A cancer stem cell model as the point of origin of cancer-associated fibroblasts in tumor microenvironment

Nair, Nisha; Calle, Anna Sanchez; Zahra, Maram H.; Prieto‐Vila, Marta; Oo, Aung Ko Ko; Hurley, Laura; Vaidyanath, Arun; Seno, Akimasa; Masuda, Junko; Iwasaki, Yoshiaki; Tanaka, Hiromi; Kasai, Tomonari; Seno, Masaharu

doi:10.1038/s41598-017-07144-5

Cited by 147 publications

(121 citation statements)

References 27 publications

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“…CAFs affect cancer cell growth through cell-cell interactions and the secretion of various invasive molecules, such as cytokines, chemokines, and inflammatory mediators. [477][478][479] CAFs in the TME play an indispensable role in the generation and maintenance of CSCs. 480 CAFs transform cancer cells into CSCs.…”

Section: Major Signaling Pathways In Cscsmentioning

confidence: 99%

Targeting cancer stem cell pathways for cancer therapy

Yang

Shi

Zhao

et al. 2020

Sig Transduct Target Ther

1,318

998

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Since cancer stem cells (CSCs) were first identified in leukemia in 1994, they have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. The biological activities of CSCs are regulated by several pluripotent transcription factors, such as OCT4, Sox2, Nanog, KLF4, and MYC. In addition, many intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Notch, Hedgehog, JAK-STAT (Janus kinase/signal transducers and activators of transcription), PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin), TGF (transforming growth factor)/SMAD, and PPAR (peroxisome proliferator-activated receptor), as well as extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, extracellular matrix, and exosomes, have been shown to be very important regulators of CSCs. Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials. This review summarizes the characterization and identification of CSCs, depicts major factors and pathways that regulate CSC development, and discusses potential targeted therapy for CSCs.Signal Transduction and Targeted Therapy (2020) 5:8; https://doi.

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Section: Major Signaling Pathways In Cscsmentioning

confidence: 99%

Targeting cancer stem cell pathways for cancer therapy

Yang

Shi

Zhao

et al. 2020

Sig Transduct Target Ther

1,318

998

View full text Add to dashboard Cite

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“…In the same context, the accumulated data show that CSCs have the ability to differentiate into multi-lineage, such as pericytes, endothelial cells, and cancer-associated fibroblasts, and they have the potential to reconstruct their microenvironment by differentiation or recruitment of other cells and, therefore, contribute to the initiation and progression of cancers [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

“…CM mimics the cancerous niche, in which miPSCs are exposed to different growth factors and chemokines secreted from cancer cells. While using this method, we successfully generated CSC models using CM from lung, pancreas, breast, and liver cancer cell lines [12,[17][18][19][20]. Furthermore, we showed that our CSC models could differentiate into vascular endothelial-like cells and cancer-associated fibroblasts, which support tumor growth in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

Hematopoietic Cells Derived from Cancer Stem Cells Generated from Mouse Induced Pluripotent Stem Cells

Hassan

Afify

Nair

et al. 2019

Cancers

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Cancer stem cells (CSCs) represent the subpopulation of cancer cells with the ability to differentiate into other cell phenotypes and initiated tumorigenesis. Previously, we reported generating CSCs from mouse induced pluripotent stem cells (miPSCs). Here, we investigated the ability of the CSCs to differentiate into hematopoietic cells. First, the primary cells were isolated from malignant tumors that were formed by the CSCs. Non-adherent cells (NACs) that arose from adherent cells were collected and their viability, as well as the morphology and expression of hematopoietic cell markers, were analyzed. Moreover, NACs were injected into the tail vein of busulfan conditioned Balb/c nude mice. Finally, CSCs were induced to differentiate to macrophages while using IL3 and SCF. The round nucleated NACs were found to be viable, positive for hematopoietic lineage markers and CD34, and expressed hematopoietic markers, just like homing to the bone marrow. When NACs were injected into mice, Wright-Giemsa staining showed that the number of white blood cells got higher than those in the control mice after four weeks. CSCs also showed the ability to differentiate toward macrophages. CSCs were demonstrated to have the potential to provide progenies with hematopoietic markers, morphology, and homing ability to the bone marrow, which could give new insight into the tumor microenvironment according to the plasticity of CSCs.

