Ketogenic Diets in Pancreatic Cancer and Associated Cachexia: Cellular Mechanisms and Clinical Perspectives

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and extremely therapy-resistant cancer. It is estimated that up to 80% of PDAC patients present with cachexia, a multifactorial disorder characterized by the involuntary and ongoing wasting of skeletal muscle that affects therapeutic response and survival. During the last decade, there has been an increased interest in exploring dietary interventions to complement the treatment of PDAC and associated cachexia. Ketogenic diets (KDs) have gained attention for their anti-tumor potential. Characterized by a very low carbohydrate, moderate protein, and high fat composition, this diet mimics the metabolic changes that occur in fasting. Numerous studies report that a KD reduces tumor growth and can act as an adjuvant therapy in various cancers, including pancreatic cancer. However, research on the effect and mechanisms of action of KDs on PDAC-associated cachexia is limited. In this narrative review, we summarize the evidence of the impact of KDs in PDAC treatment and cachexia mitigation. Furthermore, we discuss key cellular mechanisms that explain KDs’ potential anti-tumor and anti-cachexia effects, focusing primarily on reprogramming of cell metabolism, epigenome, and the gut microbiome. Finally, we provide a perspective on future research needed to advance KDs into clinical use.

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Exercise efficacy and prescription during treatment for pancreatic ductal adenocarcinoma: a systematic review

BMC Cancer ◽

10.1186/s12885-020-07733-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Dominic O’Connor ◽

Malcolm Brown ◽

Martin Eatock ◽

Richard C. Turkington ◽

Gillian Prue

Keyword(s):

Quality Of Life ◽

Systematic Review ◽

Pancreatic Cancer ◽

Adjuvant Therapy ◽

Physical Function ◽

Meta Analysis ◽

Ductal Adenocarcinoma ◽

Key Stakeholders ◽

The Impact

Abstract Background Surgical resection remains the only curative treatment for pancreatic cancer and is associated with significant post-operative morbidity and mortality. Patients eligible for surgery, increasingly receive neo-adjuvant therapy before surgery or adjuvant therapy afterward, inherently exposing them to toxicity. As such, optimizing physical function through exercise during treatment remains imperative to optimize quality of life either before surgery or during rehabilitation. However, current exercise efficacy and prescription in pancreatic cancer is unknown. Therefore, this study aims to summarise the published literature on exercise studies conducted in patients with pancreatic cancer undergoing treatment with a focus on determining the current prescription and progression patterns being used in this population. Methods A systematic review of four databases identified studies evaluating the effects of exercise on aerobic fitness, muscle strength, physical function, body composition, fatigue and quality of life in participants with pancreatic cancer undergoing treatment, published up to 24 July 2020. Two reviewers independently reviewed and appraised the methodological quality of each study. Results Twelve studies with a total of 300 participants were included. Heterogeneity of the literature prevented meta-analysis. Exercise was associated with improvements in outcomes; however, study quality was variable with the majority of studies receiving a weak rating. Conclusions High quality evidence regarding the efficacy and prescription of exercise in pancreatic cancer is lacking. Well-designed trials, which have received feedback and input from key stakeholders prior to implementation, are required to examine the impact of exercise in pancreatic cancer on key cancer related health outcomes.

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Immune Cell Modulation of the Extracellular Matrix Contributes to the Pathogenesis of Pancreatic Cancer

Biomolecules ◽

10.3390/biom11060901 ◽

2021 ◽

Vol 11 (6) ◽

pp. 901

Author(s):

Ramiz S. Ahmad ◽

Timothy D. Eubank ◽

Slawomir Lukomski ◽

Brian A. Boone

Keyword(s):

