Obesity and Pancreatic Cancer: Its Role in Oncogenesis

Abstract

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.

1. Introduction

In the United States (US), pancreatic cancer (PC) continues to have a poor prognosis due to delayed diagnosis, late-stage disease at the time of diagnosis, and limited treatment options. Since 2000, annual incidence rates have grown at a 0.6–1% in all races, both sexes, and age categories, making it the eighth most common cancer in women and the tenth most common cancer in men [1, 2]. The risk of PC increases with age. The median age of diagnosis is around 70 years old [3]. Recent incidence trends between 2000 and 2014 show a bimodal age distribution, between 20 and 29 years and >80 years [4]. The incidence is higher in males than females, with an incidence risk ratio (IRR) of 1.32; >1 for age groups >35. There may be a link between males and environmental risk factors, such as smoking and alcohol. The incidence (496,000) and deaths (466,000) in 2020 are almost equal [5]. This equal ratio has remained constant since 2010 [6]. PC accounts for 8% of all cancer-related deaths in the US and is the third leading cause after lung and colorectal cancers [7]. In the US, 5-year survival rates for all stages steadily increased from 0.9% in 1975 to 4.2% in 2011 and 10% between 2010 and 2016. Globally, the 5-year survival rates have not exceeded 10%, except for surgically resected patients; their 5-year survival rates increased from 1.5% to 17.5% [8].

The term obesity encompasses excessive fat accumulation that impairs health [9]. Indirect anthropometric measures include body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR), and body fat percentage estimated skin foldness; with the BMI being the easiest and most widely used [10]. BMI ≥ 30 is considered obese. It is further classified; class 1: 30–34, class 2 35–39, and class 3 (morbid or severe obesity) ≥ 40 [11]. In the US, the age-adjusted prevalence of obesity among adults over 20 years was 41.9% between 2017 and 2020 [12]. There was a significant rise in obesity prevalence of 30.5% between 1999 and 2000, when the Centers for Disease Control and Prevention (CDC) first recognized obesity as an epidemic [9, 13]. Adult obesity prevalence spiked by 3% between March 2020 to March 2021, the first year of the coronavirus disease 2019 (COVID-19) pandemic, which coincided with higher alcohol and tobacco use, lower rates in exercise activity due to quarantine, and higher average sleep duration [14]. Obesity can foster various detrimental health problems and increase mortality from all causes, including cardiovascular diseases, and cancers. The estimated prevalence of obesity-associated cancers is 684,000 US annually, including 210,000 among men and 470,000 among women, per CDC data. The evidence of obesity-associated cancers is consistent with breast cancer in postmenopausal women, adenocarcinoma of the esophagus, colon, endometrium, gall bladder, gastric, renal cell, pancreas, thyroid, meningioma, and multiple myeloma [15, 16].

1.1 Obesity and pancreatic cancer risk

Numerous prospective, observational, and epidemiological studies have recognized obesity as an independent and modifiable risk factor for PC [17, 18, 19, 20]. The incidence and outcomes of PC are both adversely affected by obesity [21, 22]. According to a systematic review and meta-analysis of 23 prospective studies, both general and abdominal fatness are associated with an increased PC risk with a relative risk (RR) of 1.1 [95% confidence interval (CI), 1.07–1.14], when stratified by gender and geographical location [20]. In a 12-year study by a metabolic syndrome and cancer project, obesity increased the risk of PC by 1.5 in women and no correlation was found in males [23]. In other studies, a stronger association of obesity to PC risk is found in men and further higher in smokers [22]. Confounding risk factors such as smoking and alcohol consumption in males and females may explain the contrasting findings. Higher WHR is associated with an increase in risk in women, while higher BMI is associated with an increase in risk in both men and women [17]. Incidence risk is specifically higher with a BMI ≥ 95th percentile in early adulthood and a gain of ≥10 kg/m² BMI in early adulthood years [24, 25]. Those with a calorie intake at the highest quartile experienced 70% higher risk than those with the lowest quartile in a case control study [26]. High BMI and underlying genetic profiles may also contribute to the elevated average PC risk among African Americans. A 20% higher risk of PC was found in African Americans than European Americans when adjusted for other risk factors [8].

