scholarly journals Targeting Cancer Stem Cells for Chemoprevention of Pancreatic Cancer

2018 ◽  
Vol 25 (22) ◽  
pp. 2585-2594 ◽  
Author(s):  
Dharmalingam Subramaniam ◽  
Gaurav Kaushik ◽  
Prasad Dandawate ◽  
Shrikant Anant
Keyword(s):  
United States ◽  
Pancreatic Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Signaling Pathways ◽  
Metastatic Cancer ◽  
The United States ◽  
Natural Compounds ◽  
Ductal Adenocarcinoma ◽  
Major Health Problem

Pancreatic ductal adenocarcinoma is one of the deadliest cancers worldwide and the fourth leading cause of cancer-related deaths in United States. Regardless of the advances in molecular pathogenesis and consequential efforts to suppress the disease, this cancer remains a major health problem in United States. By 2030, the projection is that pancreatic cancer will be climb up to be the second leading cause of cancer-related deaths in the United States. Pancreatic cancer is a rapidly invasive and highly metastatic cancer, and does not respond to standard therapies. Emerging evidence supports that the presence of a unique population of cells called cancer stem cells (CSCs) as potential cancer inducing cells and efforts are underway to develop therapeutic strategies targeting these cells. CSCs are rare quiescent cells, and with the capacity to self-renew through asymmetric/symmetric cell division, as well as differentiate into various lineages of cells in the cancer. Studies have been shown that CSCs are highly resistant to standard therapy and also responsible for drug resistance, cancer recurrence and metastasis. To overcome this problem, we need novel preventive agents that target these CSCs. Natural compounds or phytochemicals have ability to target these CSCs and their signaling pathways. Therefore, in the present review article, we summarize our current understanding of pancreatic CSCs and their signaling pathways, and the phytochemicals that target these cells including curcumin, resveratrol, tea polyphenol EGCG (epigallocatechin- 3-gallate), crocetinic acid, sulforaphane, genistein, indole-3-carbinol, vitamin E δ- tocotrienol, Plumbagin, quercetin, triptolide, Licofelene and Quinomycin. These natural compounds or phytochemicals, which inhibit cancer stem cells may prove to be promising agents for the prevention and treatment of pancreatic cancers.

scholarly journals Targeting SRC Kinase Signaling in Pancreatic Cancer Stem Cells

2020 ◽  
Vol 21 (20) ◽  
pp. 7437
Author(s):  
Sonia Alcalá ◽  
Víctor Mayoral-Varo ◽  
Laura Ruiz-Cañas ◽  
Juan Carlos López-Gil ◽  
Christopher Heeschen ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Tyrosine Kinases ◽  
The United States ◽  
Ductal Adenocarcinoma ◽  
Src Kinases ◽  
Tyrosine Protein Kinase ◽  
Pancreatic Cancer Stem Cells ◽  
Future Treatment Option

The proto-oncogene nonreceptor tyrosine-protein kinase SRC is a member of the SRC family of tyrosine kinases (SFKs), and its activation and overexpression have been shown to play a protumorigenic role in multiple solid cancers, including pancreatic ductal adenocarcinoma (PDAC). PDAC is currently the seventh-leading cause of cancer-related death worldwide, and, by 2030, it is predicted to become the second-leading cause of cancer-related death in the United States. PDAC is characterized by its high lethality (5-year survival of rate of <10%), invasiveness, and chemoresistance, all of which have been shown to be due to the presence of pancreatic cancer stem cells (PaCSCs) within the tumor. Due to the demonstrated overexpression of SRC in PDAC, we set out to determine if SRC kinases are important for PaCSC biology using pharmacological inhibitors of SRC kinases (dasatinib or PP2). Treatment of primary PDAC cultures established from patient-derived xenografts with dasatinib or PP2 reduced the clonogenic, self-renewal, and tumor-initiating capacity of PaCSCs, which we attribute to the downregulation of key signaling factors such as p-FAK, p-ERK1-2, and p-AKT. Therefore, this study not only validates that SRC kinases are relevant and biologically important for PaCSCs but also suggests that inhibitors of SRC kinases may represent a possible future treatment option for PDAC patients, although further studies are still needed.

scholarly journals PAWI-2 overcomes tumor stemness and drug resistance via cell cycle arrest in integrin β3-KRAS-dependent pancreatic cancer stem cells