Pancreatic Cancer ◽

Extracellular Matrix ◽

Immune Cells ◽

Immune Cell ◽

Treatment Strategies ◽

Stellate Cells ◽

Pancreatic Stellate Cells ◽

Ductal Adenocarcinoma ◽

Cellular Mechanisms ◽

Novel Treatment Strategies

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate of only 9%. PDAC is characterized by a dense, fibrotic stroma composed of extracellular matrix (ECM) proteins. This desmoplastic stroma is a hallmark of PDAC, representing a significant physical barrier that is immunosuppressive and obstructs penetration of cytotoxic chemotherapy agents into the tumor microenvironment (TME). Additionally, dense ECM promotes hypoxia, making tumor cells refractive to radiation therapy and alters their metabolism, thereby supporting proliferation and survival. In this review, we outline the significant contribution of fibrosis to the pathogenesis of pancreatic cancer, with a focus on the cross talk between immune cells and pancreatic stellate cells that contribute to ECM deposition. We emphasize the cellular mechanisms by which neutrophils and macrophages, specifically, modulate the ECM in favor of PDAC-progression. Furthermore, we investigate how activated stellate cells and ECM influence immune cells and promote immunosuppression in PDAC. Finally, we summarize therapeutic strategies that target the stroma and hinder immune cell promotion of fibrogenesis, which have unfortunately led to mixed results. An enhanced understanding of the complex interactions between the pancreatic tumor ECM and immune cells may uncover novel treatment strategies that are desperately needed for this devastating disease.

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Stromal protein βig-h3 reprogrammes tumour microenvironment in pancreatic cancer

Gut ◽

10.1136/gutjnl-2018-317570 ◽

2018 ◽

Vol 68 (4) ◽

pp. 693-707 ◽

Cited By ~ 18

Author(s):

Delphine Goehrig ◽

Jérémy Nigri ◽

Rémi Samain ◽

Zhichong Wu ◽

Paola Cappello ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumour Growth ◽

Matrix Protein ◽

Immune Escape ◽

Interaction Mechanism ◽

Tumour Microenvironment ◽

Extracellular Matrix Protein ◽

Ductal Adenocarcinoma ◽

The Impact

ObjectivePancreatic cancer is associated with an abundant stromal reaction leading to immune escape and tumour growth. This massive stroma drives the immune escape in the tumour. We aimed to study the impact of βig-h3 stromal protein in the modulation of the antitumoural immune response in pancreatic cancer.DesignWe performed studies with p48-Cre;KrasG12D, pdx1-Cre;KrasG12D;Ink4a/Arffl/fl, pdx1-Cre;KrasG12D; p53R172H mice and tumour tissues from patients with pancreatic ductal adenocarcinoma (PDA). Some transgenic mice were given injections of anti-βig-h3, anti-CD8, anti-PD1 depleting antibodies. Tumour growth as well as modifications in the activation of local immune cells were analysed by flow cytometry, immunohistochemistry and immunofluorescence. Tissue stiffness was measured by atomic force microscopy.ResultsWe identified βig-h3 stromal-derived protein as a key actor of the immune paracrine interaction mechanism that drives pancreatic cancer. We found that βig-h3 is highly produced by cancer-associated fibroblasts in the stroma of human and mouse. This protein acts directly on tumour-specific CD8+ T cells and F4/80 macrophages. Depleting βig-h3 in vivo reduced tumour growth by enhancing the number of activated CD8+ T cell within the tumour and subsequent apoptotic tumour cells. Furthermore, we found that targeting βig-h3 in established lesions released the tissue tension and functionally reprogrammed F4/80 macrophages in the tumour microenvironment.ConclusionsOur data indicate that targeting stromal extracellular matrix protein βig-h3 improves the antitumoural response and consequently reduces tumour weight. Our findings present βig-h3 as a novel immunological target in pancreatic cancer.

