The role of epithelial-mesenchymal transition in cancer pathology

Guarino, Marcello; Rubino, Barbara; Ballabio, G

doi:10.1080/00313020701329914

Cited by 693 publications

(704 citation statements)

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“…These changes are similar to those observed in epithelial-mesenchymal transition at the advancing margin of other tumors, such as colorectal carcinoma. [12][13][14]22,23 Earlier, we have noted that areas of MELF-type invasion are strongly positive for CK7 and show reduced E-cadherin and hormone receptor expression. 20 These findings sometimes differed from those of the predominant conventional tumor areas, illustrating the importance of correlating the immunophenotypic findings with tumor distribution and morphology.…”

Section: Discussionmentioning

confidence: 89%

“…19,20 Expression of cyclin D1 in MELF areas would also be consistent with epithelial-mesenchymal transition as cyclin D1 is characteristically upregulated during this process in other types of carcinoma. [12][13][14]22,23 Abnormalities of b-catenin have also been shown in a significant proportion of endometrial neoplasms. 3,5 Mutations have been recorded in 13-31% cases and appear more common in lowgrade endometrioid adenocarcinomas, [31][32][33][34][35][36] whereas an abnormal immunolocalization in the form of reduced membrane staining with diffuse cytoplasmic and/or nuclear staining has been recorded in 25-76% cases.…”

Section: Endometrial Carcinoma Invasionmentioning

confidence: 99%

“…However, convincing nuclear staining was identified in only two cases in this series, a finding that differs from that observed in colorectal carcinoma in which foci of budding invasion, corresponding to epithelial-mesenchymal transition, typically show nuclear b-catenin expression. 12,22,23 Therefore, alternate pathways may be more critical in upregulating cyclin D1 during the invasive process in endometrial cancers. We also noted b-catenin expression within reactive stromal cells surrounding MELF areas in some tumors.…”

Section: Endometrial Carcinoma Invasionmentioning

confidence: 99%

“…Reduced expression of the E-cadherin/b-catenin complex is considered a fundamental step in the progression of many types of carcinoma, notably as a cardinal feature of epithelial-mesenchymal transition, which permits epithelial cells to acquire motility and display invasive properties. [12][13][14] The Rb pathway exerts control mainly on cell proliferation by regulating cell progression through the G1/S phases of the cell cycle. The Rb protein inhibits cell division and therefore its inactivation by complexes of cyclin-dependent kinases (cdks) and cyclins, such as cdk4/6 and cyclin D1, has a pro-proliferative effect.…”

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confidence: 99%

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Expression of cell cycle regulatory proteins in endometrial adenocarcinoma: variations in conventional tumor areas and in microcystic, elongated and fragmented glands

et al. 2009

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Endometrial adenocarcinomas may show a distinctive pattern of invasion characterized by the presence of microcystic, elongated and fragmented glands, often most evident along the advancing tumor margin. Earlier, we have shown that these changes appear restricted to low-grade endometrioid carcinomas, many of which show focal mucinous differentiation and lymphovascular space invasion. However, the molecular alterations associated with this morphological alteration are not known. In this study, we have examined immunoreactivity for the cell cycle regulatory proteins cyclin D1, p16 and b-catenin in 22 endometrial carcinomas, specifically comparing the results in conventional tumor areas and in foci in which the glands exhibited microcystic, elongated and fragmented appearances. The conventional neoplastic glands exhibited cyclin D1 and p16 expression in most cases, with 450% tumor cells positive in 8 cases and 11 tumors, respectively. Membranous expression of b-catenin was usually preserved, with variable cytoplasmic and nuclear staining. Cyclin D1 and b-catenin predominantly stained cells at the peripheral or basal aspect of the conventional glands, whereas p16 was more uniformly expressed centrally. Tumor foci composed of microcystic, fragmented and elongated glands showed strong expression of cyclin D1 and p16, sometimes in contrast to unstained contiguous or adjacent conventional neoplastic elements, and there was also loss or fragmentation of membranous b-catenin staining. Intravascular tumor cells also expressed cyclin D1 and p16 and therefore the immunostains often highlighted subtle foci of lymphovascular invasion. The heterogenous expression of cell cycle regulatory proteins within endometrial adenocarcinoma illustrates the importance of assessing microanatomical variations in immunoreactivity, particularly at the advancing margin of tumors. The upregulation of cyclin D1 and p16, together with loss of membranous b-catenin expression in microcystic, fragmented and elongated glands, is similar to epithelial-mesenchymal transitions observed in other malignancies and suggests that this pattern of invasion represents an active rather than a degenerative cellular process. Modern Pathology (2009) 22, 725-733; doi:10.1038/modpathol.2009 published online 6 March 2009 Keywords: endometrial; carcinoma; invasion; MELF; epithelial-mesenchymal transition; immunohistochemistry Endometrial carcinomas can be divided into two major groups on the basis of clinicopathological, immunohistological and molecular features. 1,2 The more common (type 1) subgroup accounts for 80-85% of cases and mainly comprises endometrioid adenocarcinomas of low-to-intermediate grade. These tumors typically occur in perimenopausal and younger postmenopausal patients, often arise in hyperestrogenic states and are associated with atypical endometrial hyperplasia/endometrial intraepithelial neoplasia. Frequently, type 1 carcinomas are confined to the uterine corpus at the time of diagnosis (stage 1), and the prognosis in such patients is generally ...

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Section: Discussionmentioning

confidence: 89%

Section: Endometrial Carcinoma Invasionmentioning

confidence: 99%

Section: Endometrial Carcinoma Invasionmentioning

confidence: 99%

mentioning

confidence: 99%

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Expression of cell cycle regulatory proteins in endometrial adenocarcinoma: variations in conventional tumor areas and in microcystic, elongated and fragmented glands

et al. 2009

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“…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].…”

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confidence: 99%

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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