PC patients with obesity in all age groups, regardless of disease stage and tumor resection status, were associated with reduced overall survival of PC with a hazard ratio 1.26 (95% CI, 0.94–1.69) [22]. The risk of early and elevated PC mortality is significantly elevated by central obesity independent of BMI during early adulthood [21, 27]. People with BMI ≥ 35 have a worse survival rate after surgery for potentially curable PDAC. According to a retrospective study, patients with a BMI >35 are 12 times more likely to have lymph node metastasis, and their chances of recurrence and death double, compared with patients with BMI <35 [28]. Considering all of the above results, it is imperative to understand the underlying pathogenesis and implement obesity-specific prevention interventions for PDAC.

2. Biologic pathogenesis

The exact biologic interlink between obesity and PC remains unclear. PDAC represents more than 90% of all PC cases [8, 29]. PDAC develops from various precursor lesions, including mucinous cystic neoplasms (MCN), intraductal papillary mucinous neoplasms (IPMN), and pancreatic intraepithelial neoplasms (PanIN). PanINs are categorized into grades 1–3 which sequentially progress into PDAC. Several in vitro and in vivo studies are ongoing to decipher the molecular foundation of obesity-associated PDAC. 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].

2.1 Obesity and potentiation of Kras activity

The activating mutations in the protooncogene Kras are the key driver mutation among 90% of the PDACs. It is the earliest genetic event in the pathogenesis noted in PanIN grade 1. In 98% of Kras mutated PDACs, missense mutations occur in glycine (G)12, G13, or glutamine71 (Q61) regions, that lead to the activation of Kras permanently [33]. In pancreatic Cre driver mice models, constitutive overexpression of active Kras G12D was identified as an important step in PanIN development and carcinogenesis [34]. Kras is found in almost all PDACs, but it is insufficient in developing PDAC. In mouse models, despite the expression of mutated Kras, mice did not readily develop into PanINs/PDACs [35]. Additional genetic, epigenetic, and tumor microenvironment alterations were required in the transformation into PDAC. The further accumulation of acquired genetic alterations in tumor suppressor genes, such as CDK2N2A, SMAD4, or TP53 contributed to the inhibition of pancreatic cell death and tumor transformation [36]. 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]. Obesity-associated factors including insulin resistance, inflammation, and gut dysbiosis that are upstream of Kras enhance the downstream signals creating multi-loop effects [38]. Some have postulated the obesity-induced activation of signaling molecules downstream of Kras, including increased levels of phosphorylated mitogen-activated protein kinase (MEK) and extracellular signal-regulated kinases (ERK) may also be contributory [39]. Kras mutations further trigger the progression from PanIN1 to PanIN2. A positive feedback loop is created, demonstrating obesity and its tumor environment changes to be a major Kras potentiator, paving a path for prospective preventive avenues of this dismal cancer [29].

2.2 Adipokines

Adipose tissue (AT) is increasingly recognized as a dynamic hormonal and metabolically active organ that produces biologically active peptides known as adipokines. 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).

Leptin is positively correlated to obesity. Higher Levels of leptin are found in women than men irrespective of BMI. Leptin plays a role in appetite control and as a pro-inflammatory modulator of pancreatic tissue. Hyperleptinemia in obesity is thought to be secondary to leptin resistance and therefore, the role of leptin in PDAC development remains controversial [41]. However, in vitro and clinical studies have demonstrated elevated serum leptin levels were higher among PDAC subjects [42]. Further studies are required to confirm its role and significance in clinical settings. Adiponectin is inversely correlated to obesity by its active role in insulin regulation, glucose and fatty acid metabolism, and overall anti-inflammatory properties. The imbalance created by adiponectin and leptin creates a pro-inflammatory pathway [40]. Several preclinical studies were consistent with adiponectin’s role in pathogenesis however current evidence of adiponectin levels and PDAC is contradictory. Higher adiponectin levels correlated with lower PDAC in several prospective studies versus others showed higher levels correlated with increased risk [43, 44]. It is unclear if this is due to timing of adipokine level checking or if adipokines in pancreatic tumor environment did not correlate with serum adipokines levels, as opposed to mice studies where adipokines levels showed a positive correlation.