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Organotypic Culture of Acinar Cells for the Study of Pancreatic Cancer Initiation

Cancers ◽

10.3390/cancers12092606 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2606

Author(s):

Carlotta Paoli ◽

Alessandro Carrer

Keyword(s):

Pancreatic Cancer ◽

Ex Vivo ◽

Acinar Cells ◽

Lineage Tracing ◽

Metabolic Reprogramming ◽

Pancreatic Acinar Cells ◽

Ductal Adenocarcinoma ◽

Molecular Features ◽

The Impact

The carcinogenesis of pancreatic ductal adenocarcinoma (PDA) progresses according to multi-step evolution, whereby the disease acquires increasingly aggressive pathological features. On the other hand, disease inception is poorly investigated. Decoding the cascade of events that leads to oncogenic transformation is crucial to design strategies for early diagnosis as well as to tackle tumor onset. Lineage-tracing experiments demonstrated that pancreatic cancerous lesions originate from acinar cells, a highly specialized cell type in the pancreatic epithelium. Primary acinar cells can survive in vitro as organoid-like 3D spheroids, which can transdifferentiate into cells with a clear ductal morphology in response to different cell- and non-cell-autonomous stimuli. This event, termed acinar-to-ductal metaplasia, recapitulates the histological and molecular features of disease initiation. Here, we will discuss the isolation and culture of primary pancreatic acinar cells, providing a historical and technical perspective. The impact of pancreatic cancer research will also be debated. In particular, we will dissect the roles of transcriptional, epigenetic, and metabolic reprogramming for tumor initiation and we will show how that can be modeled using ex vivo acinar cell cultures. Finally, mechanisms of PDA initiation described using organotypical cultures will be reviewed.

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Brain stem oxidative stress and its associated signaling in the regulation of sympathetic vasomotor tone

Journal of Applied Physiology ◽

10.1152/japplphysiol.00610.2012 ◽

2012 ◽

Vol 113 (12) ◽

pp. 1921-1928 ◽

Cited By ~ 29

Author(s):

Samuel H. H. Chan ◽

Julie Y. H. Chan

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Brain Stem ◽

Ventrolateral Medulla ◽

Future Research ◽

Vasomotor Tone ◽

Cellular Mechanisms ◽

Neurogenic Hypertension ◽

The Impact ◽

Sympathetic Vasomotor Tone

There is now compelling evidence from studies in humans and animals that overexcitation of the sympathetic nervous system plays an important role in the pathogenesis of cardiovascular diseases. An excellent example is neurogenic hypertension, in which central sympathetic overactivation is involved in the development, staging, and progression of the disease, and one of the underlying mechanisms involves oxidative stress in key brain stem sites that are engaged in the regulation of sympathetic vasomotor tone. Using the rostral ventrolateral medulla (RVLM) and nucleus tractus solitarii (NTS) as two illustrative brain stem neural substrates, this article provides an overview of the impact of reactive oxygen species and antioxidants on RVLM and NTS in the pathogenesis of neurogenic hypertension. This is followed by a discussion of the redox-sensitive signaling pathways, including several kinases, ion channels, and transcription factors that underpin the augmentation in sympathetic vasomotor tone. In addition, the emerging view that brain stem oxidative stress is also causally related to a reduction in sympathetic vasomotor tone and hypotension during brain stem death, methamphetamine intoxication, and temporal lobe status epilepticus will be presented, along with the causal contribution of the oxidant peroxynitrite formed by a reaction between nitric oxide synthase II (NOS II)-derived nitric oxide and superoxide. Also discussed as a reasonable future research direction is dissection of the cellular mechanisms and signaling cascades that may underlie the contributory role of nitric oxide generated by different NOS isoforms in the differential effects of oxidative stress in the RVLM or NTS on sympathetic vasomotor tone.

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Highlights on the Role of KRAS Mutations in Reshaping the Microenvironment of Pancreatic Adenocarcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms221910219 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10219

Author(s):

Shirin Hafezi ◽

Maha Saber-Ayad ◽

Wael M. Abdel-Rahman

Keyword(s):