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“…Further studies have correlated expression of CSC ( CD44, ALDH1A1, NOTCH1 ) and Epithelial Mesenchymal Transition (EMT) ( CADHERIN, TWIST, TGF‐βeta, MMPs) markers with the process of invasion and metastasis . Additionally, microenvironment is known to be a major player in maintaining CSC properties in different cancers . Factors released from cancer associated fibroblasts (CAF), such as chondroitin‐sulfate, proteoglycan‐serglycin, promotes tumor growth, invasion, migration and colonisation in breast and lung cancers in CD44‐dependent manner .…”

Section: Introductionmentioning

confidence: 99%

“…[13][14][15] Additionally, microenvironment is known to be a major player in maintaining CSC properties in different cancers. [16][17][18] Factors released from cancer associated fibroblasts (CAF), such as chondroitin-sulfate, proteoglycan-serglycin, promotes tumor growth, invasion, migration and colonisation in breast and lung cancers in CD44-dependent manner. 19 Co-culture of stromal cells such as omental adipose derived and/or bone-marrow mesenchymal stem cells with tumor associated macrophages have been correlated with aberrant expression of stem cell profile in ovarian, myeloma, breast, and gastric cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Cancer stem cells and fibroblast niche cross talk in an in‐vitro oral dysplasia model

Kulsum

Raju²,

Raghavan³

et al. 2019

Molecular Carcinogenesis

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Understanding the cellular interactions during oral carcinogenesis has the potential to identify novel prognostic and therapeutic targets. This study aimed at investigating the cancer stem cell (CSC)‐fibroblast niche interactions using in‐vitro dysplastic cell line models developed from different stages of 4NQO‐induced oral carcinogenic mice model. The spontaneously transformed epithelial cells (DysMSCTR6, 14 and 16) were developed from three time points (mild/moderate/severe), while two fibroblast cell lines (FibroMSCTR12, 16) were developed from moderate and severe dysplastic tissue. The epithelial (Epcam+/Ck+) and the fibroblast cell lines (Vimentin+/α‐SMA+/Ck‐) were authenticated and assessment of cells representing progressive grades of dysplastic severity indicated a significant increase in dysplastic marker profile (P < 0.05). Evaluation of the CSC characteristics showed that an increase in expression of Cd133, Cd44, Aldh1a1, Notch1, and Sox2 was accompanied by an increase in migratory (P > 0.05) and colony formation capacity (P > 0.005). Targeting Notch1 (GSI inhibitor PZ0187; 30 μM), showed a significant reduction in cell proliferation capacity (P < 0.05) and in the dysplastic marker profile. Further, Notch1 inhibition resulted in down regulation of Cd133 and Aldh1a 1 (P < 0.05) and a complete abrogation of colony formation ability (P < 0.0001). The effect of niche interactions evaluated using FibroMSCTR12‐conditioned media studies, revealed an enrichment of ALDH1A1+ cells (P < 0.05), induction of spheroid formation ability (P < 0.0001) and increased proliferation capacity (3.7 fold; P < 0.005). Although PZ0187 reduced cell viability by ∼40%, was unable to abrogate the conditioned‐media induced increase in proliferation capacity completely. This study reports a Notch‐1 dependent enrichment of CSC properties during dysplastic progression and a Notch‐1 independent dysplastic cell‐fibroblast interaction during oral carcinogenesis.

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A cancer stem cell model as the point of origin of cancer-associated fibroblasts in tumor microenvironment

Cited by 147 publications

References 27 publications

Targeting cancer stem cell pathways for cancer therapy

Targeting cancer stem cell pathways for cancer therapy

Hematopoietic Cells Derived from Cancer Stem Cells Generated from Mouse Induced Pluripotent Stem Cells

Cancer stem cells and fibroblast niche cross talk in an in‐vitro oral dysplasia model

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