LCN-2 is a small extracellular protein with several biological functions including energy metabolism, inflammation, and innate immunity. Adipocytes secrete LCN-2 during metabolic stress and obesity, where LCN-2 acts as a homeostasis regulator. LCN-2 is implicated in T2DM, chronic pancreatitis, and more recently, in PDAC. Its role in both pro and anti-tumor effects has been reported. Absence of LCN-2 prevented obesity in high-fat-fed mice and decreases rate of pancreatic fibrosis, inflammation, and aberrant cell proliferation, proving its inclination toward anti-tumor activities. There is a need for more clinical studies to evaluate if LCN-2 could be a potential target in prevention of obesity and early stages of PDAC [45, 46, 47]. FGF-21 has recently come into spotlight as a regulator in glucose and lipid metabolism with the potential to treat obesity. Emerging data on its role in PDAC is underway [48]. In the presence of Kras oncogenic mutations in obese mice, FGF-21 levels were found to be significantly reduced and are implicated in the extensive inflammation, PanINs, and PDAC [49]. The intricate intracellular pathway remains unclear at this time. A pro-inflammatory adipokine, Wnt5a works in conjunction with secreted frizzled-related protein (sfrp)-5 key regulators studied in obesity. Release of Wnt5a from visceral adipose tissue (VAT) and overexpression of Wnt5a has been reported in PDAC microenvironment have shown positive correlation to downstream activity of yes-associated protein (YAP) among Kras independent aggressive squamous subtype of PDAC which operates via YAP-mediated mechanisms [50]. Further pre-clinical studies are needed to confirm such an association.

Other AT-derived cytokines include interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha that is secreted by adipocytes via effect of leptin excess and macrophages in the tumor microenvironment plays a role in obesity accentuated chronic inflammatory process as well [51]. More recently, AT is studied to have effects systemically via soluble mediators released by visceral fat depots and reach pancreatic microenvironment through systemic circulation by extracellular vesicles produced by adipocytes which attach to targets on pancreatic cells [52]. It is unknown if these extracellular vesicles communicate with the precursor PanIN or PDAC cells differently from normal pancreatic cells.

Expansion and hypertrophy of AT in obesity creates an imbalance in inflammatory and anti-inflammatory cytokine release, subsequently lead to progression to PanIN and PDAC, as described in chronic inflammation section. A differential inflammatory process is well studied in visceral AT (intrabdominal fat pads, omental, mesenteric) compared to subcutaneous AT. Adipose hyperplasia is often seen in subcutaneous AT but is associated with low levels of inflammation and balanced insulin sensitivity. In contrast, hypertrophy and hyperplasia in visceral AT predominately cause the elevated pro-inflammatory response which strongly correlates with obesity-induced metabolic dysfunction and PanIN formation compared to subcutaneous AT [32, 53, 54]. The synergistic combination of elevated inflammatory response with systemic deposition of extracellular vesicles in pancreatic microenvironment is a well accepted mechanism in the pathogenesis of PDAC [54, 55]. While the differences between VAT and subcutaneous AT is well established, recent focus has driven toward intrapancreatic fat and “fatty pancreas disease” in PDAC carcinogenesis from metanalysis showing 52% pooled prevalence of intrapancreatic fat among PDAC and premalignant lesions [56]. This creates a platform for combinational effects of VAT expansion and fatty replacement of pancreas. This association remains under investigation and requires attention to guide future screening models incorporating intra-pancreatic fat measurements. A need for adequate tools to differentiate normal versus excess pancreatic fat on imaging remains a challenge.

