Pancreatic Cancer Stem Cells and Therapeutic Approaches

Ercan, Gülinnaz; Karlıtepe, Ayfer; Özpolat, Bülent

doi:10.21873/anticanres.11628

Cited by 54 publications

(60 citation statements)

References 117 publications

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“…Pancreatic ductal adenocarcinoma (PDAC) is thought to be one of the leading causes of cancer death with 5-year survival rates of 1 to 5% [ 229 ]. It has been reported that uncontrolled activation of Hh signaling is efficient in maintaining tumor growth and progression of the pancreatic tumor [ 230 ].…”

Section: Hedgehog Signaling In Cancers and Its Inhibitorsmentioning

confidence: 99%

Hedgehog Signaling in Cancer: A Prospective Therapeutic Target for Eradicating Cancer Stem Cells

Sari

Phi

Jun

et al. 2018

Cells

143

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The Hedgehog (Hh) pathway is a signaling cascade that plays a crucial role in many fundamental processes, including embryonic development and tissue homeostasis. Moreover, emerging evidence has suggested that aberrant activation of Hh is associated with neoplastic transformations, malignant tumors, and drug resistance of a multitude of cancers. At the molecular level, it has been shown that Hh signaling drives the progression of cancers by regulating cancer cell proliferation, malignancy, metastasis, and the expansion of cancer stem cells (CSCs). Thus, a comprehensive understanding of Hh signaling during tumorigenesis and development of chemoresistance is necessary in order to identify potential therapeutic strategies to target various human cancers and their relapse. In this review, we discuss the molecular basis of the Hh signaling pathway and its abnormal activation in several types of human cancers. We also highlight the clinical development of Hh signaling inhibitors for cancer therapy as well as CSC-targeted therapy.

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Section: Hedgehog Signaling In Cancers and Its Inhibitorsmentioning

confidence: 99%

Hedgehog Signaling in Cancer: A Prospective Therapeutic Target for Eradicating Cancer Stem Cells

Sari

Phi

Jun

et al. 2018

Cells

143

View full text Add to dashboard Cite

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“…PCSC, identified by CD24 + CD44 + ESA + , have the capacity to self-renew and lead to the maintenance of the tumor mass. Importantly, PCSC are believed to be involved in the development of drug resistance [ 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

Leptin-Notch axis impairs 5-fluorouracil effects on pancreatic cancer

Harbuzariu

Gonzalez-Perez

2018

Oncotarget

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5-FU chemotherapy is a current strategy to treat pancreatic cancer (PC), but unfortunately chemoresistance is eventually developed in most patients. Obesity is a risk factor for PC that could affect 5-FU effectiveness through the adipokine leptin, which is a known proliferation, survival factor and Notch inducer. We investigated whether leptin signaling affects 5-FU cytotoxicity on PC. To this end, tumorspheres developed from BxPC-3 and MiaPaCa-2 PC cells were treated with 5-FU, leptin, inhibitors for Notch (DAPT) and leptin signaling (IONP-LPrA2) and ATP-binding cassette of proteins (Probenecid). Leptin treatment decreased 5-FU cytotoxicity, and increased cell proliferation, colony forming ability, stem cell, pluripotency, EMT markers, drug efflux proteins (ABCC5, ABCC11) and Notch. In addition, leptin reduced the 5-FU effects on apoptosis by decreasing pro-apoptotic (Bax, Caspase-3 activation and PARP degradation) and increasing anti-apoptotic factors (RIP and Bcl-XL). Leptin's effects on PC tumorspheres treated with 5-FU were reduced by IONP-LPrA2 and were mainly Notch signaling- dependent and more evident in MiaPaCa-2-derived tumorspheres. Present results suggest that leptin could impair 5-FU cytotoxicity and promote chemoresistance. Therefore, targeting the leptin-Notch axis could be a novel way to improve 5-FU therapy for PC patients, especially in obesity context.

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“…The concepts of PDAC stem cells in tumor initiation, resistance to therapeutic modalities, distant metastasis and cancer recurrence are increasingly documented (Li et al, 2013). PDAC cells enriched with CD44, and/or CD24 and/or CD133 (Hermann et al, 2007;Li et al, 2007;Hong et al, 2009;Ding et al, 2012;Salaria et al, 2015) are highly tumorigenicresistant to conventional anti-cancer therapy, and have been used as cancer stemness markers (Ercan et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

An FGFR/AKT/SOX2 Signaling Axis Controls Pancreatic Cancer Stemness

Quan

Guo

Liu

et al. 2020

Front. Cell Dev. Biol.

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Cancer stemness is associated with high malignancy and low differentiation, as well as therapeutic resistance of tumors including pancreatic ductal adenocarcinoma (PDAC). Fibroblast growth factors (FGFs) exert pleiotropic effects on a variety of cellular processes and functions including embryonic stem cell pluripotency and cancer cell stemness via the activation of four tyrosine kinase FGF receptors (FGFRs). FGF ligands have been a major component of the cocktail of growth factors contained in the cancer stemness-inducing (CSI) and organoid culture medium. Although FGF/FGFR signaling has been hypothesized to maintain cancer stemness, its function in this process is still unclear. We report that inhibition of FGF/FGFR signaling impairs sphereforming ability of PDAC in vitro, and knocking down FGFR1 and FGFR2 decreased their tumorigenesis abilities in vivo. Mechanistically, we demonstrated that SOX2 is down-regulated upon loss of FGFR signaling. The overexpression of SOX2 in SOX2negative cells, which normally do not display stemness capabilities, is sufficient to induce spheroid formation. Additionally, we found that AKT phosphorylation was reduced upon FGFR signaling inhibition. The inhibition of AKT using specific pharmacological inhibitors in the context of CSI medium leads to the loss of spheroid formation associated with loss of SOX2 nuclear expression and increased degradation. We demonstrate that an FGFR/AKT/SOX2 axis controls cancer stemness in PDAC and therefore may represent an important therapeutic target in the fight against this very aggressive form of cancer.

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Pancreatic Cancer Stem Cells and Therapeutic Approaches

Cited by 54 publications

References 117 publications

Hedgehog Signaling in Cancer: A Prospective Therapeutic Target for Eradicating Cancer Stem Cells

Hedgehog Signaling in Cancer: A Prospective Therapeutic Target for Eradicating Cancer Stem Cells

Leptin-Notch axis impairs 5-fluorouracil effects on pancreatic cancer

An FGFR/AKT/SOX2 Signaling Axis Controls Pancreatic Cancer Stemness

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