namely, the training cohort and the validation cohort, and comprises four general steps: (1) Risk factors were analyzed for the incidence of postoperative complications, cancer‐specific survival (CSS), and overall survival (OS) in the training cohort ( N = 271) using logistic and Cox‐regression analysis. (2) Nomograms were then plotted based on the above results. (3) The accuracy of the developed nomogram models was then verified with the validation cohort ( N = 134) data using consistency index (C‐index) and calibration curves. (4) We then evaluated the efficacy of these nomograms using decision curve analysis (DCA) in both the training and validation cohorts, and ultimately constructed three online calculators based on these nomograms.
Results
We identified ASA, diabetes, smoking, and lymph node invasion as predisposing risk factors for postoperative complications, and the predictive factors that affected both OS and CSS were ASA, diabetes, BMI, CA19‐9 level, and tumor diameter. By integrating the above risk factors, we constructed three nomograms on postoperative complication, CSS, and OS. The C‐index for complication, CSS, and OS were 0.824, 0.784, and 0.801 in the training cohort and 0.746, 0.718, and 0.708 in the validation cohort. Moreover, the validation curves and DCA demonstrated good calibration and robust compliance in both training and validation cohorts. We then developed three web calculators ( https://caiming.shinyapps.io/CMCD/ , https://caiming.shinyapps.io/CMCSS/ , and https://caiming.shinyapps.io/CMOS/ ) to facilitate the use of the nomograms.
Conclusions
The calculators demonstrated promising performance as an tool for predicting the safety and efficacy of PD in elderly PHC patients.
... A number of mechanisms are proposed, including, chronic inflammation, insulin resistance, circulatory lipids, adipokine and cytokine release, hormonal factors such as elevation of insulin-like growth factor 1 (IGF-1) and sex hormones, oxidative stress, changes in intestinal microbiome, food carcinogens, and potentiation by driver mutations. The pathogenesis is further convoluted with accumulating evidence of influence of variants in genes or genetic mutations in cell synthesis, metabolism, binding, and signaling [8,[30][31][32]. ...
... The non-genetic factors or alterations caused by other environmental factors including chronic inflammation or obesity in the tumor microenvironment are postulated to be critical steps in early steps of PanIN and progression into PDAC. Several preclinical studies have also convincingly demonstrated the accelerated transformation rates of ductal cells into PanIN among engineered obese mice [32]. In conditional KrasG12D mice model, an elevated risk of PDAC was observed among high-fat high-calorie-fed obese mice compared to normally fed non-obese mice, suggesting a synergistic effect of Kras and obesity [37]. ...
... Adipocytes are capable of various internal and external cellular interactions which regulate cellular processes including food intake, insulin sensitivity, inflammation, and immune responses. Leptin and adiponectin are among the first identified and highly expressed adipokines; they are known to have opposing functions on immune cell activation [32,40]. Other adipokines currently being evaluated include Lipocalin-2 (LCN-2), fibroblast growth factor (FGF)-21, and wingless-type mouse mammary tumor virus integration site family member 5A (Wnt5a). ...
Incidence rates of pancreatic cancer are increasing worldwide. The lack of screening tools, late-stage diagnosis, and resistance to chemo and radiation therapies make pancreatic cancer the fourth leading cancer-related killer. Recently, awareness has increased about obesity as a strong yet modifiable risk factor for pancreatic cancer. The prevalence of pancreatic ductal adenocarcinoma (PDAC) was significantly higher among obese patients with a body mass index of more than 35 who did not undergo bariatric surgery versus their counterparts. Global obesity rates have increased considerably over the past decades, especially since the coronavirus pandemic. There is still a lack of understanding of the mechanisms of obesity-related PDAC. Emerging evidence suggests that chronic inflammation, circulatory lipids, insulin resistance, adipokines and cytokines release, oxidative stress, and changes in the microbiome associated with obesity are linked to its initiation and progression. Obesity also potentiates driver mutations, including Kirsten Rat Sarcoma viral oncogene (Kras) in PDAC. It is also unclear why obese patients have poorer postoperative outcomes than nonobese PDAC patients highlighting the need for better mechanistic understanding. In this chapter, we aim to provide clinicians and researchers with a comprehensive overview of the carcinogenic pathogenesis of obesity in PDAC and its implications for prevention and treatment.
... This may be related to the time effect of bariatric surgery on weight maintenance. Obesity can lead to the occurrence, progression, proliferation, and metastasis of pancreatic cancer through various mechanisms such as dysregulation in lipid metabolism, adipokine-mediated inflammation, gut dysbiosis, immunosuppressive microenvironment, and hormone imbalance [37][38][39][40]. Chronic inflammation caused by obesity constitutes an established mediator of tumor initiation and progression as many inflammatory components exist in the tumor microenvironment and promote the cancerous phenotype [41,42]. ...
... Perturbations of the pancreatic microbiome caused by gut dysbiosis may induce and exacerbate the development of pancreatic inflammation and tumors. Impaired gut barrier function and concomitant metabolic endotoxemia are considered to be key factors in inducing adipose tissue inflammation [38]. In addition, obesity-related metabolic syndrome is a clustering of risk factors, such as insulin resistance and dyslipidemia, which are associated with a variety of cancers [43]. ...