2.3 Hormonal effects and insulin resistance

A high BMI and obesity are associated with elevated levels of insulin and C peptide levels, leading to hyperglycemia, insulin resistance, and type 2 diabetes mellitus (T2DM). All have demonstrated a role in the development of PDAC in prospective studies and meta-analysis [31, 57]. Elevated circulating and intrapancreatic insulin levels cause suppression of circulating insulin growth factor binding proteins (IGFBP)-1 and 2 and subsequently lead to higher levels of IGF-1. IGF-1 and insulin bind to IGF receptors (IGF-R) on pancreatic acinar cells and propagate cell proliferation, apoptosis, and angiogenesis [31, 58]. A crosstalk between insulin and IGF-R and G protein-coupled receptor (GPCR) signaling converges on the mechanistic target of rapamycin (mTOR) responsible for cell proliferation. Inhibitory function of metformin on insulin and IGF-R emerged its role in PDAC prevention [59, 60]. This cross-talk also stimulates YAP and transcriptional coactivator with PDZ binding motif (TAZ) which are critical molecules in PDAC [61]. The individual levels of IGF-1, IGF-2, and IGFBP-3 did not correlate with the risk of PDAC. However, a higher IGF-1/IGFBP-3 ratio represented increased free IGF-1 which showed a significant positive trend toward elevated risk of PDAC [62]. At this time, this ratio is not routinely used as a screening tool and would need further evidence in prospective studies. In obesity, increased insulin/IGF-1 and gastrointestinal peptides that activate the GPCRs further cause increased cell proliferation. Finally, elevated levels of glucose and advanced glycation end products are known to be tumor-promoting factors and important modulators in metabolic dysfunction and carcinogenesis [63].

Stress adaptiveness of pancreatic cells is another proposed mechanism of tumorigenesis by promoting cell growth and resistance to anti-cancer therapies. Recently, stress granules (SGs) have been described, which are the intracytoplasmic condensations of proteins and mRNA driven by oxidative stress, hypoxia, endoplasmic reticulum stress, and osmotic stress. A specific pathway described where IGF1 binds to IGF-R activates S6 kinase (S6K)-1 subsequently activates serine/ arginine protein kinase (SRPK)-2 and mediates the formation of IGF-1-driven SGs among obesity-induced PDAC carcinogenesis. This pathway of SRPK-2-dependent SGs formation highlights its uniqueness and context-specific to obesity-related pathway in PDAC however needs further validation. In addition, mutant Kras upregulates the capacity of PDAC cells to form SGs, further enhancing resistance to several stimuli and chemotherapeutic agents. However, SGs are considered to cause PDAC proliferation by Kras independent pathways as well and are thought to be one of the mechanisms of PDAC resistance to Kras targeted therapy [58].

Elevated estrogen activity was observed as an initiating factor in carcinogenesis. Leptin plays a role in transcription of aromatase; a key enzyme converts androstenedione and estrone to estrogen. The data on direct activity of these steroids on androgen and estrogen receptors on pancreatic cells remains unclear in the pathogenesis of PDAC but has shown some positive cell proliferation at low levels of estrogen compared to inhibition of cell proliferation with high doses [64]. However, further studies have shown mixed expression of estrogen receptors on PDAC cells and unclear benefits with anti-estrogen therapies and prognosis [64, 65, 66].

2.4 Chronic inflammation

Obesity is a chronic subclinical pro-inflammatory state. In general, overnutrition creates an imbalance between calorie intake and energy expenditure, leading to expansion of AT. AT expansion and imbalance of adipokines leads to reduction of anti-inflammatory immune cells such as CD4+ T helper (Th) 2 cells, IL-C2s, Tregs, eosinophils, type II natural killer (NK) T cells which occur in lean state. On the other end, AT expansion leads to activation of major histocompatibility complex (MHC) II expression and myeloid cells and stimulates CD8+ Th 1 inflammatory pathway sequentially activating interferon (IFN) gamma. This immune activation causes adipocyte apoptosis and histologic changes including formation of crown-shaped clusters of engulfed macrophages which is the signature of AT inflammation [32, 67, 68]. These hypertrophied adipocytes, lymphocytes, and macrophages in the AT increase the circulatory levels of cytokines such as TNF-alpha, IL-6, leptin, and adiponectin which promote inflammation and abnormal cell growth [69]. Chronic inflammation is a key mediator of carcinogenesis noted in several cancers. Alterations in fibro-inflammatory microenvironment triggers abnormal cell proliferation, halt apoptosis, activate angiogenesis, migration, and metastasis [69]. AT can also induce insulin resistance, hyperinsulinemia, hyperglycemia, hyperlipidemia, vascular injury which are associated with oxidative stress [30]. Inflammatory cytokines and oxidative stress mainly activate the nuclear factor-kappa B (NF-kB) pathway leading to downstream activation of PanIN and PC carcinogenesis [30, 55]. Therefore, obesity-associated inflammation is a stronger risk factor for PC than chronic inflammation alone, due to this augmented interplay. Peroxisome proliferator activated receptor-gamma (PPAR-gamma), a NFkB receptor is a key regulator of pancreatic cell metabolism, cell differentiation, and anti-inflammatory role is currently being evaluated as a potential target in prevention of PDAC [30].