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jiongjia Cheng ◽  
John R. Cashman
Keyword(s):  
Cell Cycle ◽  
Pancreatic Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cell Cycle Arrest ◽  
Specific Inhibitor ◽  
Feedback Mechanism ◽  
Major Health Problem ◽  
Cycle Arrest ◽  
Drug Inhibition

Abstract Today, pancreatic cancer (PC) remains a major health problem in the US. The fact that cancer stem cells (CSCs) become enriched in humans following anti-cancer therapy implicates CSCs as key contributors to tumor dormancy, metastasis, and relapse in PC. A highly validated CSC model (FGβ3 cells) was used to test a novel compound (PAWI-2) to eradicate CSCs. Compared to parental bulk FG cells, PAWI-2 showed greater potency to inhibit cell viability and self-renewal capacity of FGβ3 cells. For FGβ3 cells, dysregulated integrin β3-KRAS signaling drives tumor progression. PAWI-2 inhibited β3-KRAS signaling independent of KRAS. This is clinically relevant. PAWI-2 targeted the downstream TBK1 phosphorylation cascade that was negatively regulated by optineurin phosphorylation via a feedback mechanism. This was confirmed by TBK1 genetic knockdown or co-treatment with TBK1-specific inhibitor (MRT67307). PAWI-2 also overcame erlotinib (an EGFR inhibitor) resistance in FGβ3 cells more potently than bortezomib. In the proposed working model, optineurin acts as a key regulator to link inhibition of KRAS signaling and cell cycle arrest (G2/M). The findings show PAWI-2 is a new approach to reverse tumor stemness that resensitizes CSC tumors to drug inhibition.

scholarly journals Cancer stem cells markers associated with development and aggressive phenotype in pancreatic cancer

2020 ◽  
pp. 102-122
Author(s):  
Camila Juliano Salvador Rodrigues ◽  
Elita Ferreira da Silveira ◽  
Rafael da Silveira Vargas ◽  
Giordano Gatti de Giacomo ◽  
Marino Muxfeldt Bianchin
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Tumor Development ◽  
Staining Intensity ◽  
Ductal Adenocarcinoma ◽  
Clinicopathological Parameters ◽  
Tumor Initiating Cells ◽  
New Ideas

Background: Cancer stem cells, also known as tumor-initiating cells, are suggested to be responsible for drug resistance and cancer development due in part to their ability to self-renew themselves and differentiate into heterogeneous lineages of cancer cells. Objective: This study was designed to investigate the role of cancer stem cells in pancreatic cancer. Methods: A retrospective clinicopathological analysis was undertaken in 112 patients diagnosed with pancreatic ductal adenocarcinoma between 2005 and 2010, and immunohistochemistry was performed with antibodies against CD133, CD24, and OCT4. Positive nuclear, cytoplasmic or membrane staining for each antibody was rated on staining intensity, being classified into low/moderate or strong staining groups. Results were analyzed relative to each patient’s clinicopathological parameters. Results: There was an established relationship between the staining of the markers with some variables associated with worse prognosis, being the three markers present in most tumor cells and associated with tumor progression. We suppose that cancer stem cells are present from the beginning of tumor initiation and are intrinsically related to tumor development. Although the presence of stem cells has been associated with molecular biology of various tumors, their expression in pancreatic cancer has not yet been clinically reported. Conclusion: The presence of stem cells and their role in pancreatic cancer tumorigenesis may be considered as valuable prognostic factors, although the mechanism involved needs further investigation. Increasing insights into role of cancer stem cells and carcinogenesis can ultimately generate new ideas for molecularly based diagnostic and therapeutic approaches.

scholarly journals The Present Status of Immuno-Oncolytic Viruses in the Treatment of Pancreatic Cancer

Viruses ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1318
Author(s):  
Scott D. Haller ◽  
Michael L. Monaco ◽  
Karim Essani
Keyword(s):  
United States ◽  
Pancreatic Cancer ◽  
Surgical Resection ◽  
Clinical Investigation ◽  
Treatment Options ◽  
Late Phase ◽  
The United States ◽  
Oncolytic Viruses ◽  
Ductal Adenocarcinoma ◽  
Treatment Regimens

