Targeting Cancer Stem Cells and Their Niche: Current Therapeutic Implications and Challenges in Pancreatic Cancer

Zhao, Jiangang; Li, Jiahui; Schlößer, Hans; Popp, Felix; Popp, Marie; Alakus, Hakan; Jauch, Karl‐Walter; Bruns, Christiane; Zhao, Yue

doi:10.1155/2017/6012810

Cited by 9 publications

(8 citation statements)

References 108 publications

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“…Cancer stem cells (CSCs) have been reported play an essential role in the interactions involved in maintaining and regulating tumor micro-environments [28,29]. Research has revealed that OPN can promote some peculiarities in CSCs, or “stemness”, among various types of cancers.…”

Section: Discussionmentioning

confidence: 99%

Osteopontin Promotes Colorectal Cancer Cell Invasion and the Stem Cell-Like Properties through the PI3K-AKT-GSK/3β-β/Catenin Pathway

et al. 2019

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Background Osteopontin (OPN) is a molecule expressed in numerous cancers including colorectal cancer (CRC) that correlates disease progression. The interaction of OPN that promotes CRC cell migration, invasion, and cancer stem-like cells (CSCs) have not been elucidated. Hence, we aimed to investigate the mechanisms that might be involved. Material/Methods Expression of OPN in tumor tissues derived from patients was monitored with real-time quantitative polymerase chain reaction and western blot. Wound healing and Transwell assay were used to test the differences in migration and invasion in an OPN enriched environment and OPN knockdown condition. Aldehyde dehydrogenase 1 (ALDH1) positive stem cells were isolated using fluorescence-activated cell sorting (FACS) following the protocol of the ALDEFLUOR™ kit. The expression of protein participation in the PI3K-Akt-GSK/3β-β/catenin pathway was detected by western blot. Results OPN exhibited increased levels in CRC tumor tissue compared with non-tumor normal tissue and the high level of which correlated with lymphatic metastasis and late TNM stage. Additional rhOPN co-cultured low-expression CRC cells demonstrated more aggressive capability of proliferation, migration, and invasion. For knockdown of OPN in high-expression CRC cells, the bioactivities of proliferation, migration, and invasion were significantly inhibited. Interestingly, the percentage of ALDH1 labeled stem cells was dramatically decreased by OPN inhibition. The phosphorylation of PI3K-Akt-GSK/3β-β/catenin pathway was involved in the OPN signaling. Furthermore, Ly294002, a specific PI3K inhibitor, can reverse the promotion of bioactivities and stem cell proportion among rhOPN treated CRC cells. Conclusions OPN promoted cell proliferation, migration, and invasion, and was accompanied by upregulation of ALDH1-positive CSC in CRC through activation of PI3K-Akt-GSK/3β-β/catenin pathway.

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Section: Discussionmentioning

confidence: 99%

Osteopontin Promotes Colorectal Cancer Cell Invasion and the Stem Cell-Like Properties through the PI3K-AKT-GSK/3β-β/Catenin Pathway

et al. 2019

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“…The tumor biology of PDAC is conducive to early metastasis and recurrence, and contributes to chemoradiotherapy resistance ( 47 ). It has previously been reported that several tumor types, including pancreatic cancer, exhibit a minority of cells that display a stem-like phenotype; these cells have an elevated metastatic potential, thus contributing to tumor recurrence and chemoresistance ( 48 ). The present study indicated a vital role for PCSCs in metastasis and recurrence of pancreatic cancer, and suggested that targeting PCSCs may be a promising strategy for the treatment of this refractory malignancy.…”

Section: Discussionmentioning

confidence: 99%

Betulinic acid inhibits stemness and EMT of pancreatic cancer cells via activation of AMPK signaling

et al. 2018

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Cancer stem cells (CSCs), which are found in various types of human cancer, including pancreatic cancer, possess elevated metastatic potential, lead to tumor recurrence and cause chemoradiotherapy resistance. Alterations in cellular bioenergetics through the regulation of 5′ adenosine monophosphate-activated protein kinase (AMPK) signaling may be a prerequisite to stemness. Betulinic acid (BA) is a well-known bioactive compound with antiretroviral and anti-inflammatory potential, which has been reported to exert anticancer effects on various types of cancer, including pancreatic cancer. The present study aimed to investigate whether BA could inhibit pancreatic CSCs via regulation of AMPK signaling. The proliferation of pancreatic cancer cells was examined by MTT and colony formation assays. The migratory and invasive abilities of pancreatic cancer cells were assessed using wound-scratch and Transwell invasion assays. In addition, the expression levels of candidate genes were measured by reverse transcription-quantitative polymerase chain reaction and western blotting. The results revealed that BA inhibited the proliferation and tumorsphere formation of pancreatic cancer cells, suppressed epithelial-mesenchymal transition (EMT), migration and invasion, and reduced the expression of three pluripotency factors [SRY-box 2 (Sox2), octamer-binding protein 4 (Oct4) and Nanog]. Furthermore, immunohistochemical analysis confirmed that there was a significant inverse association between the expression levels of phosphorylated (P)-AMPK and Sox2 in pancreatic cancer, and it was revealed that BA may activate AMPK signaling. Notably, knockdown of AMPK reversed the suppressive effects of BA on EMT and stemness of pancreatic cancer cells. In addition, BA reversed the effects of gemcitabine on stemness and enhanced the sensitivity of pancreatic cancer cells to gemcitabine. Collectively, these results indicated that BA may effectively inhibit pluripotency factor expression (Sox2, Oct4 and Nanog), EMT and the stem-like phenotype of pancreatic cancer cells via activating AMPK signaling. Therefore, BA may be considered an attractive therapeutic candidate and an effective inhibitor of the stem-like phenotype in pancreatic cancer cells. Further investigation into the development of BA as an anticancer drug is warranted.

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“…MDSCs are important immune components in the tumor microenvironment, and are thought to mediate immune suppression in patients with cancer 30 , 31 . MDSCs provide extrinsic signals for CSC renewal and promote tumor metastatic and tumorigenic potentials 10 .…”

Section: Resultsmentioning

confidence: 99%

NEDD9 promotes cancer stemness by recruiting myeloidderived suppressor cells <i>via</i> CXCL8 in esophageal squamous cell carcinoma

Yue

Zhang

et al. 2021

Cancer Biol. Med.

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Targeting Cancer Stem Cells and Their Niche: Current Therapeutic Implications and Challenges in Pancreatic Cancer

Cited by 9 publications

References 108 publications

Osteopontin Promotes Colorectal Cancer Cell Invasion and the Stem Cell-Like Properties through the PI3K-AKT-GSK/3β-β/Catenin Pathway

Osteopontin Promotes Colorectal Cancer Cell Invasion and the Stem Cell-Like Properties through the PI3K-AKT-GSK/3β-β/Catenin Pathway

Betulinic acid inhibits stemness and EMT of pancreatic cancer cells via activation of AMPK signaling

NEDD9 promotes cancer stemness by recruiting myeloidderived suppressor cells <i>via</i> CXCL8 in esophageal squamous cell carcinoma

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