2.5 Gut and pancreatic microbiome

Alteration of gut microbiota is well studied in obesity-associated metabolic dysfunction and development of T2DM [70]. Obesity-associated altered gut microbiome is implicated in colorectal and hepatocellular carcinoma [71, 72]. Over the recent years, obesity-associated genetic, environmental, and nutritional factors have been implicated in the disequilibrium and crosstalks between intrapancreatic, intratumoral, and gut microbiome and its role in PDAC [55, 73, 74, 75]. Akkermansia muciniphila an intestinal symbiotic bacterium that plays a role in maintaining a functioning gut barrier and its abundance is correlated to a lower incidence of obesity and other metabolic diseases. Metformin use in preclinical studies showed reduced levels of Clostridium sensu stricto and elevated levels of Akkermansia bacteria in high-fat-fed mice, one of the possible benefits of metformin in PDAC prevention, introduced the possible underlying pathomechanism [76]. These microbiota dysbiosis causes a release of metabolites (short-chain fatty acids or lipopolysaccharides), activation of intestinal GPCRs, enabling gut permeability and translocation of bacteria/ bacterial components leading to a systemic pro inflammatory state [77]. Certain lipopolysaccharides (LPS) producing bacteria alter the microbial profile in pancreas by reducing probiotics and butyrate-producing bacteria. LPS acts as a pro-inflammatory protumor trigger by activating NFkB pathway which subsequently activates cytokines including IL-6, TNF, and IL-1. LPS excess could further lead to recruitment of proinflammatory M1-like macrophages, pancreatic fibrosis, chronic inflammation, and PanIN lesions [68, 74]. A positive feedback loop is initiated by amplification of Ras activity by NF-KB which triggers further inflammation and initiates a positive feedback loop found among oncogenic Ras activated mice [74].

2.6 Food carcinogens

Diet consisting of high grilled and fried meats, preservatives, some grains, and vegetables containing heterocyclic amines, aristolochic acids, polycyclic aromatic hydrocarbons, pyrrolizidine alkaloids, aflatoxins, acrylamide, N-nitroso compounds, and benzopyrenes have been positively associated with both obesity and PDAC in epidemiological studies [78, 79, 80, 81, 82]. An increased PC risk has been associated with higher exposure of these diets; however, evidence of temporal relationship and pathogenesis remains unclear. More recently, contradictory findings of deep-fried foods inversely related to risk of PDAC was found in prospective study (Figure 1) [83].

Figure 1.

Several proposed pathways of PDAC carcinogenesis. Obesity potentiates the Kras pathway via PanIN progression. Kras further reduces pancreatic FGF-21 increasing cancer propagation. High BMI, insulin resistance, and a high-fat diet contribute to increased insulin and visceral and intrapancreatic AT inflammation. AT-derived cytokine release and VAT stem cell translocation cause chronic pancreatic inflammation, including potentiation of Kras pathway. Changes in the gut microbiome cause pancreatic microbiome alterations, subsequently activating chronic inflammation via recruiting of M1 macrophages. Chronic fibroinflammatory changes lead to PanIN progression via NFkB pathway. Increased insulin and IGF-1 lead to stress granule formation that contributes to carcinogenesis via mTOR pathway independent of Kras pathway.

3. Implications in prevention

Epidemiology demonstrates obesity is one of the vital modifiable risk factors of PDAC [17, 18, 19]. Measures to combat obesity is therefore of utmost importance in prevention of this lethal cancer with delayed diagnosis, aggressive nature, and poor responses to current treatment options. At the national level, several strategies were implemented after the recognition of obesity as an epidemic. These include environmental changes, increase access to healthy foods, increasing fruit and vegetable intake, dietary approaches to stop hypertension (DASH) diet, encouraging breastfeeding, more physical activity for general health and cardiovascular disease prevention, and further focus on its role in PC prevention.

