Cancer stem cells as therapeutic targets of pancreatic cancer

Razi, Ebrahim; Radak, Mehran; Mahjoubin‐Tehran, Maryam; Talebi, Samaneh; Shafiee, Alimohammad; Hajighadimi, Sarah; Moradizarmehri, Sanaz; Mirzaei, Hossein; Mousavi, Nousin; Sarvizadeh, Mostafa; Nejati, Majid; Taghizadeh, Mohsen; Ghasemi, Faezeh

doi:10.1111/fcp.12521

Cited by 16 publications

(13 citation statements)

References 157 publications

(172 reference statements)

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“…Abnormal sialylation is responsible for altering many cellular signaling pathways which are responsible for cancer cell survival and metastasis [30,31]. The drug-resistant cancer cells generally possess self-renewal and differentiation properties and are considered the main source of tumor recurrence and are termed as CSCs [32]. Higher sialylation is one of the key features of CSCs which is also associated with tumor aggressiveness [33].…”

Section: Discussionmentioning

confidence: 99%

Desialylation of Sonic-Hedgehog by Neu2 Inhibits Its Association with Patched1 Reducing Stemness-Like Properties in Pancreatic Cancer Sphere-forming Cells

Nath

Mondal

Butti

et al. 2020

Cells

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Cancer stem cells (CSCs) are crucial regulators of tumor recurrence/progression. The maintenance of CSCs is dependent on aberrant activation of various pathways, including Hedgehog. Prevalent sialylations contribute to aggressiveness in CSCs. Here, we have addressed the role of sialylation in regulating stemness-like properties of pancreatic cancer sphere-forming cells (PCS) through modulation of the Hedgehog (Hh) pathway. The status of CD133/CD44/surface-sialylation was checked by flow cytometry and effects of Neu2 overexpression in PCS were compared using qPCR, immunoblotting, co-immunoprecipitation and also by colony-formation assays. The work was also validated in a xenograft model after Neu2 overexpression. Neu2 and Shh status in patient tissues were examined by immunohistochemistry. PCS showed higher Hh-pathway activity and sialylation with reduced cytosolic-sialidase (Neu2). Neu2 overexpression caused desialylation of Shh, thereby reducing Shh-Patched1 binding thus causing decreased Hh-pathway activity with lower expression of Snail/Slug/CyclinD1 leading to reduction of stemness-like properties. Neu2-overexpression also induced apoptosis in PCS. Additionally, Neu2-overexpressed PCS demonstrated lower mTORC2 formation and inhibitory-phosphorylation of Gsk3β, reflecting a close relationship with reduced Hh pathway. Moreover, both Neu2 and Rictor (a major component of mTORC2) co-transfection reduced stem cell markers and Hh-pathway activity in PCS. Neu2-overexpressed tumors showed reduction in tumor mass with downregulation of stem cell markers/Shh/mTOR and upregulation of Bax/Caspase8/Caspase3. Thus, we established that reduced sialylation by Neu2 overexpression leads to decreased stemness-like properties by desialylation of Shh, which impaired its association with Patched1 thereby inhibiting the Hh pathway. All these may be responsible for enhanced apoptosis in Neu2-overexpressed PCS.

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Section: Discussionmentioning

confidence: 99%

Desialylation of Sonic-Hedgehog by Neu2 Inhibits Its Association with Patched1 Reducing Stemness-Like Properties in Pancreatic Cancer Sphere-forming Cells

Nath

Mondal

Butti

et al. 2020

Cells

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“…The foregoing discussion provided ample evidence related to the role of PCSCs in carcinogenesis, growth, metastasis, EMT, and chemoresistance in PDAC. The above aberrant signaling pathways govern cancer cell plasticity, which give rise to tumor cellular heterogeneity, EMT, therapeutic resistance, and recurrence through clonal replacement and activation of dormant CSCs in PDAC as well as other cancers [80,88,153,154] . PDAC is characterized by molecular alterations regulating PCSCs, including mutations of K-RAS, TP53, transforming growth factor-β, Hedgehog, WNT and NOTCH signaling pathways.…”

