Epithelial-mesenchymal transitions (EMTs) are a key requirement for cancer cells to metastasize and colonize in a new environment. Epithelial-mesenchymal plasticity is mediated by master transcription factors and is also subject to complex epigenetic regulation. This Review outlines our current understanding of the interactions between EMT-inducing transcription factors and epigenetic modulators during cancer progression and the therapeutic implications of exploiting this intricate regulatory process. During the course of malignant cancer progression, neoplastic cells undergo dynamic and reversible transitions between multiple phenotypic states, the extremes of which are defined by the expression of epithelial and mesenchymal phenotypes. This plasticity is enabled by underlying shifts in epigenetic regulation. A small cohort of pleiotropically acting transcription factors is widely recognized to effect these shifts by controlling the expression of a constituency of key target genes. These master regulators depend on complex epigenetic regulatory mechanisms, notably the induction of changes in the modifications of chromatin-associated histones, in order to achieve the widespread changes in gene expression observed during epithelial-mesenchymal transitions (EMTs). These associations indicate that an understanding of the functional interactions between such EMT-inducing transcription factors and the modulators of chromatin configuration will provide crucial insights into the fundamental mechanisms underlying cancer progression and may, in the longer term, generate new diagnostic and therapeutic modalities for treating high-grade malignancies.

The epigenetics of epithelial-mesenchymal plasticity in cancer

Carcinoma cells residing in an intermediate phenotypic state along the epithelial-mesenchymal (E-M) spectrum are associated with malignant phenotypes, such as invasiveness, tumor-initiating ability, and metastatic dissemination. Using the recently described CD104+/CD44hi antigen marker combination, we isolated highly tumorigenic breast cancer cells residing stably-both in vitro and in vivo-in an intermediate phenotypic state and coexpressing both epithelial (E) and mesenchymal (M) markers. We demonstrate that tumorigenicity depends on individual cells residing in this E/M hybrid state and cannot be phenocopied by mixing two cell populations that reside stably at the two ends of the spectrum, i.e., in the E and in the M state. Hence, residence in a specific intermediate state along the E-M spectrum rather than phenotypic plasticity appears critical to the expression of tumor-initiating capacity. Acquisition of this E/M hybrid state is facilitated by the differential expression of EMT-inducing transcription factors (EMT-TFs) and is accompanied by the expression of adult stem cell programs, notably, active canonical Wnt signaling. Furthermore, transition from the highly tumorigenic E/M state to a fully mesenchymal phenotype, achieved by constitutive ectopic expression of Zeb1, is sufficient to drive cells out of the E/M hybrid state into a highly mesenchymal state, which is accompanied by a substantial loss of tumorigenicity and a switch from canonical to noncanonical Wnt signaling. Identifying the gatekeepers of the various phenotypic states arrayed along the E-M spectrum is likely to prove useful in developing therapeutic approaches that operate by shifting cancer cells between distinct states along this spectrum.

https://www.pnas.org/content/pnas/116/15/7353.full.pdf

Acquisition of a hybrid E/M state is essential for tumorigenicity of basal breast cancer cells.

Are cancer cells really softer than normal cells

Developmental signaling pathways control a vast array of biological processes during embryogenesis and in adult life. The WNT pathway was discovered simultaneously in cancer and development. Recent advances have expanded the role of WNT to a wide range of pathologies in humans. Here, we discuss the WNT pathway and its role in human disease and some of the advances in WNT-related treatments.

/pdf/wnt-signaling-in-disease-y39lz650gd.pdf

WNT Signaling in Disease

From 1962 to 1989, 67 patients with stage I epithelial ovarian cancer were treated in our hospital. They were divided into three groups according to the time period of treatment. Thirteen patients treated in the 1960s were in group 1, 23 in the 1970s in group 2, and 31 in 1980s in group 3. There were no other significant differences other than the adjuvant chemotherapy in the three groups. In this study, the 5-year survival rate was 46% in group 1 (1962-1969), 82% in group 2 (1970-1979), and 97% in group 3 (1980-1989). The prognosis was improved significantly from 1960s to 1970s (P < 0.005), as well as from 1970s to 1980s (P < 0.05). Multivariate analysis indicated adjuvant chemotherapy (P < 0.01), stage (P < 0.01), and histological grade (P < 0.05) as having independent prognostic effects. Patients with more than 4 courses of combination chemotherapy, stage Ia, grade I and grade II had a better survival rate. The chemotherapy, complete surgical staging and preservation of fertility in surgical treatment of stage I epithelial ovarian cancer were also discussed.

Prognostic factors in patients with stage I epithelial ovarian cancer

Wnt5a is involved in activating several non-canonical WNT signaling pathways, through binding to different members of the Frizzled- and Ror-family receptors. Wnt5a signaling is critical for regulating normal developmental processes, including proliferation, differentiation, migration, adhesion and polarity. However, the aberrant activation or inhibition of Wnt5a signaling is emerging as an important event in cancer progression, exerting both oncogenic and tumor suppressive effects. Recent studies show the involvement of Wnt5a in regulating cancer cell invasion, metastasis, metabolism and inflammation. In this article, we review findings regarding the molecular mechanisms and roles of Wnt5a signaling in various cancer types, and highlight Wnt5a in ovarian cancer.

https://www.mdpi.com/2072-6694/8/9/79/pdf

Wnt5a Signaling in Cancer

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy. EOC dissemination is predominantly via direct extension of cells and multicellular aggregates (MCAs) into the peritoneal cavity, which adhere to and induce retraction of peritoneal mesothelium and proliferate in the submesothelial matrix to generate metastatic lesions. Metastasis is facilitated by the accumulation of malignant ascites (500 ml to >2 l), resulting in physical discomfort and abdominal distension, and leading to poor prognosis. Although intraperitoneal fluid pressure is normally subatmospheric, an average intraperitoneal pressure of 30 cmH2O (22.1 mmHg) has been reported in women with EOC. In this study, to enable experimental evaluation of the impact of high intraperitoneal pressure on EOC progression, two new in vitro model systems were developed. Initial experiments evaluated EOC MCAs in pressure vessels connected to an Instron to apply short-term compressive force. A Flexcell Compression Plus system was then used to enable longer-term compression of MCAs in custom-designed hydrogel carriers. Results show changes in the expression of genes related to epithelial-mesenchymal transition as well as altered dispersal of compressed MCAs on collagen gels. These new model systems have utility for future analyses of compression-induced mechanotransduction and the resulting impact on cellular responses related to intraperitoneal metastatic dissemination. This article has an associated First Person interview with the first authors of the paper.

/pdf/modeling-the-effect-of-ascites-induced-compression-on-39ynhvce3i.pdf

Rebecca B. Wates

Papers

Wnt5a Signaling in Cancer

Modeling the effect of ascites-induced compression on ovarian cancer multicellular aggregates.

Modeling the effect of ascites-induced compression on ovarian cancer multicellular aggregates