Dormancy and breast cancer

Meltzer, Adolph

doi:10.1002/jso.2930430312

Cited by 95 publications

(32 citation statements)

References 16 publications

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“…There is increasing evidence from clinical observations (37)(38)(39)(40)(41)(42)(43), experimental models of dormancy (44)(45)(46)(47)(48)(49), and the findings of circulating tumor cells in patients with clinically organ-confined disease as shown in the present study that suggests that many cancers are chronic systemic diseases that are not cured by present day therapy.…”

Section: Discussionmentioning

confidence: 84%

Detection and characterization of carcinoma cells in the blood

Racila

Euhus

Weiss

et al. 1998

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

628

449

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A highly sensitive assay combining immunomagnetic enrichment with multiparameter f low cytometric and immunocytochemical analysis has been developed to detect, enumerate, and characterize carcinoma cells in the blood. The assay can detect one epithelial cell or less in 1 ml of blood. Peripheral blood (10-20 ml) from 30 patients with carcinoma of the breast, from 3 patients with prostate cancer, and from 13 controls was examined by f low cytometry for the presence of circulating epithelial cells defined as nucleic acid ؉ , CD45 ؊ , and cytokeratin ؉ . Highly significant differences in the number of circulating epithelial cells were found between normal controls and patients with cancer including 17 with organ-confined disease. To determine whether the circulating epithelial cells in the cancer patients were neoplastic cells, cytospin preparations were made after immunomagnetic enrichment and were analyzed. Epithelial cells from patients with breast cancer generally stained with mAbs against cytokeratin and 3 of 5 for mucin-1. In contrast, no cells that stained for these antigens were observed in the blood from normal controls. The morphology of the stained cells was consistent with that of neoplastic cells. Of 8 patients with breast cancer followed for 1-10 months, there was a good correlation between changes in the level of tumor cells in the blood with both treatment with chemotherapy and clinical status. The present assay may be helpful in early detection, in monitoring disease, and in prognostication.Evidence is accumulating that primary cancers begin shedding neoplastic cells into the circulation at an early stage (1-4); however, the natural history of these cells, their ability to establish metastases, and their bearing on future relapses are unclear. For instance, circulating tumor cells have been detected by PCR in a variety of patients with a good prognosis who are unlikely to develop metastatic disease (5-8). In addition, immunocytochemistry has detected cancer cells in the bone marrow in a proportion of patients with clinically localized disease (9-11). If tumor cell shedding is, in fact, an early event in tumorigenesis, it may be possible to detect cancer cells in the bloodstream before the primary tumor is large enough to be detected by standard screening examinations.To explore this possibility, we have developed a cellular assay that is more sensitive than PCR and that allows precise enumeration and characterization of circulating carcinoma cells. In model studies, the sensitivity of the technique is below 1 epithelial cell͞ml of blood regardless of the number of leukocytes present and the recovery is between 75 and 100%. The assay was used to study the blood of 30 patients with breast cancer, 3 with prostate cancer, and 13 control individuals. An excess of circulating epithelial cells was found in virtually all of the cancer patients unless they were being treated with chemotherapy. In addition, 8 patients with breast cancer undergoing chemotherapy were followed for 1-10 months to determin...

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Section: Discussionmentioning

confidence: 84%

Detection and characterization of carcinoma cells in the blood

Racila

Euhus

Weiss

et al. 1998

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

628

449

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“…1, after 5 years postresection, 91% of primary recurrences are at distant sites). Further, the long duration between resection and relapse is thought inexplicable from continual growth of secondary cancers (1)(2)(3)(4)(5). Thus, the unseen micrometastases must undergo a phase of growth restriction where there is a balance between cell proliferation, cell death, and cell migration.…”