Pancreatic Cancer ◽

Cancer Progression ◽

Human Cancer ◽

Ductal Adenocarcinoma ◽

Ras Gene ◽

Kras Mutations ◽

Oncogenic Mutations ◽

History Of ◽

Novel Therapeutic Strategies ◽

The Impact

The most frequent mutated oncogene family in the history of human cancer is the RAS gene family, including NRAS, HRAS, and, most importantly, KRAS. A hallmark of pancreatic cancer, recalcitrant cancer with a very low survival rate, is the prevalence of oncogenic mutations in the KRAS gene. Due to this fact, studying the function of KRAS and the impact of its mutations on the tumor microenvironment (TME) is a priority for understanding pancreatic cancer progression and designing novel therapeutic strategies for the treatment of the dismal disease. Despite some recent enlightening studies, there is still a wide gap in our knowledge regarding the impact of KRAS mutations on different components of the pancreatic TME. In this review, we will present an updated summary of mutant KRAS role in the initiation, progression, and modulation of the TME of pancreatic ductal adenocarcinoma (PDAC). This review will highlight the intriguing link between diabetes mellitus and PDAC, as well as vitamin D as an adjuvant effective therapy via TME modulation of PDAC. We will also discuss different ongoing clinical trials that use KRAS oncogene signaling network as therapeutic targets.

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Amounts and Botanical Diversity of Dietary Fruits and Vegetables Affect Distinctly the Human Gut Microbiome

Current Developments in Nutrition ◽

10.1093/cdn/nzaa062_002 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1545-1545

Author(s):

Ayoub Al Othaim ◽

Noah Voreades ◽

Natalie Goodwin ◽

Jenae Curley ◽

Daya Marasini ◽

...

Keyword(s):

Fruits And Vegetables ◽

Illumina Miseq ◽

Future Research ◽

Dietary Interventions ◽

Human Gut ◽

Funding Sources ◽

Rrna Sequencing ◽

Stool Samples ◽

Botanical Diversity ◽

The Impact

Abstract Objectives While increasing fruit and vegetable (FV) intake is a near-universal recommendation for improved health outcomes, information on dietary FV amount and diversity impact on health biomarkers is scarce. FV are a major dietary source of gut microbiota (GM) accessible carbohydrates and phytochemicals, however, most studies have focused on single food items or their extracted components, with few holistic studies available. Here, two separate randomized dietary interventions were used to assess the impact of low vs high FV intake and low vs high botanical diversity on GM profiles in healthy adults. We hypothesized that increasing FV would result in beneficial modulations to GM with further increases benefits in those consuming FV from diverse botanical families. Methods Study 1 was a crossover design with, 11 males randomized to starting diets of low FV (L) or high FV (H) over 9 days. Stool samples were obtained at day 0, 3, 6 and 9 of each treatment period. In Study 2, 21 individuals were provided a low FV (L) lead-in diet for 4 days and then randomly assigned to a high FV diet with either low (LB; 11 families) or high botanical diversity (HB; 24 families) for an additional 4 days. Stool was collected at baseline, and after each diet intervention. GM was analyzed using 16S rRNA sequencing performed on an Illumina MiSeq. The Mothur pipeline was used for preliminary data analysis, followed by statistical analyses in PAST. Results In Study 1, the L treatment resulted in minimal microbiota alterations, while a significant increase in Bacteroidetes and decrease in Firmicutes (which peaked at day 6) was observed in the H group. Intriguingly, the L group experienced a short-term increase in Bifidobacterium and Lactobacillus, and both treatments incurred significant increases in Bacteroides and Akkermansia and a decline of Faecalibacterium. In study 2 the transition from low to high FV resulted in similar trends than in Study 1. However, the HB treatment resulted in a more diverse GM, characterized by increased relative abundances of beneficial Firmicutes (Lachnospiraceae, Faecalibacterium and Clostridium XIVa). Conclusions Our results suggest that both amounts of FV consumed and botanical diversity modulate the GM. Determining better FV combinations from a GM perspective thus appears as a possible task for future research. Funding Sources Colorado Agriculture Experiment Station.

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The Impact of Step Recommendations on Body Composition and Physical Activity Patterns in College Freshman Women: A Randomized Trial

Journal of Obesity ◽

10.1155/2019/4036825 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Bruce W. Bailey ◽

Ciera L. Bartholomew ◽

Caleb Summerhays ◽

Landon Deru ◽

Sharla Compton ◽

...

