Metabolic Alterations as a Signpost to Early Pancreatic Cancer

Khalaf, Natalia; Wolpin, Brian M.

doi:10.1053/j.gastro.2019.03.028

Cited by 19 publications

(14 citation statements)

References 21 publications

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“…ROS‐induced oxidative stress transforms the metabolism of fibroblasts, creating a nutrient‐rich microenvironment for tumour cells and further promoting their growth 28‐30 . Metabolic changes in PDAC cells play an important role in the progression of PDAC 31 . Here, we showed a novel mechanism by which PSCs enhance PDAC malignant progression that depends on stroma‐tumour metabolic coupling (Figure 6).…”

Section: Discussionmentioning

confidence: 76%

Positive feedback in Cav‐1‐ROS signalling in PSCs mediates metabolic coupling between PSCs and tumour cells

Shao

Tao

Qian

et al. 2020

J Cellular Molecular Medi

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Caveolin‐1 (Cav‐1) is the principal structural component of caveolae, and its dysregulation occurs in cancer. However, the role of Cav‐1 in pancreatic cancer (PDAC) tumorigenesis and metabolism is largely unknown. In this study, we aimed to investigate the effect of pancreatic stellate cell (PSC) Cav‐1 on PDAC metabolism and aggression. We found that Cav‐1 is expressed at low levels in PDAC stroma and that the loss of stromal Cav‐1 is associated with poor survival. In PSCs, knockdown of Cav‐1 promoted the production of reactive oxygen species (ROS), while ROS production further reduced the expression of Cav‐1. Positive feedback occurs in Cav‐1‐ROS signalling in PSCs, which promotes PDAC growth and induces stroma‐tumour metabolic coupling in PDAC. In PSCs, positive feedback in Cav‐1‐ROS signalling induced a shift in energy metabolism to glycolysis, with up‐regulated expression of glycolytic enzymes (hexokinase 2 (HK‐2), 6‐phosphofructokinase (PFKP) and pyruvate kinase isozyme type M2 (PKM2)) and transporter (Glut1) expression and down‐regulated expression of oxidative phosphorylation (OXPHOS) enzymes (translocase of outer mitochondrial membrane 20 (TOMM20) and NAD(P)H dehydrogenase [quinone] 1 (NQO1)). These events resulted in high levels of glycolysis products such as lactate, which was secreted by up‐regulated monocarboxylate transporter 4 (MCT4) in PSCs. Simultaneously, PDAC cells took up these glycolysis products (lactate) through up‐regulated MCT1 to undergo OXPHOS, with down‐regulated expression of glycolytic enzymes (HK‐2, PFKP and PKM2) and up‐regulated expression of OXPHOS enzymes (TOMM20 and NQO1). Interrupting the metabolic coupling between the stroma and tumour cells may be an effective method for tumour therapy.

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Section: Discussionmentioning

confidence: 76%

Positive feedback in Cav‐1‐ROS signalling in PSCs mediates metabolic coupling between PSCs and tumour cells

Shao

Tao

Qian

et al. 2020

J Cellular Molecular Medi

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“…On the other hand, the use of liquid biopsies for screening and early cancer detection remains challenging [40], mainly because analytes, such as CTCs [2] and ctDNA [17,48], are often below optimal levels for analysis, particularly in early-stage patients. A potential solution to improve the sensitivity of cancer detection would be to evaluate multiple circulating analytes (e.g., ctDNA, RNA, proteins [94], and metabolites [95]), however, the specificity and cost-effectiveness of such tests would probably be compromised [2]. In fact, the low specificity of liquid biopsy tests is a concern, given that their use for cancer screening would result in the detection of high numbers of false positives, making healthy individuals undergo unnecessary invasive procedures and distress.…”

