Cancer stem cells in breast cancer and metastasis

Lawson, Jessica C.; Blatch, Gregory L.; Edkins, Adrienne L.

doi:10.1007/s10549-009-0524-9

Cited by 109 publications

(77 citation statements)

References 166 publications

(215 reference statements)

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“…With our models and noninvasive imaging, we could monitor early tumor growth and the activities of defined subsets of human breast cancer cells. The relevance of CD44 + CSCs function and clinical outcome has been questioned (17,45,46). This work further supports reports from many other groups that CD44 + cells correlate with EMT, unfavorable prognosis, and metastasis of clinical breast cancer (17,20,21,47).…”

Section: Discussionsupporting

confidence: 80%

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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.

405

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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Section: Discussionsupporting

confidence: 80%

“…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).…”

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.

405

419

View full text Add to dashboard Cite

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“…Thus, deregulation of EMT-regulating factors in the mammary gland could induce EMT in epithelial mammary cells and/or in stem-like cells, and thus, these cells could later acquire mesenchymal characteristics with invasive and self-renewal capabilities, enabling these cells to develop micrometastasis and macrometastasis in distant organs. These data also support the hypothesis that breast cancer cells may have a stem cell origin (49)(50)(51).…”

Section: Discussionsupporting

confidence: 85%

Deregulation of the Pit-1 transcription factor in human breast cancer cells promotes tumor growth and metastasis

Ben-Batalla¹,

Seoane²,

García‐Caballero³

et al. 2010

J. Clin. Invest.

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The Pit-1 transcription factor (also know as POU1F1) plays a critical role in cell differentiation during organogenesis of the anterior pituitary in mammals and is a transcriptional activator for pituitary gene transcription. Increased expression of Pit-1 has been reported in human tumorigenic breast cells. Here, we found that Pit-1 overexpression or knockdown in human breast cancer cell lines induced profound phenotypic changes in the expression of proteins involved in cell proliferation, apoptosis, and invasion. Some of these protumorigenic effects of Pit-1 were mediated by upregulation of Snai1, an inductor of the epithelial-mesenchymal transition. In immunodeficient mice, Pit-1 overexpression induced tumoral growth and promoted metastasis in lung. In patients with invasive ductal carcinoma of the breast and node-positive tumor, high expression of Pit-1 was significantly correlated with Snai1 positivity. Notably, in these patients elevated expression of Pit-1 was significantly and independently associated with the occurrence of distant metastasis. These findings suggest that Pit-1 could help to make a more accurate prognosis in patients with node-positive breast cancer and may represent a new therapeutic target.

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“…Identification of specific molecular determinants involved in tumour cell homing and colonisation of bone are fundamental for the development of effective therapeutic regimes. During metastatic conversion, breast cancer cells acquire molecular changes enabling invasion of surrounding tissue, vascular spread to distant sites, and proliferation and survival in secondary sites (Lawson Blatch & Edkins 2009, Ding Ellis et al 2010. It is likely that metastasis is a result of a stepwise accumulation of genetic mutations, with different molecular alterations being required for different stages in the metastatic process.…”

Section: Introductionmentioning

confidence: 99%

Different molecular profiles are associated with breast cancer cell homing compared with colonisation of bone: evidence using a novel bone-seeking cell line

Nutter¹,

Holen²,

Brown³

et al. 2014

Endocrine-Related Cancer

106

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Advanced breast cancer is associated with the development of incurable bone metastasis. The two key processes involved, tumour cell homing to and subsequent colonisation of bone, remain to be clearly defined. Genetic studies have indicated that different genes facilitate homing and colonisation of secondary sites. To identify specific changes in gene and protein expression associated with bone-homing or colonisation, we have developed a novel bone-seeking clone of MDA-MB-231 breast cancer cells that exclusively forms tumours in long bones following i.v. injection in nude mice. Bone-homing cells were indistinguishable from parental cells in terms of growth rate in vitro and when grown subcutaneously in vivo. Only bone-homing ability differed between the lines; once established in bone, tumours from both lines displayed similar rates of progression and caused the same extent of lytic bone disease. By comparing the molecular profile of a panel of metastasis-associated genes, we have identified differential expression profiles associated with bone-homing or colonisation. Bone-homing cells had decreased expression of the cell adhesion molecule fibronectin and the migration and calcium signal binding protein S100A4, in addition to increased expression of interleukin 1B. Bone colonisation was associated with increased fibronectin and upregulation of molecules influencing signal transduction pathways and breakdown of extracellular matrix, including hRAS and matrix metalloproteinase 9. Our data support the hypothesis that during early stages of breast cancer bone metastasis, a specific set of genes are altered to facilitate bone-homing, and that disruption of these may be required for effective therapeutic targeting of this process.

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Cancer stem cells in breast cancer and metastasis

Cited by 109 publications

References 166 publications

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

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

Deregulation of the Pit-1 transcription factor in human breast cancer cells promotes tumor growth and metastasis

Different molecular profiles are associated with breast cancer cell homing compared with colonisation of bone: evidence using a novel bone-seeking cell line

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