Keyword(s):

Physical Activity ◽

Body Composition ◽

Body Weight ◽

Weight Gain ◽

Activity Patterns ◽

Future Research ◽

First Year ◽

Dietary Interventions ◽

First Year Of College ◽

The Impact

Purpose. Transitioning from high school to college generally results in reduced physical activity and weight gain at a rate that is higher than the general population. The purpose of this study was to examine the effects of three progressively higher step recommendations over 24 weeks on changes in body weight and body composition. Methods. Ninety-two freshmen college women wore a multifunction pedometer for 24 weeks after being randomly assigned to a daily step level: 10,000, 12,500, or 15,000. Pedometer data were downloaded every two weeks and participants were counseled on meeting their step recommendation. Body weight and body composition were assessed at baseline and 24 weeks. Body composition was assessed by dual X-ray absorptiometry. Results. On average, women took 10,786 ± 1501, 12,650 ± 2001, and 13,762 ± 2098 steps per day for the 10,000-, 12,500-, and 15,000-step groups, respectively (F = 15.48, P<0.0001). Participants gained 1.4 ± 2.6, 1.8 ± 2.1, and 1.4 ± 2.1 kg for the 10,000-, 12,500-, and 15,000-step groups, respectively (F = 37.74, P<0.0001). Weight gain was not significantly different between groups (F = 0.18, P=0.8385). There was also no difference in fat weight gain (F = 0.41, P=0.7954). Discussion. A step recommendation beyond 10,000 does not prevent weight or fat gain over the first year of college. Future research should focus on either intensity of physical activity or the addition of dietary interventions to prevent weight gain during the first year of college.

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Impact of G-CSF during neoadjuvant therapy on outcomes of operable pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.4126 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 4126-4126

Author(s):

Pranav Murthy ◽

Mazen S Zenati ◽

Samer S. AlMasri ◽

Aatur D. Singhi ◽

Annissa DeSilva ◽

...

Keyword(s):

Pancreatic Cancer ◽

Overall Survival ◽

Neoadjuvant Therapy ◽

Tumor Staging ◽

Neutrophil Extracellular Trap ◽

Oncologic Outcomes ◽

Ductal Adenocarcinoma ◽

Common Side Effect ◽

Interleukin 17 ◽

The Impact

4126 Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by chronic inflammation and a tolerogenic immune response. Neutropenia is a common side effect of cytotoxic chemotherapy, managed with administration of recombinant granulocyte-colony stimulating factor (G-CSF, Filgrastim). The interleukin 17 – G-CSF – neutrophil extracellular trap (NET) axis promotes oncogenesis and progression of PDAC, inhibiting adaptive immunity. We evaluated the impact of G-CSF administration during neoadjuvant therapy (NAT) on oncologic outcomes in patients with operable pancreatic cancer. Methods: A retrospective review of all patients with localized PDAC treated with NAT prior to pancreatic resection between 2014 – 2020 was completed at a single institution. G-CSF administration, type, and dose were collected from inpatient and outpatient medical records. Results: Of 351 patients treated, 138 (39%) received G-CSF during NAT with a median follow-up of 45.8 months. Patients who received G-CSF were younger (64.0 vs 66.7, p = 0.008), had lower BMI (26.5 vs 27.9, p = 0.021), and were more likely to receive 5-FU based chemotherapy (42% vs 28.2%, p < 0.0001), NAT dose reduction (40.6% vs 25.4%, p = 0.003), or experience febrile neutropenia (8.7% vs 3.3%, p = 0.029). No differences were observed in baseline or pathologic tumor staging. In patients who received G-CSF, 130 (94%) received Pegfilgrastim with a median cumulative dose of 12 mg (IQR 6-12). Patients who received G-CSF were more likely to have an elevated post-NAT neutrophil to lymphocyte ratio (45% vs 29.6%, p = 0.004) and systemic immune-inflammation index (39.5% vs 29.6%, p = 0.061). Receiving G-CSF was an independent predictor of perineural invasion (HR 2.4, 95 CI [1.08, 5.5], p = 0.031) and margin positive resection (HR 1.69, 95 CI [1.01, 2.83], p = 0.043). Patients who received G-CSF had decreased overall survival compared to patients who did not receive G-CSF (median OS: 29.2 vs 38.7 months, p = 0.0001). Receiving G-CSF during NAT was an independent negative predictor of progression free (HR 1.38, 95 CI [1.04, 1.83], p = 0.022) and overall survival (HR 2.02, 95 CI [1.45, 2.79], p < 0.0001). In a subset of patients with available pre- and post-NAT serum specimens (n = 28), G-CSF administration resulted in an increased number of citrullinated histone H3 complexes following NAT (+1378±1502 vs -300.7±1147 pg/ml, p = 0.007), indicative of enhanced peripheral NET formation. Conclusions: In patients with localized PDAC receiving NAT prior to surgical extirpation, G-CSF administration is associated with worse oncologic outcomes and should be administered with caution. Prospective randomized as well as confirmatory clinical studies are in order.

