Migrating cancer stem cells — an integrated concept of malignant tumour progression

Brabletz, Thomas; Jung, Andreas; Spaderna, Simone; Hlubek, Falk; Kirchner, Thomas

doi:10.1038/nrc1694

Cited by 1,276 publications

(1,083 citation statements)

References 49 publications

Supporting

Mentioning

1,003

Contrasting

Unclassified

Order By: Relevance

“…This intermediate phenotype is observed in normal ovarian epithelium [34], at the invasive front of colon [32] and breast [35] cancer, and in normal epidermal tissue during wound repair [36]. These recent findings suggest that even an "incomplete" EMT may contribute to migratory behavior and tumor invasion.…”

Section: Phenotypic Plasticity In Cancermentioning

confidence: 94%

“…In recent years, it has become clear that partial or incomplete EMT can occur in tumors whereby cells retain some epithelial features and migrate or invade while maintaining cell:cell contacts [32,33]. This intermediate phenotype is observed in normal ovarian epithelium [34], at the invasive front of colon [32] and breast [35] cancer, and in normal epidermal tissue during wound repair [36].…”

Section: Phenotypic Plasticity In Cancermentioning

confidence: 99%

“…In certain cases, de novo expression of neural (N)-cadherin is evident in tumors lacking E-cadherin and N-cadherin is frequently used as a marker for the mesenchymal phenotype. Some mechanisms for down-regulation of E-cadherin (ie inactivating mutations or promoter hypermethylation) lead to a persistent mesenchymal phenotype [27,29].In recent years, it has become clear that partial or incomplete EMT can occur in tumors whereby cells retain some epithelial features and migrate or invade while maintaining cell:cell contacts [32,33]. This intermediate phenotype is observed in normal ovarian epithelium [34], at the invasive front of colon [32] and breast [35] cancer, and in normal epidermal tissue during wound repair [36].…”

mentioning

confidence: 99%

See 2 more Smart Citations

Phenotypic plasticity of neoplastic ovarian epithelium: unique cadherin profiles in tumor progression

Hudson

Zeineldin

Stack

2008

Clin Exp Metastasis

163

172

View full text Add to dashboard Cite

The mesodermally derived normal ovarian surface epithelium (OSE) displays both epithelial and mesenchymal characteristics and exhibits remarkable phenotypic plasticity during post-ovulatory repair. The majority of epithelial ovarian carcinomas (EOC) are derived from the OSE and represent the most lethal of all gynecological malignancies, as most patients (~70%) present at diagnosis with disseminated intra-abdominal metastasis. The predominant pattern of EOC metastasis involves pelvic dissemination rather than lymphatic or hematologic spread, distinguishing EOC from other solid tumors. Acquisition of the metastatic phenotype involves a complex series of interrelated cellular events leading to dissociation (shedding) and dispersal of malignant cells. A key event in this process is disruption of cell-cell contacts via modulation of intercellular junctional components. In contrast to most carcinomas that downregulate E-cadherin expression during tumor progression, an unique feature of primary well-differentiated ovarian cancers is a gain of epithelial features, characterized by an increase in expression of E-cadherin. Subsequent reacquisition of mesenchymal features is observed in more advanced tumors with concomitant loss of E-cadherin expression and/ or function during progression to metastasis. The functional consequences of this remarkable phenotypic plasticity are not fully understood, but may play a role in modulation of cell survival in suspension (ascites), chemoresistance, and intraperitoneal anchoring of metastatic lesions. Keywords ovarian cancer; epithelium; cadherin; keratin; vimentin; epithelial-mesenchymal transition; plasticity Ovarian Cancer-OverviewTumors arising from the ovarian epithelium account for ~90% of ovarian malignancies and epithelial ovarian carcinoma (EOC) is the leading cause of death from gynecologic malignancy, resulting in approximately 15,280 deaths in the United States alone in 2006 [1]. These distressing statistics are largely due to the low detection rate of disease confined to the ovary (stage 1) when 5-year survival is >90%. Approximately 75% of women are initially diagnosed with disseminated intra-abdominal disease (stage III-IV) and have a 5-year survival of <20%.Ovarian tumors are pathologically heterogeneous with four major histotypes: serous, endometroid, clear cell and mucinous. These classifications are histogenetically based on The early steps of EOC metastasis involve shedding of the cells from the primary tumor to form free floating cells or multi-cellular aggregates (MCAs) in ascites [ Fig. 1]. Cell-cell and cell-matrix adhesion molecules mediate interaction of metastasizing tumor cells with mesothelial cells lining the inner surface of the peritoneal cavity and the sub-mesothelial extracellular matrix (ECM). Localized proteolytic degradation of sub-mesothelial ECM components facilitates migration of tumor cells and anchoring of secondary lesions on adjacent pelvic organs, and at later stages, metastasis to distant organs [9,10]. However, the majority of wo...

show abstract

Section: Phenotypic Plasticity In Cancermentioning

confidence: 94%

Section: Phenotypic Plasticity In Cancermentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Phenotypic plasticity of neoplastic ovarian epithelium: unique cadherin profiles in tumor progression

Hudson

Zeineldin

Stack

2008

Clin Exp Metastasis

163

172

View full text Add to dashboard Cite

show abstract

“…The characteristic of EMT is that cells acquire mesenchymal cell markers (eg, N‐cadherin and vimentin) and lose epithelial cell markers (eg, E‐cadherin) 5, 6. EMT occurs during the progression of tumors of various origins, including prostate, breast, hepatic, gastric, pancreatic, and colorectal cancer 7, 8, 9, 10, 11, 12…”

