Side Population Is Enriched in Tumorigenic, Stem-Like Cancer Cells, whereas ABCG2+ and ABCG2− Cancer Cells Are Similarly Tumorigenic

Patrawala, Lubna; Calhoun, Tammy; Schneider‐Broussard, Robin; Zhou, Jianjun; Claypool, Kent; Tang, Dean G.

doi:10.1158/0008-5472.can-05-0592

Cited by 841 publications

(927 citation statements)

References 54 publications

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“…Consistent with these observations, we find that B80% of our purified CD44 þ PCa cells are of the CD44 þ /a2b1 hi /CD133 À tumor progenitor phenotype (Patrawala et al, unpublished observations). Our work (this study; Patrawala et al, 2005) and others' (Maitland et al, 2005), together, suggest that solid tumors such as PCa will likely contain multiple populations of tumorigenic cells, all of which will be able to give rise to tumors but with different efficiencies.…”

Section: Discussionsupporting

confidence: 67%

“…We have recently shown that the LAPC-9 tumors have B0.1% SP, which is about 1000 times more tumorigenic than the non-SP cells (Patrawala et al, 2005). In contrast, the highly purified ABCG2 þ (which mediates the SP phenotype in some cell types) PCa cell population has very similar tumorigenic potentials to the ABCG2 À cells (Patrawala et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…However, the percentages of CD44 and BrdU-colocalized cells significantly increased in spheres that had been BrdUpulsed for 48 h and chased for 10 days ( Figure S4B; arrows), peaked in spheres chased for 25 days, and then declined in spheres chased for 33 days (Figure 4Ab Table S2 for primer information. Patrawala et al, 2005). Using semiquantitative RT-PCR analyses, we found that CD44 þ PCa cells acutely purified from xenograft tumors expressed higher mRNA levels of Bmi, b-catenin, and Smoothened (SMO; Figure 4B).…”

Section: Cd44 Expression In Pca Cells or Pca Cell-derived Spheres Cormentioning

confidence: 97%

“…The LAPC-4 tumor was derived from a lymph node metastasis whereas the LAPC-9 tumor from a bony metastasis and both tumors are AR positive. When purified LAPC-4 cells were plated in IMDM medium supplemented with 20% FBS (Figure 2Aa), or LAPC-9 tumor cells freshly purified from the xenograft tumors were plated on a fibroblast feeder layer in the same medium ( Figure 2Ab), both cell types formed prominent spheres indicative of the presence of stem-like tumor cells (Patrawala et al, 2005). On average, B0.7 and 0.2% of the LAPC-4 and LAPC-9 cells, respectively, had sphere-forming abilities.…”

Section: Cd44 Expression In Pca Cells or Pca Cell-derived Spheres Cormentioning

confidence: 99%

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Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells

et al. 2006

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CD44 is a multifunctional protein involved in cell adhesion and signaling. The role of CD44 in prostate cancer (PCa) development and progression is controversial with studies showing both tumor-promoting and tumor-inhibiting effects. Most of these studies have used bulk-cultured PCa cells or PCa tissues to carry out correlative or overexpression experiments. The key experiment using prospectively purified cells has not been carried out. Here we use FACS to obtain homogeneous CD44 þ and CD44 À tumor cell populations from multiple PCa cell cultures as well as four xenograft tumors to compare their in vitro and in vivo tumor-associated properties. Our results reveal that the CD44 þ PCa cells are more proliferative, clonogenic, tumorigenic, and metastatic than the isogenic CD44 À PCa cells. Subsequent molecular studies demonstrate that the CD44 þ PCa cells possess certain intrinsic properties of progenitor cells. First, BrdU pulse-chase experiments reveal that CD44 þ cells colocalize with a population of intermediate label-retaining cells. Second, CD44 þ PCa cells express higher mRNA levels of several 'stemness' genes including Oct-3/4, Bmi, b-catenin, and SMO. Third, CD44 þ PCa cells can generate CD44 À cells in vitro and in vivo. Fourth, CD44 þ PCa cells, which are AR À , can differentiate into AR þ tumor cells. Finally, a very small percentage of CD44 þ PCa cells appear to undergo asymmetric cell division in clonal analyses. Altogether, our results suggest that the CD44 þ PCa cell population is enriched in tumorigenic and metastatic progenitor cells.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Cd44 Expression In Pca Cells or Pca Cell-derived Spheres Cormentioning

confidence: 97%

Section: Cd44 Expression In Pca Cells or Pca Cell-derived Spheres Cormentioning

confidence: 99%

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Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells

et al. 2006

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“…7G) that the number of sarcospheres generated from vector and R248W/P72R cells in each passage remained consistent; however, R248W/P72R cells formed~2-fold sarcospheres than vector cells, demonstrating their higher in vitro self-renewing potential. In addition, in a colony-forming assay that correlates with self renewal [37], R248W/P72R cells formed more numerous and larger colonies than vector cells (Fig. 7H).…”

Section: P53-r248w/p72r-knockdown Affects the Expression Of Stem-cellmentioning

confidence: 96%

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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Overview of Cancer Stem Cells (CSCs) and Mechanisms of Their Regulation: Implications for Cancer Therapy

et al. 2013

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The identification of small subpopulations of cancer stem cells (CSCs) from blood mononuclear cells in human acute myeloid leukemia (AML) in 1997 was the landmark observation for recognizing the potential role of CSCs in tumor aggressiveness. Two critical properties contribute to the functional role of CSCs in the establishment and recurrence of cancerous tumors: their self-renewal capacity and their potential to differentiate into unlimited heterogeneous populations of cancer cells. These findings suggest that CSCs may represent novel therapeutic targets for the treatment and/or prevention of tumor progression as they appear to be involved in cell migration, invasion, metastasis, and treatment resistance, all of which lead to poor clinical outcomes. The identification of CSC-specific markers, the isolation and characterization of CSCs from malignant tissues, and targeting strategies for the destruction of CSCs provides a novel opportunity for cancer research. Described in this overview is the potential implication of several common CSC markers in the identification of CSC subpopulation restricted to common malignant diseases e.g., leukemia, breast, prostate, pancreatic and lung cancers. The role of microRNAs (miRNAs) in the regulation of CSC function is also discussed, as are several methods commonly used in CSC research. The potential role of the anti-diabetic drug metformin that has been shown to have effects on CSCs, and known function as an anti-tumor agent, provides an example of this new class of chemotherapeutics.

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Side Population Is Enriched in Tumorigenic, Stem-Like Cancer Cells, whereas ABCG2+ and ABCG2− Cancer Cells Are Similarly Tumorigenic

Cited by 841 publications

References 54 publications

Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells

Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells

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

Overview of Cancer Stem Cells (CSCs) and Mechanisms of Their Regulation: Implications for Cancer Therapy

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