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Antioxidants (Basel, Switzerland) Jun 2024The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) represents the master regulator of the cellular antioxidant response and plays a critical... (Review)
Review
The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) represents the master regulator of the cellular antioxidant response and plays a critical role in tumorigenesis. This includes a preventive effect of Nrf2 on cell death through ferroptosis, which represents an essential mechanism of therapy resistance in malignant tumors, such as pancreatic ductal adenocarcinoma (PDAC) as one of the most aggressive and still incurable tumors. Addressing this issue, we provide an overview on Nrf2 mediated antioxidant response with particular emphasis on its effect on mitochondria as the organelle responsible for the execution of ferroptosis. We further outline how deregulated Nrf2 adds to the progression and therapy resistance of PDAC, especially with respect to the role of ferroptosis in anti-cancer drug mediated cell killing and how this is impaired by Nrf2 as an essential mechanism of drug resistance. Our review further discusses recent approaches for Nrf2 inhibition by natural and synthetic compounds to overcome drug resistance based on enhanced ferroptosis. Finally, we provide an outlook on therapeutic strategies based on Nrf2 inhibition combined with ferroptosis inducing drugs.
PubMed: 38929135
DOI: 10.3390/antiox13060696 -
International Journal of Molecular... Jun 2024Pancreatic ductal adenocarcinoma (PDAC)'s resistance to therapies is mainly attributed to pancreatic cancer stem cells (PCSCs). Mitochondria-impairing agents can be used...
Pancreatic ductal adenocarcinoma (PDAC)'s resistance to therapies is mainly attributed to pancreatic cancer stem cells (PCSCs). Mitochondria-impairing agents can be used to hamper PCSC propagation and reduce PDAC progression. Therefore, to develop an efficient vector for delivering drugs to the mitochondria, we synthesized tris(3,5-dimethylphenyl)phosphonium-conjugated palmitic acid. Triphenylphosphonium (TPP) is a lipophilic cationic moiety that promotes the accumulation of conjugated agents in the mitochondrion. Palmitic acid (PA), the most common saturated fatty acid, has pro-apoptotic activity in different types of cancer cells. TPP-PA was prepared by the reaction of 16-bromopalmitic acid with TPP, and its structure was characterized by H and C NMR and HRMS. We compared the proteomes of TPP-PA-treated and untreated PDAC cells and PCSCs, identifying dysregulated proteins and pathways. Furthermore, assessments of mitochondrial membrane potential, intracellular ROS, cardiolipin content and lipid peroxidation, ER stress, and autophagy markers provided information on the mechanism of action of TPP-PA. The findings showed that TPP-PA reduces PDAC cell proliferation through mitochondrial disruption that leads to increased ROS, activation of ER stress, and autophagy. Hence, TPP-PA might offer a new approach for eliminating both the primary population of cancer cells and PCSCs, which highlights the promise of TPP-derived compounds as anticancer agents for PDAC.
Topics: Humans; Mitochondria; Pancreatic Neoplasms; Palmitic Acid; Organophosphorus Compounds; Proteomics; Cell Line, Tumor; Carcinoma, Pancreatic Ductal; Cell Proliferation; Membrane Potential, Mitochondrial; Reactive Oxygen Species; Apoptosis; Proteome; Antineoplastic Agents; Neoplastic Stem Cells; Autophagy
PubMed: 38928494
DOI: 10.3390/ijms25126790 -
International Journal of Molecular... Jun 2024Diagnostic markers are desperately needed for the early detection of pancreatic ductal adenocarcinoma (PDA). We describe sets of markers expressed in temporal order in...
Diagnostic markers are desperately needed for the early detection of pancreatic ductal adenocarcinoma (PDA). We describe sets of markers expressed in temporal order in mouse models during pancreatitis, PDA initiation and progression. Cell type specificity and the differential expression of PDA markers were identified by screening single cell (sc) RNAseq from tumor samples of a mouse model for PDA (KIC) at early and late stages of PDA progression compared to that of a normal pancreas. Candidate genes were identified from three sources: (1) an unsupervised screening of the genes preferentially expressed in mouse PDA tumors; (2) signaling pathways that drive PDA, including the Ras pathway, calcium signaling, and known cancer genes, or genes encoding proteins that were identified by differential mass spectrometry (MS) of mouse tumors and conditioned media from human cancer cell lines; and (3) genes whose expression is associated with poor or better prognoses (PAAD, oncolnc.org). The developmental progression of PDA was detected in the temporal order of gene expression in the cancer cells of the KIC mice. The earliest diagnostic markers were expressed in epithelial cancer cells in early-stage, but not late-stage, PDA tumors. Other early markers were expressed in the epithelium of both early- and late-state PDA tumors. Markers that were expressed somewhat later were first elevated in the epithelial cancer cells of the late-stage tumors, then in both epithelial and mesenchymal cells, or only in mesenchymal cells. Stromal markers were differentially expressed in early- and/or late-stage PDA neoplasia in fibroblast and hematopoietic cells (lymphocytes and/or macrophages) or broadly expressed in cancer and many stromal cell types. Pancreatitis is a risk factor for PDA in humans. Mouse models of pancreatitis, including caerulein treatment and the acinar-specific homozygous deletion of differentiation transcription factors (dTFs), were screened for the early expression of all PDA markers identified in the KIC neoplasia. Prognostic markers associated with a more rapid decline were identified and showed differential and cell-type-specific expression in PDA, predominately in late-stage epithelial and/or mesenchymal cancer cells. Select markers were validated by immunohistochemistry in mouse and human samples of a normal pancreas and those with early- and late-stage PDA. In total, we present 2165 individual diagnostic and prognostic markers for disease progression to be tested in humans from pancreatitis to late-stage PDA.
