Tumor-Initiating Cells Are Rare in Many Human Tumors

Ishizawa, Kota; Rasheed, Zeshaan A.; Karisch, Robert; Wang, Qiuju; Kowalski, Jeanne; Susky, Erica; Pereira, Keira; Karamboulas, Christina; Moghal, Nadeem; Rajeshkumar, N. V.; Hidalgo, Manuel; Tsao, Ming‐Sound; Ailles, Laurie; Waddell, Thomas K.; Maitra, Anirban; Neel, Benjamin G.; Matsui, William

doi:10.1016/j.stem.2010.08.009

Cited by 198 publications

(167 citation statements)

References 21 publications

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“…These results are compatible with reported cancer stem-like cell/tumor-initiating cell frequencies, which ranged from 1 in 2500 to 1 in 36 000 in various cancers. 47 There are several limitations to our study. First are the limitations inherent to any retrospective study.…”

Section: Discussionmentioning

confidence: 94%

Prognostic impact of the expression of ALDH1 and SOX2 in urothelial cancer of the upper urinary tract

et al. 2013

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Aldehyde dehydrogenase 1 (ALDH1) and sex determining region-Y-related high mobility group box 2 (SOX2) have been identified as putative cancer stem-like cell/tumor-initiating cell markers in various cancer tissues. The aim of this study was to elucidate the prognostic impact of these putative cancer stem-like cell/tumorinitiating cell markers in upper urinary tract urothelial cell carcinoma. Immunohistochemical staining for ALDH1 and SOX2 was carried out on archival specimens from 125 patients with upper urinary tract urothelial cell carcinoma who underwent radical nephroureterectomy. The prognostic value of ALDH1 and SOX2 expression and other clinicopathological features was evaluated. On univariate analysis, tumor grade, pathological T stage, pathological N stage, lymphovascular invasion, ALDH1 expression and SOX2 expression were associated with a poor prognosis. On multivariate analysis, the independent factors of prognosis were tumor grade (P ¼ 0.014), pathological N stage (P ¼ 0.005) and ALDH1 expression (P ¼ 0.002). In subgroup analysis, those subgroups with no positive, one positive or two positive results in immunohistochemistry for ALDH1 and SOX2 expression had estimated 5-year cancer-specific survival rates of 80%, 49% and 22%, respectively (Po0.001). Neither ALDH1 nor SOX2 expression correlated with intravesical recurrence after radical nephroureterectomy. These findings suggest that cancer stem-like cells/tumor-initiating cells are linked to more aggressive behavior of upper urinary tract urothelial cell carcinoma, supporting the current cancer stem cell hypothesis. Thus, therapeutic targeting of cancer stem-like cells/tumor-initiating cells in upper urinary tract urothelial cell carcinoma is a future possibility.

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Section: Discussionmentioning

confidence: 94%

Prognostic impact of the expression of ALDH1 and SOX2 in urothelial cancer of the upper urinary tract

et al. 2013

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“…This point is important also when considering that in vivo, CSCs may differ between different patient tumors and may constantly change as the disease progresses. Fifth, CSCs may or may not be rare [46,47], and their relative abundance likely varies with individual patient tumors, tumor type, grade, and treatment status. This is a critical point as it has been mistakenly assumed (and presumed) by many that CSCs must be rare.…”

Section: Cscsmentioning

confidence: 99%

Understanding cancer stem cell heterogeneity and plasticity

2012

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Heterogeneity is an omnipresent feature of mammalian cells in vitro and in vivo. It has been recently realized that even mouse and human embryonic stem cells under the best culture conditions are heterogeneous containing pluripotent as well as partially committed cells. Somatic stem cells in adult organs are also heterogeneous, containing many subpopulations of self-renewing cells with distinct regenerative capacity. The differentiated progeny of adult stem cells also retain significant developmental plasticity that can be induced by a wide variety of experimental approaches. Like normal stem cells, recent data suggest that cancer stem cells (CSCs) similarly display significant phenotypic and functional heterogeneity, and that the CSC progeny can manifest diverse plasticity. Here, I discuss CSC heterogeneity and plasticity in the context of tumor development and progression, and by comparing with normal stem cell development. Appreciation of cancer cell plasticity entails a revision to the earlier concept that only the tumorigenic subset in the tumor needs to be targeted. By understanding the interrelationship between CSCs and their differentiated progeny, we can hope to develop better therapeutic regimens that can prevent the emergence of tumor cell variants that are able to found a new tumor and distant metastases.

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“…NOTE: Order sufficient numbers of female athymic nude or other, more immunocompromised mouse models such as NOD-SCID, SCID-Beige, or NSG for the experiments 33 . Autoclave all surgical instruments prior to the experiment and allow them to cool down to RT before use.…”

Section: Xenograft Model For Human Pancreatic Cancer In Immunocomprommentioning

confidence: 99%

Studying Pancreatic Cancer Stem Cell Characteristics for Developing New Treatment Strategies

Lonardo

Cioffi

Sancho

et al. 2015

JoVE

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Pancreatic ductal adenocarcinoma (PDAC) contains a subset of exclusively tumorigenic cancer stem cells (CSCs) which have been shown to drive tumor initiation, metastasis and resistance to radio-and chemotherapy. Here we describe a specific methodology for culturing primary human pancreatic CSCs as tumor spheres in anchorage-independent conditions. Cells are grown in serum-free, non-adherent conditions in order to enrich for CSCs while their more differentiated progenies do not survive and proliferate during the initial phase following seeding of single cells. This assay can be used to estimate the percentage of CSCs present in a population of tumor cells. Both size (which can range from 35 to 250 micrometers) and number of tumor spheres formed represents CSC activity harbored in either bulk populations of cultured cancer cells or freshly harvested and digested tumors 1,2 . Using this assay, we recently found that metformin selectively ablates pancreatic CSCs; a finding that was subsequently further corroborated by demonstrating diminished expression of pluripotency-associated genes/surface markers and reduced in vivo tumorigenicity of metformin-treated cells. As the final step for preclinical development we treated mice bearing established tumors with metformin and found significantly prolonged survival. Clinical studies testing the use of metformin in patients with PDAC are currently underway (e.g., NCT01210911, NCT01167738, and NCT01488552). Mechanistically, we found that metformin induces a fatal energy crisis in CSCs by enhancing reactive oxygen species (ROS) production and reducing mitochondrial transmembrane potential. In contrast, non-CSCs were not eliminated by metformin treatment, but rather underwent reversible cell cycle arrest. Therefore, our study serves as a successful example for the potential of in vitro sphere formation as a screening tool to identify compounds that potentially target CSCs, but this technique will require further in vitro and in vivo validation to eliminate false discoveries.

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Tumor-Initiating Cells Are Rare in Many Human Tumors

Cited by 198 publications

References 21 publications

Prognostic impact of the expression of ALDH1 and SOX2 in urothelial cancer of the upper urinary tract

Prognostic impact of the expression of ALDH1 and SOX2 in urothelial cancer of the upper urinary tract

Understanding cancer stem cell heterogeneity and plasticity

Studying Pancreatic Cancer Stem Cell Characteristics for Developing New Treatment Strategies

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