Section: Introductionmentioning

confidence: 99%

Breast Cancer Dormancy Can Be Maintained by Small Numbers of Micrometastases

et al. 2010

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Late relapse of breast cancer can occur more than 25 years after primary diagnosis. During the intervening years between initial treatment and relapse, occult cancers are maintained in an apparent state of dormancy that is poorly understood. In this study, we applied a probabilistic mathematical model to long-term follow-up studies of postresection patients to investigate the factors involved in mediating breast cancer dormancy. Our results suggest that long-term dormancy is maintained most often by just one growth-restricted dangerous micrometastasis. Analysis of the empirical data by Approximate Bayesian Computation indicated that patients in dormancy have between 1 and 5 micrometastases at 10 years postresection, when they escape growth restriction with a half-life of <69 years and are >0.4 mm in diameter. Before resection, primary tumors seed at most an average of 6 dangerous micrometastases that escape from growth restriction with a half-life of at least 12 years. Our findings suggest that effective preventive treatments will need to eliminate these small numbers of micrometastases, which may be preangiogenic and nonvascularized until they switch to growth due to one oncogenic mutation or tumor suppressor gene inactivation. In summary, breast cancer dormancy seems to be maintained by small numbers of sizeable micrometastases that escape from growth restriction with a half-life exceeding 12 years. Cancer Res; 70(11); 4310-7. ©2010 AACR.

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“…The tumor initiating and resistant CSCs survive, often in dormancy, and patients suffer from relapse with a more aggressive tumor, occurring sometimes even years after initial treatment. 14,15 One of the most prominent markers is CD44, which was used to isolate CSCs from breast, 16 prostate, 17,18 pancreatic 19 and colorectal tumors. 20 CD44 is a cell surface protein that modulates cell signaling by forming coreceptor complexes with various receptor tyrosine kinases.…”

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confidence: 99%

A self‐enforcing CD44s/ZEB1 feedback loop maintains EMT and stemness properties in cancer cells

Preca

Bajdak

Mock

et al. 2015

Intl Journal of Cancer

157

138

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Invasion and metastasis of carcinomas are often activated by induction of aberrant epithelial-mesenchymal transition (EMT). This is mainly driven by the transcription factor ZEB1, promoting tumor-initiating capacity correlated with increased expression of the putative stem cell marker CD44. However, the direct link between ZEB1, CD44 and tumourigenesis is still enigmatic. Remarkably, EMT-induced repression of ESRP1 controls alternative splicing of CD44, causing a shift in the expression from the variant CD44v to the standard CD44s isoform. We analyzed whether CD44 and ZEB1 regulate each other and show that ZEB1 controls CD44s splicing by repression of ESRP1 in breast and pancreatic cancer. Intriguingly, CD44s itself activates the expression of ZEB1, resulting in a self-sustaining ZEB1 and CD44s expression. Activation of this novel CD44s-ZEB1 regulatory loop has functional impact on tumor cells, as evident by increased tumor-sphere initiation capacity, drug-resistance and tumor recurrence. In summary, we identified a self-enforcing feedback loop that employs CD44s to activate ZEB1 expression. This renders tumor cell stemness independent of external stimuli, as ZEB1 downregulates ESRP1, further promoting CD44s isoform synthesis.Tumor recurrence and metastasis represent the two major obstacles in the successful treatment of cancer. Increasing evidence suggests that the aggressive phenotype of this disease is associated with the activation of an embryonic program termed epithelial-mesenchymal transition (EMT), a process in which epithelial cells lose apical-basal cell polarity and change to a mesenchymal phenotype. [1][2][3] In order to initiate and complete an EMT, several distinct molecular programsKey words: cancer stem cells, epithelial-mesenchymal transition (EMT), metastasis, drug resistance, differential splicing Abbreviations: bHLH: basic helix-loop-helix; CD44s: cluster of differentiation 44, standard isoform; CD44v: cluster of differentiation 44, variant isoforms; ChIP: chromatin immunoprecipitation; CSC: cancer stem cell; Dox: doxycycline; EGF: epidermal growth factor; EMT: epithelial-mesenchymal transition; ESRP1: epithelial splicing regulatory protein 1; FGF: fibroblast growth factor; HGF/SF: hepatic growth factor/scatter factor; hnRNPM: heterogeneous nuclear ribonucleoprotein M; PDAC: pancreas ductal adenocarcinoma; shRNA: small hairpin ribonucleic acid; siRNA: small interference ribonucleic acid; TGFb: transforming growth factor b; ZEB: zinc-finger and E-box binding; ZFH: zinc-finger homeodomain

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Dormancy and breast cancer

Cited by 95 publications

References 16 publications

Detection and characterization of carcinoma cells in the blood

Detection and characterization of carcinoma cells in the blood

Breast Cancer Dormancy Can Be Maintained by Small Numbers of Micrometastases

A self‐enforcing CD44s/ZEB1 feedback loop maintains EMT and stemness properties in cancer cells

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