Topics: Animals; Carcinoma, Pancreatic Ductal; Pancreatitis; Mice; Pancreatic Neoplasms; Biomarkers, Tumor; Humans; Prognosis; Gene Expression Regulation, Neoplastic; Disease Models, Animal; Cell Line, Tumor; Disease Progression
PubMed: 38928326
DOI: 10.3390/ijms25126619 -
Cancers Jun 2024Pancreatic Ductal Adenocarcinoma (PDAC) remains one of the most formidable challenges in oncology, characterized by its late detection and poor prognosis. Artificial... (Review)
Review
Pancreatic Ductal Adenocarcinoma (PDAC) remains one of the most formidable challenges in oncology, characterized by its late detection and poor prognosis. Artificial intelligence (AI) and machine learning (ML) are emerging as pivotal tools in revolutionizing PDAC care across various dimensions. Consequently, many studies have focused on using AI to improve the standard of PDAC care. This review article attempts to consolidate the literature from the past five years to identify high-impact, novel, and meaningful studies focusing on their transformative potential in PDAC management. Our analysis spans a broad spectrum of applications, including but not limited to patient risk stratification, early detection, and prediction of treatment outcomes, thereby highlighting AI's potential role in enhancing the quality and precision of PDAC care. By categorizing the literature into discrete sections reflective of a patient's journey from screening and diagnosis through treatment and survivorship, this review offers a comprehensive examination of AI-driven methodologies in addressing the multifaceted challenges of PDAC. Each study is summarized by explaining the dataset, ML model, evaluation metrics, and impact the study has on improving PDAC-related outcomes. We also discuss prevailing obstacles and limitations inherent in the application of AI within the PDAC context, offering insightful perspectives on potential future directions and innovations.
PubMed: 38927945
DOI: 10.3390/cancers16122240 -
Cancers Jun 2024The "vein definition" for locally advanced pancreatic ductal adenocarcinoma (LA PDAC) assumes portal-to-superior mesenteric vein (PV/SMV) unreconstructability due to...
The "vein definition" for locally advanced pancreatic ductal adenocarcinoma (LA PDAC) assumes portal-to-superior mesenteric vein (PV/SMV) unreconstructability due to tumor involvement or occlusion. Radical pancreatectomies with SMV resection without PV/SMV reconstruction are scarcely discussed in the literature. Retrospective analysis of 19 radical pancreatectomies for "low" LA PDAC with SMV and all its tributaries resection without PV/SMV reconstruction has shown zero mortality; overall morbidity-56%; Dindo-Clavien-3-10.5%; R0-rate-82%; mean operative procedure time-355 ± 154 min; mean blood loss-330 ± 170 mL; delayed gastric emptying-25%; and clinically relevant postoperative pancreatic fistula-8%. In three cases, surgery was associated with superior mesenteric (n2) and common hepatic artery (n1) resection. Surgery was completed without vein reconstruction (n13) and with inferior mesenteric-to-splenic anastomosis (n6). There were no cases of liver, gastric, or intestinal ischemia. A specific complication of the SMV resection without reconstruction was 2-3 days-long intestinal edema (48%). Median overall survival was 25 months, and median progression-free survival was 18 months. All the relapses, except two, were distant. The possibility of successful SMV resection without PV/SMV reconstruction can be predicted before surgery by CT-based reconstructions. The mandatory anatomical conditions for the procedure were as follows: (1) preserved SMV-SV confluence; (2) occluded SMV for any reason (tumor or thrombus); (3) well-developed inferior mesenteric vein collaterals with dilated intestinal veins; (4) no right-sided vein collaterals; and (5) no varices in the upper abdomen. Conclusion: "Low" LA PDACs involving SMV with all its tributaries can be radically and safely resected in highly and specifically selected cases without PV/SMV reconstruction with an acceptable survival rate.