Section: Introductionmentioning

confidence: 99%

Prognostic value of association of OCT4 with LEF1 expression in esophageal squamous cell carcinoma and their impact on epithelial‐mesenchymal transition, invasion, and migration

Zhao

Huang

et al. 2018

Cancer Medicine

View full text Add to dashboard Cite

Esophageal squamous cell carcinoma (ESCC) is a malignant disease with poor prognosis. Because of early metastasis prior to diagnosis and therapeutic resistance, ESCC has become one of the leading causes of cancer‐related death. Here, we investigated the clinicopathological significance of the association of octamer‐binding transcription factor 4 (OCT4) with lymphoid enhancer‐binding factor 1 (LEF1) expression and the potential molecular mechanism in the epithelial‐mesenchymal transition (EMT), invasion, and migration of ESCC. The expression of OCT4 and LEF1 was detected via immunohistochemistry analysis. High levels of LEF1 expression were observed in 95 ESCC specimens and were obviously associated with aberrant clinicopathological features and poor patient prognosis. Our previous study showed that OCT4 expression level is elevated in ESCC, and statistical analysis showed that the elevated expression of OCT4 and LEF1 in ESCC was significantly associated with histologic grade, lymph node metastasis, TNM stage, and poor patient prognosis. The specific inhibition of OCT4 expression via a lentivirus encoding OCT4‐shRNA (LV‐shOCT4) in Eca109 cells led to decreased levels of OCT4 and LEF1 in vitro. Additionally, we applied a rescue strategy by infecting LV‐shOCT4 Eca109 cells with a LEF1 overexpression plasmid (p‐LEF1) and detected changes in EMT, migration, and invasion. Unsurprisingly, the p‐LEF1 group exhibited greater EMT, invasion, and migration than did the LV‐shOCT4 and negative control groups. This study demonstrates for the first time the relationship between OCT4 and LEF1 expression. The combination of high expression of OCT4 and LEF1 was associated with clinicopathological features of atypical patients, and this combination might be an ideal prognostic factor in ESCC. OCT4 positively regulated LEF1 expression, and LEF1 mediated the effects of OCT4 in cancer cell EMT, invasion, and migration. The data presented here suggest that the inhibition of OCT4‐LEF1 signaling may be a new therapeutic target for the treatment of ESCC.

show abstract

“…7,10 The epithelial to mesenchymal transition has also been implicated in the dissemination of primary tumors owing to invasion or intravasation, as well as to the generation of distant tumors by migrating cancer stem cells. 11 The Hippo pathway has been implicated in epithelial to mesenchymal transition and stemness, 12 and it is a pathway that coordinates cell proliferation, apoptosis, and differentiation associated with the regulation of organ development and regeneration. 13 The pathway involves a conserved kinase cascade, and the final transcriptional co-activators TAZ and YAP have been implicated in tissue homeostasis and the control of organ size through tissue-specific stem cell regulation.…”

mentioning

confidence: 99%

A role for the transducer of the Hippo pathway, TAZ, in the development of aggressive types of endometrial cancer

et al. 2015

View full text Add to dashboard Cite

Although TAZ, the final effector of the Hippo pathway that modulates epithelial to mesenchymal transition and stemness, has been implicated in the development of different types of cancer, its role in endometrial cancer has not yet been studied. Thus, we evaluated the expression of TAZ in different types of endometrial cancer by immunohistochemistry. TAZ expression was detected in 76% of undifferentiated endometrial carcinomas, 54% of endometrial carcinosarcomas, 46% of endometrial serous carcinomas, 36% of grade 3 endometrioid carcinomas, and 18% of grade 1-2 endometrioid carcinomas, with statistically significant differences. We analyzed the WWTR1 gene that encodes TAZ by FISH and MassARRAY spectrometry, ruling out gene amplification and differential promoter methylation as the main mechanisms that modulate TAZ expression in endometrial tumors. However, we did detect a significant association between Scribble hypoexpression and delocalization with TAZ expression. Moreover, we demonstrated that TAZ promoted invasiveness, and it favored cell motility and tumor growth, in endometrial cancer cell lines. In addition, TAZ expression was associated with the transition from an epithelial to mesenchymal phenotype, both in vitro and in human tumors. Together, these data reveal a previously unknown role for TAZ and the Hippo pathway in the progression of aggressive subtypes of endometrial cancer. Modern Pathology (2015Pathology ( ) 28, 1492Pathology ( -1503 doi:10.1038/modpathol.2015 published online 18 September 2015 In developed countries, endometrial carcinoma is the most common malignant tumor of the female genital tract. 1 On the basis of epidemiological, clinical, pathological, and molecular features, endometrial carcinoma can be classified into at least two main categories: 2 type I estrogen-dependent carcinomas that account for 80-85% of cases and that are typically represented by low-grade (grade 1 and 2) endometrioid carcinomas, and type II endometrial carcinomas that are not estrogen dependent and that are mainly represented by a serous subtype but also by other high-grade histological tumors like clear cell or undifferentiated carcinomas. 2 In endometrial carcinoma, the epithelial to mesenchymal transition has been associated with high-grade and aggressive features. [3][4][5][6] Epithelial to

show abstract

Migrating cancer stem cells — an integrated concept of malignant tumour progression

Cited by 1,276 publications

References 49 publications

Phenotypic plasticity of neoplastic ovarian epithelium: unique cadherin profiles in tumor progression

Phenotypic plasticity of neoplastic ovarian epithelium: unique cadherin profiles in tumor progression

Prognostic value of association of OCT4 with LEF1 expression in esophageal squamous cell carcinoma and their impact on epithelial‐mesenchymal transition, invasion, and migration

A role for the transducer of the Hippo pathway, TAZ, in the development of aggressive types of endometrial cancer

Contact Info

Product

Resources

About