The CD44+/CD24− phenotype relates to ‘triple-negative’ state and unfavorable prognosis in breast cancer patients

Giatromanolaki, Alexandra; Sivridis, Efthimios; Fiska, Aliki; Koukourakis, Michael I.

doi:10.1007/s12032-010-9530-3

Cited by 117 publications

(100 citation statements)

References 44 publications

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“…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). In some instances, mice were injected with tumor cells at two different sites.…”

Section: Discussionsupporting

confidence: 79%

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: 79%

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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“…In fact, the majority of studies to date have tended to concentrate on CD44 + /CD24 - (13)(14)(15)(16)(17) and there have been few that have examined a larger range of markers in the same cohort. Giatromanolaki et al (18) investigated the significance of these 2 molecules in connection with tumor aggression and prognosis. The phenotypic profile of 139 breast carcinomas was investigated in paraffin sections using markers previously associated with stem cell-like properties (CD44, CD24), the ̔triple-state' (ER, PR, c-erb-B2) and angiogenesis (CD31).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the expression of stem cell markers in human breast cancer reveals a correlation with clinical progression and metastatic disease in ductal carcinoma

Martin

Jiang

2013

Oncology Reports

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Abstract. The tumor stem cell theory could explain how patients with metastatic disease show clinical relapse several months after starting treatment due to the survival of a small group of cells with unique characteristics. We examined the distribution and expression of a panel of stem cell markers in human breast cancer primary tumors. Human breast tissues were processed for immunohistochemistry, and RNA was extracted for analysis by quantitative-PCR. Immunohistochemical assay revealed that CD44 was strongly expressed in background endothelia and epithelia. CD133 expression was lost in tumor-associated endothelial cells. Conversely, CD49b was strongly stained in the tumors, associated vessels and ducts but was weakly stained in the background epithelia. q-PCR analysis revealed that CD44 and PSCA were reduced in patients with poor outcome (metastatic disease and death from breast cancer), with a marked reduction in ductal carcinoma, particularly with metastasis to bone although these did not reach significant difference. CD133 was significantly reduced in patients with metastatic disease and was also significantly reduced in patients with ductal carcinoma/bone metastasis. Conversely, CD49F was increased in patients with a poor outcome and those with ductal cancer and bone metastases. This is the first study to determine the distribution and expression pattern of these stem cell markers in human breast cancer. There was a significant association between loss of expression and metastatic disease in patients with breast cancer. Such differential expression may play a part in breast cancer disease progression, and suggests that the current stem cell theory may not hold true for all cancer types.

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“…This tumor phenotype appears to be common in basal like tumors (11,12) and in triple negative tumors (13). It has been suggested that tumor cells with a CD44 + CD24 -subpopulation may have a worse clinical behavior (13,14).…”

Section: Introductionmentioning

confidence: 99%

Prognostic significance of CD24 and claudin-7 immunoexpression in ductal invasive breast cancer

et al. 2011

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The CD44+/CD24− phenotype relates to ‘triple-negative’ state and unfavorable prognosis in breast cancer patients

Cited by 117 publications

References 44 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

Evaluation of the expression of stem cell markers in human breast cancer reveals a correlation with clinical progression and metastatic disease in ductal carcinoma

Prognostic significance of CD24 and claudin-7 immunoexpression in ductal invasive breast cancer

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