3.1 Calorie restriction

Animal models have shown calorie restriction slowed the PC growth and development. In a study using conditional KrasG12D mice, intermittent calorie restriction and chronic calorie restriction have shown a relatively lower percentage of PanIN3 lesions. Calorie restriction and diet modifications have been proven to reduce incidence of breast and endometrial cancers in observational studies. Efforts to combat obesity are increasingly identified. The biggest challenge is short-term weight loss occurs with calorie restriction and a vast majority of people cannot keep up and gain back the lost weight in the long term [55].

3.2 Bariatric surgery

A significant reduction in risk of PDAC and mortality was found in obese patients who underwent bariatric surgery consistently among several studies. Of note, 73% of patients in bariatric surgery arm were female and 79% were younger than 65 years of age. Relatively small sample size and short follow-up duration studies were unable to detect a significant difference in PC risk. Several mechanisms are proposed in its beneficial role in PDAC. A significant reduction of inflammatory markers (CRP, IL-6) activated T cells ratio and increased anti-inflammatory regulatory T cells in epididymal adipose tissues was noted as early as 3 weeks post-surgery [84]. Bariatric surgery significantly improved insulin resistance and improved intestinal microbiota profile with equal benefits with both Roux-en-Y gastric bypass and vertical banded gastroplasty [85]. Bariatric surgery provides a long term and durable weight loss than calorie restriction. At this time, overall survival rates in PDAC patients who underwent prior bariatric surgery are unclear.

3.3 Antidiabetic treatments

Metformin is implicated in reduction of PC risk by inhibition of cell growth, proliferation, migration, and cell invasion, however, is still not completely understood [39, 59, 60, 61, 86]. Inhibition of crosstalk of GPCR and insulin/IGFR pathway, activation of liver kinase B1 (LKB1), repurposing the adenosine monophosphate-activated protein kinase (AMPK) and ultimately the disruption of downstream mTOR pathway is a well-accepted mechanism [59, 87]. Metformin also downregulates the expression of YAP and TAZ in pancreas acinar cells in addition to reduction of insulin/IGF-1 levels [39, 61]. Mice studies have shown metformin in high-fat-fed mice normalized the obesity-induced gut dysbiosis and maintained higher levels of Akkermansia related to Clostridium sensu stricto microbiota which helps in maintaining a functioning gut barrier [75]. In an epidemiological meta-analysis, metformin reduced the risk to one-third compared to other diabetic treatments [88]. Metformin has shown significant survival benefits in patients among T2DM, early stage and resected PCs in contrast to metastatic stages where the benefits were unclear per a large meta-analysis [89, 90]. It is proposed that in the later stages, amount of metformin is relatively less in the tumor cells to show its fullest benefits owing from the observation that metformin showed increased survival rates among resected advanced-stage PDAC. Overall, current evidence has not proven metformin-associated survival benefits in PDAC. Given its well tolerability, a potential beneficial role in chemoprevention is favored rather than therapeutic setting. Metformin is not currently a part of guideline-based protocols. Randomized controlled trials are required to explore this further. Recent evidence has shown synergistic effects of aspirin and metformin in chemoprevention in PDAC by inhibition of COX and NFKB pathway in addition to mTOR pathway which might essentially benefit obese population [74, 91].

The idea of use of thiozolidiones and PPAR-gamma agonists navigated its way into experimental studies of PDAC prevention, as PPAR-gamma a vital regulator in cell differentiation and inflammation. In vitro studies demonstrated that PPAR-gamma agonists induce apoptosis, ductal differentiation, reduce cell motility, tissue invasion, and arrest in G0/G1 phase by PPAR-gamma dependent and independent mechanisms [92]. PPAR-gamma agonists also alter the total urokinase activity by reducing urokinase plasminogen activator, which is causally involved in PDAC pathogenesis, further studies are required for its use in therapeutic setting [30].

3.4 Anti-inflammatory agents

Mice studies demonstrated disruption of NFkB-mediated inflammatory pathway by decreasing the expression of NFkB kinase 2 or Cox-2. Interruption of the positive feedback loop by Cox-2 inhibitors is a potential preventive strategy among Ras-mediated cancers including pancreas, colon, and lung. This paved path for aspirin in PDAC and a synergistic effect with metformin, especially among obese patients [74]. However, an earlier prospective study of extended aspirin use showed statistically increased risk of PDAC among women [93]. Further studies are required for its validation.

