Mechanisms of metastasis: Epithelial‐to‐mesenchymal transition and contribution of tumor microenvironment

Tse, Joyce C.; Kalluri, Raghu

doi:10.1002/jcb.21215

Cited by 313 publications

(254 citation statements)

References 120 publications

(125 reference statements)

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Section: Phenotypic Plasticity In Cancermentioning

confidence: 99%

“…Numerous mechanisms for down-regulation of E-cadherin protein and/or function including promoter methylation, transcriptional repression, mutation of the E-cadherin gene, and protein internalization have been identified in cancer [see reviews [27][28][29][30][31][64][65][66]. Although control of E-cadherin expression in EOC has not been studied extensively, examples of mechanisms detected in other tumor types have been identified.…”

Section: Regulation Of E-cadherin In Ovarian Tumorsmentioning

confidence: 99%

“…EMT transforms relatively immobile epithelial cells to motile and invasive cells and this transformation is accompanied by loss of stable cell:cell contacts mediated by E-cadherin and expression of vimentin intermediate filaments (reviewed in [26]). A similar process is common in cancer where metastatic behavior is frequently associated with a loss of epithelial phenotype and decreased or absent intercellular junctions resulting in loss of polarity and reduced cell:cell adhesion (reviewed in [27][28][29][30][31]. A hallmark of this transformation is loss of Ecadherin expression and/or function which is clinically associated with poor patient prognosis in many tumors [29].…”

Section: Phenotypic Plasticity In Cancermentioning

confidence: 99%

“…This led the authors to conclude that there are different "EMT programs" corresponding to different states of epithelial plasticity and that specific pathways contribute to distinct aspects of EMT [37]. Thus, tumor phenotype would likely reflect the particular complement of EMT regulatory factors expressed in cells or within the tumor microenvironment [30,31,38] and account for the divergence from a "classical" EMT that is frequently observed in cancer.There are increasing examples of tumor cells reverting to an epithelial phenotype following EMT and retention of epithelial characteristics in highly invasive tumors [30,33,39]. Among the tumors where a well differentiated phenotype may be detected in metastatic lesions are those of the prostate, breast, squamous cell carcinoma of the head and neck, and colorectal cancer [32,33].…”

mentioning

confidence: 99%

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

Hudson

Zeineldin

Stack

2008

Clin Exp Metastasis

165

172

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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...

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Section: Phenotypic Plasticity In Cancermentioning

confidence: 99%

Section: Regulation Of E-cadherin In Ovarian Tumorsmentioning

confidence: 99%

Section: Phenotypic Plasticity In Cancermentioning

confidence: 99%

mentioning

confidence: 99%

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

Hudson

Zeineldin

Stack

2008

Clin Exp Metastasis

165

172

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“…7 A number of factors in the tumour environment, such as transforming growth factor beta (TGFβ), growth factors and cytokines modulate EMT by regulating EMT-TFs. 8 Dynamic regulatory circuits integrating EMT-TFs with numerous microRNAs 9 additionally control epithelial plasticity (reviewed in Lamouille 3 ).…”

mentioning

confidence: 99%

Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFβ expression

et al. 2014

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Epithelial-to-mesenchymal transition (EMT) is essential for embryonic morphogenesis and wound healing and critical for tumour cell invasion and dissemination. The AP-1 transcription factor Fra-1 has been implicated in tumorigenesis and in tumour-associated EMT in human breast cancer. We observed a significant inverse correlation between Fra-1 mRNA expression and distant-metastasis-free survival in a large cohort of breast cancer patients derived from multiple array data sets. This unique correlation among Fos genes prompted us to assess the evolutionary conservation between Fra-1 functions in EMT of human and mouse cells. Ectopic expression of Fra-1 in fully polarized, non-tumourigenic, mouse mammary epithelial EpH4 cells induced a mesenchymal phenotype, characterized by a loss of epithelial and gain of mesenchymal markers. Proliferation, motility and invasiveness were also increased in the resulting EpFra1 cells, and the cells were tumourigenic and efficiently colonized the lung upon transplantation. Molecular analyses revealed increased expression of Tgfβ1 and the EMT-inducing transcription factors Zeb1, Zeb2 and Slug. Mechanistically, Fra-1 binds to the tgfb1 and zeb2 promoters and to an evolutionarily conserved region in the first intron of zeb1. Furthermore, increased activity of a zeb2 promoter reporter was detected in EpFra1 cells and shown to depend on AP-1-binding sites. Inhibiting TGFβ signalling in EpFra1 cells moderately increased the expression of epithelial markers, whereas silencing of zeb1 or zeb2 restored the epithelial phenotype and decreased migration in vitro and tumorigenesis in vivo. Thus Fra-1 induces changes in the expression of genes encoding EMT-related transcription factors leading to the acquisition of mesenchymal, invasive and tumorigenic capacities by epithelial cells. This study defines a novel function of Fra-1/AP-1 in modulating tgfb1, zeb1 and zeb2 expression through direct binding to genomic regulatory regions, which establishes a basis for future in vivo genetic manipulations and preclinical studies using mouse models. Epithelial-to-mesenchymal transition (EMT) is a complex biological programme that occurs in physiological processes during embryonic development and wound healing as well as in pathological conditions, such as organ fibrosis and carcinogenesis. During EMT, cells lose epithelial features and acquire mesenchymal characteristics. The acquisition of a mesenchymal state by malignant cancer cells is associated with decreased cell-cell adhesion, and increased migratory and invasive properties, which are crucial for metastasis. [1][2][3][4][5] The adherens junction (AJ) protein E-cadherin, encoded by cdh1, is a central determinant of the epithelial state and its downregulation is the hallmark of EMT. A number of molecular pathways converging on E-cadherin have been implicated in EMT. Transcription factors (TF) of the Snail, Zeb and Twist families, initially identified as regulators of epithelialmesenchymal plasticity during morphogenesis were shown to orchestrate EMT by...

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Biomimetic Nanomedicine Coupled with Neoadjuvant Chemotherapy to Suppress Breast Cancer Metastasis via Tumor Microenvironment Remodeling

Liu

Wang

et al. 2021

Adv Funct Materials

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The biomimetic enzyme activity of cerium oxide nanoparticles (CeNPs) prefers ultrasmall particle size and bare surface. Unfortunately, those two features are not favorable for its in vivo application due to easy aggregation and fast renal filtration. To take advantage of the activity of CeNP for cancer therapy, a homologous targeted cerium oxide nanoparticle system, targeted CeNP (T-CeNP), with the integration of a biodegradable dendritic mesoporous silica nanoparticle, superoxide dismutase and catalase mimicking CeNPs, and the camouflage coating of cancer cell membrane has been developed. Attributed to the homologous targeting effect of cancer cell membrane, nanoparticles with camouflage coating are retained in the tumor in an orthotopic breast cancer metastatic model. Subsequently, T-CeNP effectively hinders cancer-associated fibroblast transdifferentiation and reprograms it back to a normal fibroblast. Consequently, T-CeNP coupled with doxorubicin reduces the size of primary tumors and prevents the post-surgery lung metastasis and liver metastasis of breast cancer.

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Mechanisms of metastasis: Epithelial‐to‐mesenchymal transition and contribution of tumor microenvironment

Cited by 313 publications

References 120 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

Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFβ expression

Biomimetic Nanomedicine Coupled with Neoadjuvant Chemotherapy to Suppress Breast Cancer Metastasis via Tumor Microenvironment Remodeling

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