Pancreatic ductal adenocarcinoma (PDAC) is the fifth leading cause of cancer-related death in Western countries. The incidence of PDAC has increased over the last 40 years and is projected to be the second leading cause of cancer death by 2030. Despite aggressive treatment regimens, prognosis for patients diagnosed with PDAC is very poor; PDAC has the lowest 5-year survival rate for any form of cancer in the United States (US). PDAC is very rarely detected in early stages when surgical resection can be performed. Only 20% of cases are suitable for surgical resection; this remains the only curative treatment when combined with adjuvant chemotherapy. Treatment regimens excluding surgical intervention such as chemotherapeutic treatments are associated with adverse effects and genetherapy strategies also struggle with lack of specificity and/or efficacy. The lack of effective treatments for this disease highlights the necessity for innovation in treatment options for patients diagnosed with early- to late-phase PDAC and immuno-oncolytic viruses (OVs) have been of particular interest since 2006 when the first oncolytic virus was approved as a therapy for nasopharyngeal cancers in China. Interest resurged in 2015 when T-Vec, an oncolytic herpes simplex virus, was approved in the United States for treatment of advanced melanoma. While many vectors have been explored, few show promise as treatment for pancreatic cancer, and fewer still have progressed to clinical trial evaluation. This review outlines recent strategies in the development of OVs targeting treatment of PDAC, current state of preclinical and clinical investigation and application.

T1724 Characterization of MUC1 Signaling Pathways in Pancreatic Cancer Stem Cells

2010 ◽  
Vol 138 (5) ◽  
pp. S-565
Author(s):  
Maria M. Rei ◽  
Rita Freitas ◽  
Andreia Sousa ◽  
Thomas C. Caffrey ◽  
Michael A. Hollingsworth ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Signaling Pathways ◽  
Pancreatic Cancer Stem Cells

scholarly journals Induction of Lysosome Membrane Permeabilization as a Therapeutic Strategy to Target Pancreatic Cancer Stem Cells

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1790 ◽  
Author(s):  
Timothy P. Cash ◽  
Sonia Alcalá ◽  
María del Rosario Rico-Ferreira ◽  
Elena Hernández-Encinas ◽  
Jennifer García ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Therapeutic Strategy ◽  
Membrane Permeabilization ◽  
Ductal Adenocarcinoma ◽  
Chemical Library ◽  
Specific Chemical ◽  
Pancreatic Cancer Stem Cells

Despite significant efforts to improve pancreatic ductal adenocarcinoma (PDAC) clinical outcomes, overall survival remains dismal. The poor response to current therapies is partly due to the existence of pancreatic cancer stem cells (PaCSCs), which are efficient drivers of PDAC tumorigenesis, metastasis and relapse. To find new therapeutic agents that could efficiently kill PaCSCs, we screened a chemical library of 680 compounds for candidate small molecules with anti-CSC activity, and identified two compounds of a specific chemical series with potent activity in vitro and in vivo against patient-derived xenograft (PDX) cultures. The anti-CSC mechanism of action of this specific chemical series was found to rely on induction of lysosomal membrane permeabilization (LMP), which is likely associated with the increased lysosomal mass observed in PaCSCs. Using the well characterized LMP-inducer siramesine as a tool molecule, we show elimination of the PaCSC population in mice implanted with tumors from two PDX models. Collectively, our approach identified lysosomal disruption as a promising anti-CSC therapeutic strategy for PDAC.

scholarly journals The Role of miRNAs in the Regulation of Pancreatic Cancer Stem Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Sabrina Bimonte ◽  
Antonio Barbieri ◽  
Maddalena Leongito ◽  
Giuseppe Palma ◽  
Vitale del Vecchio ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Drug Resistance ◽  
Cancer Stem Cells ◽  
Biological Activities ◽  
Biological Properties ◽  
Ductal Adenocarcinoma ◽  
Small Noncoding Rnas ◽  
Pancreatic Cancer Stem Cells

Pancreatic ductal adenocarcinoma is currently one of the deadliest cancers with low overall survival rate. This disease leads to an aggressive local invasion and early metastases and is poorly responsive to treatment with chemotherapy or chemoradiotherapy. Several studies have shown that pancreatic cancer stem cells (PCSCs) play different roles in the regulation of drug resistance and recurrence in pancreatic cancer. MicroRNA (miRNA), a class of newly emerging small noncoding RNAs, is involved in the modulation of several biological activities ranging from invasion to metastases development, as well as drug resistance of pancreatic cancer. In this review, we synthesize the latest findings on the role of miRNAs in regulating different biological properties of pancreatic cancer stem cells.