3.5 Fibroblast growth factor-21 supplements

Normal pancreatic acinar cells express high levels of adipokine FGF-21 as described above. Among obese Kras mutated mice, FGF-21 levels were significantly low. In preclinical studies, FGF-21 injections have shown prevention of extensive inflammation, PanINs and PDAC among obese mice [48, 49]. FGF-21 might be used in chemoprevention and treatment of PDAC and requires further preclinical and clinical studies.

3.6 Beta-blockers and statins

Beta-blockers have come into focus in PDAC chemoprevention by its effects on downregulation of cAMP-dependent endothelin growth factor (EGF) and vaso endothelin (VEGF) production. Statins are being evaluated in PDAC prevention by its effects of inhibition of 3 hydroxy3 methylglutaryl coenzyme A (HMGcoA) reductase effects on degradation of TP53 and reduced Ras activity. However, these agents have not been studied in relation to obesity-associated PDAC [86].

3.7 Screening

Currently, no screening guidelines exist for PDAC in high-risk obesity. Computed tomography (CT) screening was evaluated in T2DM at the time of diagnosis, however, has not reached evidence of significance. A predefined elevated IGF-1/IGFBP-3 ratio could be used as a screening tool to identify high-risk obesity patients. It is possible to identify prediction models based on epigenomic, transcriptomic, and proteomic approaches for obesity-driven carcinogenesis using appropriate in vitro and in vivo models that may be used for early detection of PDAC in obese high-risk individuals [29].

4. Implications in treatment

Surgery remains the mainstay for curative intent. However, at presentation, only 15–20% of PDAC are resectable. For locally advanced unresectable and metastatic PDACs, palliative systemic therapy including combinational chemotherapy has shown improvement in disease-related symptoms and prolonged survival. Genetic testing is recommended in all newly diagnosed PDAC patients and molecular testing for mutations in metastatic setting. Currently, we have limited treatment options beyond first line therapies. Treatment choices must be weighed against best supportive care.

4.1 Targeted agents

At this time, there are limited targeted therapy options in PDAC outside of clinical trials. Currently, targeted options are approved for BReast CAncer gene (BRCA) 1/2 mutations (olaparib), Microsatellite Instability (MSI) high (pembrolizumab), Neurotrophic tyrosine receptor kinase (NTRK) mutations (entrectinib, Larotrectinib), and B-Rapidly Accelerated Fibrosarcoma (BRAF) V600E mutations (Dabrafenib+ Trametinib) [94, 95, 96, 97, 98]. Although Kras mutations are major drivers of PDAC, several decades of research has not been able to find a targeted therapy against Kras due to its high affinity for GTP activity and absence of an amenable surface topologic target [33]. As a result, past efforts have mainly focused on indirect strategies to target the downstream signals. Recent success in identifying small molecules that directly bind to RAS, has fueled hope that RAS may be druggable after all. Sotorasib, a KrasG12C inhibitor traps Kras in the inactive GDP-bound conformational state by fitting tightly into a unique phosphate binding pocket and is recently FDA approved. A phase 1/2 trial, CodeBreak100 (NCT03600883), demonstrated that 8/38 (21%) patients had confirmed partial responses and 32/38 (84%) patients had disease control in a median follow-up of 16.8 months. Only 1–2% of PDAC patients have KrasG12C mutations and its inhibitor is clinically meaningful in these cases [99, 100]. Currently, there are ongoing trials for KrasG12D siRNA-targeted therapies (NCT03608631). Understanding pathogenesis of obesity-driven PDAC could potentially recognize further therapeutic targets. Several studies in preclinical settings are ongoing for targeting various steps in the pathogenesis of PDAC. One such example is blocking the downstream step of SG formation. Hyperactivation of IGF-1/PI3K/mTOR/S6K1 pathway leads to SRPK2-mediated SG formation, a vital step in obesity-associated PDAC. S6K1 inhibition selectively attenuates IGF-1-driven SGs formation and can potentially be a treatment target [58].

4.2 Future perspectives for adjunctive therapies

Strategies for microbiome modification or other options could potentially control metabolic endotoxemia as an adjunctive treatment of PDAC remains unknown [70].