PubMed: 38927939
DOI: 10.3390/cancers16122234 -
Bioengineering (Basel, Switzerland) Jun 2024Tumor organoid cultures play a crucial role in clinical practice, particularly in guiding medication by accurately determining the morphology and size of the organoids....
Tumor organoid cultures play a crucial role in clinical practice, particularly in guiding medication by accurately determining the morphology and size of the organoids. However, segmenting individual tumor organoids is challenging due to their inhomogeneous internal intensity and overlapping structures. This paper proposes a convexity-preserving level-set segmentation 4 model based on the characteristics of tumor organoid images to segment individual tumor organoids precisely. Considering the predominant spherical shape exhibited by organoid growth, we propose a level-set model that includes a data-driven term, a curvature term, and a regularization term. The data-driven term pulls the contour to the vicinity of the boundary; the curvature term ensures the maintenance of convexity in the targeted segmentation, and the regularization term controls the smoothness and propagation of the contour. The proposed model aids in overcoming interference from factors such as overlap and noise, enabling the evolving curve to converge to the actual boundary of the target accurately. Furthermore, we propose a selectable and targeted initialization method that guarantees precise segmentation of specific regions of interest. Experiments on 51 pancreatic ductal adenocarcinoma organoid images show that our model achieved excellent segmentation results. The average Dice value and computation time are 98.81±0.48% and 20.67 s. Compared with the C-V and CPLSE models, it is more accurate and takes less time.
PubMed: 38927837
DOI: 10.3390/bioengineering11060601 -
Biomedicines May 2024Polyamines are small polycationic alkylamines that are absolutely required for the continual growth and proliferation of cancer cells. The polyamine analogue ivospemin,...
Polyamines are small polycationic alkylamines that are absolutely required for the continual growth and proliferation of cancer cells. The polyamine analogue ivospemin, also known as SBP-101, has shown efficacy in slowing pancreatic and ovarian tumor progression in vitro and in vivo and has demonstrated encouraging results in early pancreatic cancer clinical trials. We sought to determine if ivospemin was a viable treatment option for the under-served platinum-resistant ovarian cancer patient population by testing its efficacy in combination with commonly used chemotherapeutics. We treated four ovarian adenocarcinoma cell lines in vitro and found that each was sensitive to ivospemin regardless of cisplatin sensitivity. Next, we treated patients with ivospemin in combination with four commonly used chemotherapeutics and found that ivospemin increased the toxicity of each; however, only gemcitabine and topotecan combination treatments were more effective than ivospemin alone. Using the VDID8 murine ovarian cancer model, we found that the addition of ivospemin to either topotecan or gemcitabine increased median survival over untreated animals alone, delayed tumor progression, and decreased the overall tumor burden. Our results indicate that the combination of ivospemin and chemotherapy is a worthwhile treatment option to further explore clinically in ovarian cancer.
PubMed: 38927364
DOI: 10.3390/biomedicines12061157 -
BMC Cancer Jun 2024Pancreatic ductal adenocarcinoma (PDAC) is a 'difficult-to-treat' entity. To forecast its prognosis, we introduced a new biomarker, SARIFA (stroma areactive invasion...
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is a 'difficult-to-treat' entity. To forecast its prognosis, we introduced a new biomarker, SARIFA (stroma areactive invasion front areas), which are areas at the tumour invasion front lacking desmoplastic stroma reaction upon malignant invasion in the surrounding tissue, leading to direct contact between tumour cells and adipocytes. SARIFA showed its significance in gastric and colorectal carcinoma, revealing lipid metabolism alternations that promote tumour progression.
METHODS
We reviewed the SARIFA status of 166 PDAC cases on all available H&E-stained tumour slides from archival Whipple-resection specimens. SARIFA positivity was defined as SARIFA detection in at least 66% of the available slides. To investigate alterations in tumour metabolism and microenvironment, we performed immunohistochemical staining for FABP4, CD36 and CD68. To verify and quantify a supposed delipidation of adipocytes, adipose tissue was digitally morphometrised.
RESULTS
In total, 53 cases (32%) were classified as SARIFA positive and 113 (68%) as SARIFA negative. Patients with SARIFA-positive PDAC showed a significantly worse overall survival compared with SARIFA-negative cases (median overall survival: 11.0 months vs. 22.0 months, HR: 1.570 (1.082-2.278), 95% CI, p = 0.018), which was independent from other prognostic markers (p = 0.014). At the invasion front of SARIFA-positive PDAC, we observed significantly higher expression of FABP4 (p < 0.0001) and higher concentrations of CD68 macrophages (p = 0.031) related to a higher risk of tumour progression. CD36 staining showed no significant expression differences. The adipocyte areas at the invasion front were significantly smaller, with mean values of 4021 ± 1058 µm and 1812 ± 1008 µm for the SARIFA-negative and -positive cases, respectively (p < 0.001).