Section: Advantages and Disadvantages Of Liquid Biopsiesmentioning

confidence: 99%

Liquid Biopsies: Applications for Cancer Diagnosis and Monitoring

Martins

Ribeiro

Jorge

et al. 2021

Genes

117

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The minimally—or non-invasive detection of circulating tumor-derived components in biofluids, such as blood, liquid biopsy is a revolutionary approach with significant potential for the management of cancer. Genomic and transcriptomic alterations can be accurately detected through liquid biopsies, which provide a more comprehensive characterization of the heterogeneous tumor profile than tissue biopsies alone. Liquid biopsies could assist diagnosis, prognosis, and treatment selection, and hold great potential to complement current surveilling strategies to monitor disease evolution and treatment response in real-time. In particular, these are able to detect minimal residual disease, to predict progression, and to identify mechanisms of resistance, allowing to re-orient treatment strategies in a timelier manner. In this review we gathered current knowledge regarding the role and potential of liquid biopsies for the diagnosis and follow-up of cancer patients. The presented findings emphasize the strengths of liquid biopsies, revealing their chance of improving the diagnosis and monitoring of several tumor types in the near future. However, despite growing evidence supporting their value as a management tool in oncology, some limitations still need to be overcome for their implementation in the routine clinical setting.

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“…One of the most common metabolic alterations of cancer cells is aerobic glycolysis, also known as Warburg effect, which provides cancer cells with sufficient intermediary metabolites for generation of reducing equivalents and macromolecules (nucleotides) required for rapid proliferation and to avoid apoptosis [5,6]. Aerobic glycolysis can be regulated by many oncogenic signals, such as MYC, HIF-1α, and PI3K/AKT pathway [7][8][9]. Recently, emerging evidence suggests that long non-coding RNA (lncRNA) plays crucial roles in a variety of cellular processes, such as chromatin remodeling, embryonic development, cell differentiation, energy metabolism, and tumorigenesis by regulating gene expression through multiple mechanisms [10,11].…”

Section: Ivyspringmentioning

confidence: 99%

Deciphering the genomic and lncRNA landscapes of aerobic glycolysis identifies potential therapeutic targets in pancreatic cancer

Zhu

et al. 2021

Int. J. Biol. Sci.

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Aerobic glycolysis, also known as the Warburg effect, is emerged as a hallmark of most cancer cells. Increased aerobic glycolysis is closely associated with tumor aggressiveness and predicts a poor prognosis. Pancreatic ductal adenocarcinoma (PDAC) is characterized by prominent genomic aberrations and increased glycolytic phenotype. However, the detailed molecular events implicated in aerobic glycolysis of PDAC are not well understood. In this study, we performed a comprehensive molecular characterization using multidimensional ''omic'' data from The Cancer Genome Atlas (TCGA). Detailed analysis of 89 informative PDAC tumors identified substantial copy number variations ( MYC , GATA6 , FGFR1 , IDO1, and SMAD4 ) and mutations ( KRAS , SMAD4 , and RNF43 ) related to aerobic glycolysis. Moreover, integrated analysis of transcriptional profiles revealed many differentially expressed long non-coding RNAs involved in PDAC aerobic glycolysis. Loss-of-function studies showed that LINC01559 and UNC5B-AS1 knockdown significantly inhibited the glycolytic capacity of PDAC cells as revealed by reduced glucose uptake, lactate production, and extracellular acidification rate. Moreover, genetic silencing of LINC01559 and UNC5B-AS1 suppressed tumor growth and resulted in alterations in several signaling pathways, such as TNF signaling pathway, IL-17 signaling pathway, and transcriptional misregulation in cancer. Notably, high expression of LINC01559 and UNC5B-AS1 predicted poor patient prognosis and correlated with the maximum standard uptakevalue (SUVmax) in PDAC patients who received preoperative 18 F-FDG PET/CT. Taken together, our results decipher the glycolysis-associated copy number variations, mutations, and lncRNA landscapes in PDAC. These findings improve our knowledge of the molecular mechanism of PDAC aerobic glycolysis and may have practical implications for precision cancer therapy.

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Metabolic Alterations as a Signpost to Early Pancreatic Cancer

Cited by 19 publications

References 21 publications

Positive feedback in Cav‐1‐ROS signalling in PSCs mediates metabolic coupling between PSCs and tumour cells

Positive feedback in Cav‐1‐ROS signalling in PSCs mediates metabolic coupling between PSCs and tumour cells

Liquid Biopsies: Applications for Cancer Diagnosis and Monitoring

Deciphering the genomic and lncRNA landscapes of aerobic glycolysis identifies potential therapeutic targets in pancreatic cancer

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