A growing body of evidence suggests that bariatric surgery is associated with a reduced risk of some cancers. This meta-analysis aims to determine whether bariatric surgery affects pancreatic cancer risk. We conducted a comprehensive literature search of PubMed, Embase, and Web of Science databases. Fixed-effect models were used to estimate pooled data and presented as odds ratio (OR) and 95% confidence interval (CI). Heterogeneity was assessed using the Cochran Q test and I² test. A total of 9 cohort studies involving 1,147,473 patients were included in the analysis. The pooled OR was 0.76 (95% CI = 0.64-0.90). The Cochran Q test and I² test indicated only mild heterogeneity (P = 0.12, I² = 38%). In the subgroup analyses, the pooled OR was 0.67 (95% CI = 0.54–0.82) for North America. In the subgroup analyses by mean follow-up time, the pooled OR was 0.46 (95% CI = 0.28–0.74) for less than 5 years. In conclusion, bariatric surgery has a positive effect on pancreatic cancer reduction, especially in North America. This effect may diminish or disappear with time.
... However, the precise causative pathway is unknown and may include various local and systemic changes caused by obesity. Understanding the chemicals and molecular signaling pathways that drive pancreatic cancer formation and growth is critical for creating tailored prevention/interception therapies (Eibl & Rozengurt, 2021). ...
Obesity has emerged as a severe public health concern worldwide, with an increasing number of studies linking it to an increased risk of various forms of cancer, including pancreatic cancer. Although the underlying pathways behind this relationship are unknown, different putative biological and metabolic pathways have been discovered. These are examples of chronic low-grade inflammation, insulin resistance, altered hormone levels, and exposure to external environmental risk factors. These underlying processes are believed to combine with genetic and environmental variables in obese individuals to contribute to the development and progression of pancreatic cancer. More study is needed to thoroughly understand the complicated relationship between obesity and pancreatic cancer to create effective preventive and early detection measures for this fatal illness.
... Conversely, the visceral adipose tissue still tended to increase after 14 years, particularly in individuals with visceral fat tissue at the 50 percentile and above (35), causing a more adverse effect on metabolic function (36). Moreover, visceral fat was significantly associated with chronic disease and cancer compared with subcutaneous fat (37), suggesting the significance of paying attention to the VFL at a young age in children with high FA risk. Additionally, particularly at the age of 14, a more detailed physical check should be performed to detect the adverse effect of FA and facilitate timely intervention. ...
Objective
Food addiction (FA) is associated with a higher body mass index z-score (BMIZ) in children and adolescents; however, whether these two aspects evolve interdependently remains unknown. This study aimed to address this question using a cross-lagged study.
Methods
Weight status, including BMIZ, fat content (FC), and visceral fat level (VFL), was determined in 880 children and adolescents (mean age = 14.02 years [range = 8.83–17.52 years]) at two-time points with an interval of 6 months. FA was characterized using the Chinese version of the dimensional Yale Food Addiction Scale for Children 2.0. Furthermore, FC and VFL were measured using direct segmental multi-frequency bioelectrical impedance analysis at each time point.
Results
Higher FA was associated with increased BMIZ, FC, and VFL (P < 0.05). FA at T0 could predict increased FC at T1 (P < 0.05). The characteristics of females, primary students, and living in urban areas may aggravate the adverse effect of FA on weight status over time and age, particularly the increased VFL in participants aged > 14 years.
Conclusion
Children and adolescents with a high FA level were at risk for weight gain attributed to increased FC, and the adverse effect could be aggravated with time and age. Novel FA-targeting interventions may help mitigate the risk of getting obesity.
... Pancreatic cancer (PC) is one of the most significant and aggressive tumors [1] since it accounts for approximately 5% of cancer-related deaths worldwide [2]. Smoking habit is the most important factor leading to pancreatic cancer, although the disease can also be associated with other factors such as individuals' exposure to certain metal types [3], caloric intake and/or obesity [4,5], aging [6], as well as with some chronic conditions such as diabetes, chronic pancreatitis and cirrhosis [7,8], and with genetic factors that account for 10% of PC cases [6]. Most PC (95%) cases comprise adenocarcinomas, which are highly aggressive tumors [3]. ...
Pancreatic cancer is one of the most aggressive tumors since it accounts for approximately 5% of cancer-related deaths worldwide. Immunotherapy based on compounds capable of acting as toll-like receptor (TLRs) agonists may be a valuable strategy to treat cancer, either alone or in association with prevailing therapies. Thus, P-MAPA (Protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride) has emerged as a likely candidate to treat some cancer types, such as pancreatic cancer (PC). The current study reports the effects of an emerging alternative therapy against PC, which lies in associating P-MAPA immunotherapy with gemcitabine-based chemotherapy to treat PC in murine models. Besides, the study reports the potential mechanisms of action of this new therapeutic association involving the TLR4 signaling pathway. PC chemically induced in animal model based on 7,12-dimethylbenz(a)anthracene carcinogen administered by thermosensitive copolymer effectively induced pancreatic tumors in 100% of the investigated rats. P-MAPA-based immunotherapy application alone has shown histopathological repair in 40% of rats, whereas those only treated with gemcitabine have shown 100% of malignant tumors. P-MAPA/Gemcitabine-associated treatment was highly effective in reducing neoplastic lesion progression and enabling histopathological improvement in 80% of the investigated rats. P-MAPA and P-MAPA/Gemcitabine treatments led to increased TLR4 protein contents, which led to increased interferon signaling pathways and positive antitumor effectiveness due to suppressed abnormal cell proliferation. Thus, it is a possible conclusion that the P-MAPA immunotherapy/gemcitabine association had a positive effect on murine models with PC and that it may be a valuable alternative to treat this tumor type.
