The therapeutic promise of the cancer stem cell concept

Frank, Natasha Y.; Schatton, Tobias; Frank, Markus H.

doi:10.1172/jci41004

Cited by 565 publications

(503 citation statements)

References 124 publications

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“…TICs are able to generate the heterogeneous lineages of cancer cells that comprise the tumour, and hence have been advocated to constitute the sustaining force to maintain and renew fully established malignancy. These properties of TICs have therefore led to the proposal that TICs are responsible for tumour occurrence, metastasis and recurrence, and TIC-targeted therapeutic approaches may provide promising strategies to improve clinical cancer therapy 4 .…”

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confidence: 99%

PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells

Han

Zhao

et al. 2015

Nat Commun

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Tumour-initiating cells (TICs) are advocated to constitute the sustaining force to maintain and renew fully established malignancy; however, the molecular mechanisms responsible for these properties are elusive. We previously demonstrated that voltage-gated calcium channel a2d1 subunit marks hepatocellular carcinoma (HCC) TICs. Here we confirm directly that a2d1 is a HCC TIC surface marker, and identify let-7c, miR-200b, miR-222 and miR-424 as suppressors of a2d1 þ HCC TICs. Interestingly, all the four miRNAs synergistically target PBX3, which is sufficient and necessary for the acquisition and maintenance of TIC properties. Moreover, PBX3 drives an essential transcriptional programme, activating the expression of genes critical for HCC TIC stemness including CACNA2D1, EpCAM, SOX2 and NOTCH3. In addition, the expression of CACNA2D1 and PBX3 mRNA is predictive of poor prognosis for HCC patients. Collectively, our study identifies an essential signalling pathway that controls the switch of HCC TIC phenotypes.

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confidence: 99%

PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells

Han

Zhao

et al. 2015

Nat Commun

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“…Increasing evidence from hematopoietic malignancies and solid tumors (including brain, breast, colorectal, head and neck cancers) has strongly supported the concept that a subpopulation of cancer cells in each tumor has greater potential of cancer initiation and repopulation (Lapidot et al, 1994;Bonnet and Dick, 1997;Al-Hajj et al, 2003;Hemmati et al, 2003;Singh et al, 2003;Galli et al, 2004;Singh et al, 2004;Ricci-Vitiani et al, 2007;O'Brien et al, 2007;Dalerba et al, 2007;Prince et al, 2007;Schatton et al, 2008). These cells were called cancer stem cells (CSCs) or tumor-initiating or propagating cells because they share some critical characteristics with normal stem cells, including the capacities for self-renewal, multi-lineage differentiation, and maintained proliferation (Reya et al, 2001;Vescovi et al, 2006;Bao et al, 2006a;Rosen and Jordan, 2009;Park and rich, 2009;Heddleston et al, 2010;Frank et al, 2010). Although cancer stem cell or stem cell-like cancer cell terminology is imperfect due to its distinct differences from normal stem cell, but it does capture the shared characteristics with normal stem cells especially somatic stem cells.…”

Section: Introductionmentioning

confidence: 97%

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

et al. 2010

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Glioblastomas (GBMs) are highly lethal primary brain tumors. Despite current therapeutic advances in other solid cancers, the treatment of these malignant gliomas remains essentially palliative. GBMs are extremely resistant to conventional radiation and chemotherapies. We and others have demonstrated that a highly tumorigenic subpopulation of cancer cells called GBM stem cells (GSCs) promotes therapeutic resistance. We also found that GSCs stimulate tumor angiogenesis by expressing elevated levels of VEGF and contribute to tumor growth, which has been translated into a useful therapeutic strategy in the treatment of recurrent or progressive GBMs. Furthermore, stem cell-like cancer cells (cancer stem cells) have been shown to promote metastasis. Although GBMs rarely metastasize beyond the central nervous system, these highly infiltrative cancers often invade into normal brain tissues preventing surgical resection, and GSCs display an aggressive invasive phenotype. These studies suggest that targeting GSCs may effectively reduce tumor recurrence and significantly improve GBM treatment. Recent studies indicate that cancer stem cells share core signaling pathways with normal somatic or embryonic stem cells, but also display critical distinctions that provide important clues into useful therapeutic targets. In this review, we summarize the current understanding and advances in glioma stem cell research, and discuss potential targeting strategies for future development of anti-GSC therapies.

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“…It is well known that most solid tumors contain a distinct subpopulation of cancer stem cells (CSCs), which represent the source for tissue renewal, hold malignant potential and can be responsible for therapy resistance [3][4][5][6], and it has been suggested that a successful cure of cancer should requires eradication of CSCs [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Mutant p53 gain of function can be at the root of dedifferentiation of human osteosarcoma MG63 cells into 3AB-OS cancer stem cells

Fiore

Marcatti

Drago-Ferrante

et al. 2014

Bone

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Osteosarcoma is a highly metastatic tumor affecting adolescents, for which there is no second-line chemotherapy. As suggested for most tumors, its capability to overgrow is probably driven by cancer stem cells (CSCs), and finding new targets to kill CSCs may be critical for improving patient survival. TP53 is the most frequently mutated tumor suppressor gene in cancers and mutant p53 protein (mutp53) can acquire gain of function (GOF) strongly contributing to malignancy. Studies thus far have not shown p53-GOF in osteosarcoma. Here, we investigated TP53 gene status/role in 3AB-OS cells-a highly aggressive CSC line previously selected from human osteosarcoma MG63 cells-to evaluate its involvement in promoting proliferation, invasiveness, resistance to apoptosis and stemness. By RT-PCR, methylation-specific PCR, fluorescent in situ hybridization, DNA sequence, western blot and immunofluorescence analyses, we have shown that-in comparison with parental MG63 cells where TP53 gene is hypermethylated, rearranged and in single copy-in 3AB-OS cells, TP53 is unmethylated, rearranged and in multiple copies, and mutp53 (p53-R248W/P72R) is post-translationally modified and with nuclear localization. p53-R248W/P72R-knockdown by short-interfering RNA reduced the growth and replication rate of 3AB-OS cells, markedly increasing cell cycle inhibitor levels and sensitized 3AB-OS cells to TRAILinduced apoptosis by DR5 up-regulation; moreover, it strongly decreased the levels of stemness and invasiveness genes. We have also found that the ectopic expression of p53-R248W/P72R in MG63 cells promoted cancer stemlike features, as high proliferation rate, sphere formation, clonogenic growth, high migration and invasive ability; furthermore, it strongly increased the levels of stemness proteins. Overall, the findings suggest the involvement of p53-R248W/P72R at the origin of the aberrant characters of the 3AB-OS cells with the hypothesis that its GOF can be at the root of the dedifferentiation of MG63 cells into CSCs.

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The therapeutic promise of the cancer stem cell concept

Cited by 565 publications

References 124 publications

PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells

PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

Mutant p53 gain of function can be at the root of dedifferentiation of human osteosarcoma MG63 cells into 3AB-OS cancer stem cells

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