4.3 Exercise interventions

Individualized exercise interventions are increasingly identified as effective therapy as an adjunct in PDAC management, improving quality and quantity of life, reducing treatment side effects, enhancing fitness preoperatively, combating cancer-related fatigue, and overall psychological health benefits [101, 102, 103]. Aerobic and resistance exercise reduced symptoms of depression and anxiety in all PDAC stages and settings, in line with other common cancers such as breast cancer [103, 104]. Exercise regimens tailored to improve skeletal muscle health preoperatively and in neoadjuvant settings has shown to improve clinical and quality of life outcomes [101, 105]. The feasibility of multimodal cachexia intervention with resistance training, nutritional supplements, and anti-inflammatory agents such as celecoxib was tested in PDAC-related cachexia. These modalities have cleared the safety threshold and compliance goals. Currently, phase II studies are underway to test the efficacy [106, 107]. A systematic review that looked at overall exercise effects did not show any adverse effects related to exercise in PDAC patients. However, limitation includes a smaller sample size and finite data from case reports/studies. Overall results supported safety and feasibility of exercise training in PDAC patients [103]. The underlying mechanism of this benefit remains unclear. Due to the high burden of disease and treatment-related adverse effects, exercise compliance also is a major challenge for PDAC patients. Individualized regular exercise regimens and shorter assessment intervals are required to evaluate the short-term benefits of exercise in a disease which has shorter life expectancy.

5. Conclusion

Obesity is a major independent and modifiable risk factor of PDAC. The biological link between obesity and PDAC is complex and convoluted. The interplay is driven by genetic, hormonal factors, insulin resistance, adipokines, circulating lipids, and gut microbiome dysbiosis. These findings indicate that there is unlikely to be a single mechanism to explain obesity-associated PDAC. Awareness and deeper knowledge could help implement potential preventive measures (diet modifications, exercise, and bariatric surgeries) and treatment modalities. Prospective trials to evaluate metformin in chemoprevention, screening in high-risk obese populations, risk predictive models, KrasG12D directed therapies, adjunct use of gut microbiota transplantation, and personalized therapies are some future perspectives.

Conflict of interest

The authors declare no conflict of interest.

Appendices and nomenclature

None.

List of abbreviations

PDAC	pancreatic ductal adenocarcinoma
Kras	Kirsten Rat Sarcoma viral oncogene
US	United States
PC	pancreatic cancer
IRR	incidence risk ratio
BMI	body mass index
WC	waist circumference
WHR	waist-hip ratio
CDC	Centers for Disease Control
COVID19	Coronavirus Disease 2019
RR	relative risk
CI	confidence interval
MCN	mucinous cystic neoplasms
IPMN	intraductal papillary mucinous neoplasms
PanIN	pancreatic intraepithelial neoplasms
IGF1	insulin-like growth factor 1
MEK	mitogen-activated protein kinase
ERK	extracellular signal-regulated kinase
AT	adipose tissue
LCN-2	lipocalin-2
FGF-21	fibroblast growth factor
Wnt5a	wingless-type mouse mammary tumor virus integration site family member 5A
Sfrp-5	secreted frizzled-related protein
VAT	visceral adipose tissue
YAP	yes-associated protein
IL	interleukin
TNF	tumor necrosis factor
T2DM	type 2 diabetes mellitus
IGFBP	insulin growth factor binding proteins
GPCR	G protein coupled receptors
TAZ	PDZ binding motif
SG	stress granules
S6K	S6 kinase
SRPK	serine/arginine protein kinase
Th	T helper
NK	natural killer
MHC	major histocompatibility complex
IFN	interferon
NFkB	nuclear factor kappa B
PPAR-gamma	peroxisome proliferator-activated receptor-gamma
LPS	liposaccharides
DASH	dietary approaches to stop hypertension
LKB1	liver kinase B1
AMPK	adenosine monophosphate-activated protein kinase
EGF	endothelin growth factor
VEGF	vaso endothelin growth factor
HMGcoA	3 hydroxy 3 methylglutaryl coenzyme A
CT	computed tomography
BRCA	BReast CAncer gene
MSI	microsatellite instability
NTRK	neurotrophic tyrosine receptor kinase
BRAF	B rapidly accelerated fibrosarcoma