CONCLUSIONS
SARIFA is a promising prognostic biomarker for PDAC. Its assessment is characterised by simplicity and low effort. The mechanisms behind SARIFA suggest a tumour-promoting increased lipid metabolism and altered immune background, both showing new therapeutic avenues.
Topics: Humans; Carcinoma, Pancreatic Ductal; Female; Male; Biomarkers, Tumor; Prognosis; Pancreatic Neoplasms; Aged; Middle Aged; Fatty Acid-Binding Proteins; Neoplasm Invasiveness; Tumor Microenvironment; Lipid Metabolism; Antigens, Differentiation, Myelomonocytic; Antigens, CD; Stromal Cells; CD36 Antigens; Adipocytes; Adult; Aged, 80 and over; CD68 Molecule
PubMed: 38926671
DOI: 10.1186/s12885-024-12519-9 -
Frontiers of Medicine Jun 2024Synthetic lethality is a novel model for cancer therapy. To understand the function and mechanism of BEN domain-containing protein 4 (BEND4) in pancreatic cancer, eight...
Synthetic lethality is a novel model for cancer therapy. To understand the function and mechanism of BEN domain-containing protein 4 (BEND4) in pancreatic cancer, eight cell lines and a total of 492 cases of pancreatic neoplasia samples were included in this study. Methylation-specific polymerase chain reaction, CRISPR/Cas9, immunoprecipitation assay, comet assay, and xenograft mouse model were used. BEND4 is a new member of the BEN domain family. The expression of BEND4 is regulated by promoter region methylation. It is methylated in 58.1% (176/303) of pancreatic ductal adenocarcinoma (PDAC), 33.3% (14/42) of intraductal papillary mucinous neoplasm, 31.0% (13/42) of pancreatic neuroendocrine tumor, 14.3% (3/21) of mucinous cystic neoplasm, 4.3% (2/47) of solid pseudopapillary neoplasm, and 2.7% (1/37) of serous cystic neoplasm. BEND4 methylation is significantly associated with late-onset PDAC (> 50 years, P < 0.01) and tumor differentiation (P < 0.0001), and methylation of BEND4 is an independent poor prognostic marker (P < 0.01) in PDAC. Furthermore, BEND4 plays tumor-suppressive roles in vitro and in vivo. Mechanistically, BEND4 involves non-homologous end joining signaling by interacting with Ku80 and promotes DNA damage repair. Loss of BEND4 increased the sensitivity of PDAC cells to ATM inhibitor. Collectively, the present study revealed an uncharacterized tumor suppressor BEND4 and indicated that methylation of BEND4 may serve as a potential synthetic lethal marker for ATM inhibitor in PDAC treatment.
PubMed: 38926248
DOI: 10.1007/s11684-023-1053-3 -
Annals of Surgical Oncology Jun 2024Although some clinical trials have demonstrated the benefits of neoadjuvant therapy for resectable pancreatic ductal adenocarcinoma (PDAC), its optimal candidate has not...
BACKGROUND
Although some clinical trials have demonstrated the benefits of neoadjuvant therapy for resectable pancreatic ductal adenocarcinoma (PDAC), its optimal candidate has not been clarified. This study aimed to detect predictive prognostic factors for resectable PDAC patients who underwent upfront surgery and identify patient cohorts with long-term survival without neoadjuvant therapy.
PATIENTS AND METHODS
A total of 232 patients with resectable PDAC who underwent upfront surgery between January 2008 and December 2019 were evaluated.
RESULTS
The median overall survival (OS) time and 5-year OS rate of resectable PDAC with upfront surgery was 31.5 months and 33.3%, respectively. Multivariate analyses identified tumor diameter in computed tomography (CT) ≤ 19 mm [hazard ratio (HR) 0.40, p < 0.001], span-1 within the normal range (HR 0.54, p = 0.023), prognostic nutritional index (PNI) ≥ 44.31 (HR 0.51, p < 0.001), and lymphocyte-to-monocyte ratio (LMR) ≥ 3.79 (HR 0.51, p < 0.001) as prognostic factors that influence favorable prognoses after upfront surgery. According to the prognostic prediction model based on these four factors, patients with four favorable prognostic factors had a better prognosis with a 5-year OS rate of 82.4% compared to others (p < 0.001). These patients had a high R0 resection rate and a low frequency of tumor recurrence after upfront surgery.
CONCLUSIONS
We identified patients with long-term survival after upfront surgery by prognostic prediction model consisting of tumor diameter in CT, span-1, PNI, and LMR. Evaluation of anatomical, biological, nutritional, and inflammatory factors may be valuable to introduce an optimal treatment strategy for resectable PDAC.
PubMed: 38926210
DOI: 10.1245/s10434-024-15648-4