Persistence of Leukemia-Initiating Cells in a Conditional Knockin Model of an Imatinib-Responsive Myeloproliferative Disorder

Oravecz-Wilson, Katherine; Philips, Steven; Yılmaz, Ömer H.; Ames, Heather M.; Li, Lina; Crawford, Brandon L.; Gauvin, Alice; Lucas, Peter C.; Sitwala, Kajal; Downing, James R.; Morrison, Sean J.; Ross, Theodora S.

doi:10.1016/j.ccr.2009.06.007

Cited by 65 publications

(56 citation statements)

References 31 publications

(64 reference statements)

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“…6 Inhibition of ABL-kinase alone is not sufficient to completely eliminate LSC/Ps, presumably due to drug refractoriness. 7 However, mechanistic studies on downstream signals responsible for the BCR/ABL-mediated transformation phenotype are hindered by the lack of studies in HSC-initiated in vivo models. 8 Rac GTPases play integral roles in HSC and progenitor (HSC/P) proliferation, survival, homing, and engraftment.…”

Section: Introductionmentioning

confidence: 99%

Rac2 GTPase deficiency depletes BCR-ABL+ leukemic stem cells and progenitors in vivo

Sengupta

Arnett

Dunn

et al. 2010

Blood

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Section: Introductionmentioning

confidence: 99%

Rac2 GTPase deficiency depletes BCR-ABL+ leukemic stem cells and progenitors in vivo

Sengupta

Arnett

Dunn

et al. 2010

Blood

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“…In addition to providing a driving force for tumor growth and maintenance, CSC may display different sensitivity to cytotoxic drugs and radiotherapy than the bulk tumor cell population that they generate (8)(9)(10). Thus, in at least some tumor types, CSC may withstand conventional anticancer therapy consistent with their presumed role in relapse following therapy, while possibly responding to approaches that impair pluripotency.…”

Section: Introductionmentioning

confidence: 99%

Targeting Cancer Stem–like Cells as an Approach to Defeating Cellular Heterogeneity in Ewing Sarcoma

et al. 2014

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Plasticity in cancer stem-like cells (CSC) may provide a key basis for cancer heterogeneity and therapeutic response. In this study, we assessed the effect of combining a drug that abrogates CSC properties with standardof-care therapy in a Ewing sarcoma family tumor (ESFT). Emergence of CSC in this setting has been shown to arise from a defect in TARBP2-dependent microRNA maturation, which can be corrected by exposure to the fluoroquinolone enoxacin. In the present work, primary ESFT from four patients containing CD133þ CSC subpopulations ranging from 3% to 17% of total tumor cells were subjected to treatment with enoxacin, doxorubicin, or both drugs. Primary ESFT CSC and bulk tumor cells displayed divergent responses to standard-ofcare chemotherapy and enoxacin. Doxorubicin, which targets the tumor bulk, displayed toxicity toward primary adherent ESFT cells in culture but not to CSC-enriched ESFT spheres. Conversely, enoxacin, which enhances miRNA maturation by stimulating TARBP2 function, induced apoptosis but only in ESFT spheres. In combination, the two drugs markedly depleted CSCs and strongly reduced primary ESFTs in xenograft assays. Our results identify a potentially attractive therapeutic strategy for ESFT that combines mechanism-based targeting of CSC using a low-toxicity antibiotic with a standard-of-care cytotoxic drug, offering immediate applications for clinical evaluation. Cancer Res; 74(22); 6610-22. Ó2014 AACR.

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“…Because CSCs are characterized from various types of cancers, CD44 has been a useful marker for enriching CSCs not only for breast tumors but also a variety of other epithelial tumor models (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). We and others have previously reported that CSCs are more resistant to traditional cancer therapies (4,18,19). There is circumstantial evidence that CSCs may be involved in metastasis of solid tumors, including breast cancer.…”

mentioning

confidence: 99%

Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models

Liu

Patel

Prescher

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

396

419

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To examine the role of breast cancer stem cells (BCSCs) in metastasis, we generated human-in-mouse breast cancer orthotopic models using patient tumor specimens, labeled with optical reporter fusion genes. These models recapitulate human cancer features not captured with previous models, including spontaneous metastasis in particular, and provide a useful platform for studies of breast tumor initiation and progression. With noninvasive imaging approaches, as few as 10 cells of stably labeled BCSCs could be tracked in vivo, enabling studies of early tumor growth and spontaneous metastasis. These advances in BCSC imaging revealed that CD44 + cells from both primary tumors and lung metastases are highly enriched for tumor-initiating cells. Our metastatic cancer models, combined with noninvasive imaging techniques, constitute an integrated approach that could be applied to dissect the molecular mechanisms underlying the dissemination of metastatic CSCs (MCSCs) and to explore therapeutic strategies targeting MCSCs in general or to evaluate individual patient tumor cells and predict response to therapy.breast cancer | human-in-mouse cancer models | fused optical reporters | bioluminescence imaging C ancer stem cells (CSCs) were first identified in human leukemia (1, 2) and exhibited capacity to form tumors in immunodeficient mice. Because CSCs are characterized from various types of cancers, CD44 has been a useful marker for enriching CSCs not only for breast tumors but also a variety of other epithelial tumor models (3-17). We and others have previously reported that CSCs are more resistant to traditional cancer therapies (4,18,19). There is circumstantial evidence that CSCs may be involved in metastasis of solid tumors, including breast cancer. Breast CSCs (BCSCs) possess an "invasiveness" gene signature that correlates with poor overall survival and shortened metastasis-free survival in cancer patients (20). Importantly, BCSCs are enriched for cells that can undergo epithelial-mesenchymal cell transition (EMT), which likely plays a critical role in metastases in at least some tumors (21). The observation that microRNAs in normal breast stem cells and BCSCs can regulate both EMT and self-renewal further suggests that CSCs might somehow play a role in metastasis (22). Nonetheless, there remains uncertainty surrounding the contributions of CSCs to metastasis.Understanding the role of CSCs in metastasis requires a reliable, noninvasive measure of BCSC outgrowth and dissemination in representative and predictive models of human metastatic disease. Because of genetic differences in mouse tumors or genetic changes that occur with establishment of cell lines, the commonly used models to study metastases, including those involving human cancer cell lines, mouse tumor models, and/or metastatic tumor models via bloodstream injections, do not fully recapitulate human disease (9,(23)(24)(25). Here, by implanting patient tumors or BCSCs into mouse mammary fat pads and using noninvasive imaging strategies, we established represen...

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Persistence of Leukemia-Initiating Cells in a Conditional Knockin Model of an Imatinib-Responsive Myeloproliferative Disorder

Cited by 65 publications

References 31 publications

Rac2 GTPase deficiency depletes BCR-ABL+ leukemic stem cells and progenitors in vivo

Rac2 GTPase deficiency depletes BCR-ABL+ leukemic stem cells and progenitors in vivo

Targeting Cancer Stem–like Cells as an Approach to Defeating Cellular Heterogeneity in Ewing Sarcoma

Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models

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