Section: Relevance Of Pcscs In Pdac Developmentmentioning

confidence: 99%

“…As discussed above, recent advances in the role of EMT and PCSCs in tumor progression, metastasis, chemo-resistance, and the mechanisms integrated with aberrant biochemical signals and the underlying pathways have been surveyed in this review. Furthermore, WNT signaling cascades cross-interaction with the FGF, Notch, Hedgehog and TGFβ/BMP signaling cascades and regulate expression of functional CSC markers, such as CD44, CD133 (PROM1), EPCAM and LGR5 (GPR49) [40,[153][154][155][156][157][158] . Aberrant canonical and non-canonical WNT signaling in human malignancies, including PDAC are involved in CSC survival, bulk-tumor expansion and invasion/metastasis [158] .…”

Section: Relevance Of Pcscs In Pdac Developmentmentioning

confidence: 99%

Epithelial-mesenchymal transition: a hallmark in pancreatic cancer stem cell migration, metastasis formation, and drug resistance

Safa

2020

JCMT

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Metastasis, tumor progression, and chemoresistance are the major causes of death in patients with pancreatic ductal adenocarcinoma (PDAC). Tumor dissemination is associated with the activation of an epithelial-tomesenchymal transition (EMT) process, a program by which epithelial cells lose their cell polarity and cell-tocell adhesion, and acquire migratory and invasive abilities to become mesenchymal stem cells (MSC). These MSCs are multipotent stromal cells capable of differentiating into various cell types and trigger the phenotypic transition from an epithelial to a mesenchymal state. Therefore, EMT promotes migration and survival during cancer metastasis and confers stemness features to particular subsets of cells. Furthermore, a major problem limiting our ability to treat PDAC is the existence of rare populations of pancreatic cancer stem cells (PCSCs) or cancer-initiating cells in pancreatic tumors. PCSCs may represent sub-populations of tumor cells resistant to therapy which are most crucial for driving invasive tumor growth. These cells are capable of regenerating the cellular heterogeneity associated with the primary tumor when xenografted into mice. Therefore, the presence of PCSCs has prognostic relevance and influences the therapeutic response of tumors. PCSCs express markers of cancer stem cells (CSCs) including CD24, CD133, CD44, and epithelial specific antigen as well as the drug transporter ABCG2 grow as spheroids in a defined growth medium. A major difficulty in studying tumor cell dissemination and metastasis has been the identification of markers that distinguish metastatic cancer cells from cells that are normally circulating in the bloodstream or at sites where these cells metastasize. Evidence highlights a linkage between CSC and EMT. In this review, The current understanding of the PCSCs, signaling pathways regulating these cells, PDAC heterogeneity, EMT mechanism, and links between EMT and metastasis in PCSCs

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“…In view of this, pancreatic cancers are no exceptions, being among the most challenging‐to‐treat tumours. In their review article, Razi et al present an overview of CSC properties in the context of pancreatic cancer, looking into their origins, biological characteristics, identification and current targeting techniques . In order to be used as therapeutic targets, CSCs must be first identified.…”

mentioning

confidence: 99%

“…The authors also highlight the important role played by epigenetic alterations (miRNA) in pancreatic cancer and present the two sides of the coin regarding the mechanisms behind microRNA functions and regulations of CSCs. Since miRNAs modulate key pathways (PI3K/AKT and Hedgehog signalling) in cellular proliferation, their abnormal expression is generally correlated with the resistance mechanisms developed by pancreatic cancers . One of the most commonly investigated miRNAs, miR‐21, was associated with gemcitabine resistance, while other miRNAs that are related to pancreatic CSCs (miR‐221, miR‐30, etc.)…”

mentioning

confidence: 99%