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Real-world treatment and outcomes of frontline chemotherapy in patients with metastatic pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e16249 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e16249-e16249

Author(s):

Salwan Al Mutar ◽

Muhammad Shaalan Beg ◽

Eric Hansen ◽

Andrew J. Belli ◽

Maegan Vaz ◽

...

Keyword(s):

Pancreatic Cancer ◽

Clinical Trial ◽

Real World ◽

Univariate Analysis ◽

The United States ◽

Metastatic Pancreatic Cancer ◽

Future Research ◽

Real World Data ◽

The Real ◽

The Impact

e16249 Background: The difference between the FOLFIRINOX and gemcitabine/nab-paclitaxel (GnP) regimens’ clinical trial designs limit the ability to generate cross-study comparisons. Therefore, there is a significant need to understand the impact of various demographic and clinical characteristics on the effectiveness of these systemic therapies in the real-world treatment setting. This study seeks to compare the real-world outcomes of patients with metastatic pancreatic cancer treated with frontline FOLFIRINOX or GnP. Methods: Patients with primary metastatic pancreatic cancer who received first-line (1L) FOLFIRINOX or GnP were identified in the COTA real-world database. The COTA database is a de-identified database of real-world data (RWD) derived from the electronic health records of healthcare providers in the United States. Real-world overall response rate (rwORR) was calculated as the proportion of patients achieving complete response (CR) or partial response (PR). Overall survival (OS) was calculated using the Kaplan-Meier method and multivariate analyses utilized Cox proportional hazards. Results: The overall qualified cohort (n=236) was stratified by 1L FOLFIRINOX (n=109) or GnP (n=127). Select patient characteristics are shown in table. Patients treated with 1L FOLFIRINOX showed greater rwORR as compared to those treated with GnP (68.8% vs. 55.9%, p=0.04). Additionally, patients treated with 1L FOLFIRINOX had longer median OS (14.4 vs 11.4 mos, respectively). In univariate analysis, patients treated with GnP had a greater chance of mortality (HR: 1.3, 95% CI: 1.0, 1.8, p=0.05). This relationship strengthened in multivariate analysis (GnP treated HR: 1.6, 95% CI: 1.1, 2.1, p=0.01). Conclusions: Due to lack of enrollment of representative patients in clinical trials and in the absence of a comparative clinical trial, real-world experience with chemotherapy regimens provide critical insights on the outcome of treatments. In our cohort, patients treated with frontline GnP had a significantly greater chance of mortality as compared to patients treated with frontline FOLFIRINOX. The FOLFIRINOX cohort also showed greater rwORR. Future research will continue to expand on treatment patterns in subsequent lines of therapy, as well as emerging therapy types, in order to better understand the optimal treatment sequence in metastatic pancreatic cancer.[Table: see text]

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