scholarly journals Natural Compounds Targeting Cancer Stem Cells: A Promising Resource for Chemotherapy

2019 ◽  
Vol 19 (15) ◽  
pp. 1796-1808 ◽  
Author(s):  
Plabon K. Das ◽  
Tasnim Zahan ◽  
Md. Abdur Rakib ◽  
Jahan A. Khanam ◽  
Suja Pillai ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Cancer Recurrence ◽  
Therapy Resistance ◽  
Natural Compounds ◽  
Biologically Active ◽  
Cancer Pathogenesis ◽  
Distant Organ

Background:Cancer Stem Cells (CSCs) are the subpopulation of cancer cells which are directly involved in drug resistance, metastases to distant organ and cancer recurrence.Methods:A systematic literature search was conducted through various electronic databases including, Pubmed, Scopus, Google scholar using the keywords "cancer stem cells" and "natural compounds" in the present study. Articles published between 1999 and 2019 were reviewed. All the expositions concerning CSCs associated cancer pathogenesis and therapy resistance, as well as targeting these properties of CSCs by natural compounds were selected for the current study.Results:Natural compounds have always been thought as a rich source of biologically active principles, which target aberrantly activated signaling pathways and other modalities of CSCs, while tethering painful side effects commonly involved in the first-line and second-line chemo-radiotherapies. In this review, we have described the key signaling pathways activated in CSCs to maintain their survival and highlighted how natural compounds interrupt these signaling pathways to minimize therapy resistance, pathogenesis and cancer recurrence properties of CSCs, thereby providing useful strategies to treat cancer or aid in cancer therapy improvement. Like normal stem cells, CSCs rely on different signaling pathways and other properties for their maintenance. Therefore, the success of cancer treatment depends on the development of proper anti-neoplastic drugs capable of intercepting those signaling pathways as well as other properties of CSCs in order to eradicate this evasive subpopulation of cancer cells.Conclusion:Compounds of natural origin might act as an outstanding source to design novel therapies against cancer stem cells.

Pancreatic Cancer Clinical Trials and Accrual in the United States

2013 ◽  
Vol 31 (27) ◽  
pp. 3432-3438 ◽  
Author(s):  
William A. Hoos ◽  
Porsha M. James ◽  
Lola Rahib ◽  
Anitra W. Talley ◽  
Julie M. Fleshman ◽  
...  
Keyword(s):  
United States ◽  
Pancreatic Cancer ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Supply And Demand ◽  
The United States ◽  
Disease Stage ◽  
Ductal Adenocarcinoma ◽  
Cancer Clinical Trials ◽  
Cancer Trials

Purpose Pancreatic cancer clinical trials open in the United States and their accrual were examined to identify opportunities to accelerate progress in the treatment of pancreatic cancer. Methods Pancreatic cancer–specific clinical trials open in the United States in the years 2011 and 2012 were obtained from the Pancreatic Cancer Action Network database. Accrual information was obtained from trial sponsors. Results The portfolio of pancreatic cancer clinical trials identified by type (adenocarcinoma or neuroendocrine), phase, disease stage, and treatment approach is reported. More than half of trials for patients with pancreatic ductal adenocarcinoma applied biologic insights to new therapeutic approaches, and 38% focused on optimization of radiation or chemotherapy delivery or regimens. In 2011, pancreatic cancer trials required total enrollment of 11,786 patients. Actual accrual to 93.2% of trials was 1,804 patients, an estimated 4.57% of the patients with pancreatic cancer alive in that year. The greatest need was for patients with resectable cancer. Trials open in 2011 enrolled an average of 15% of their total target accrual. Physician recommendations greatly influenced patients' decision to enroll or not enroll onto a clinical trial. Matching to a clinical trial within a 50-mile radius and identifying trials for recurrent/refractory disease were documented as challenges for patient accrual. Conclusion Overall trial enrollment indicates that pancreatic cancer trials open in 2011 would require 6.7 years on average to complete accrual. These results suggest that harmonizing patient supply and demand for clinical trials is required to accelerate progress toward improving survival in pancreatic cancer.

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