Epithelial-mesenchymal Transition In Cancer Metastasis Research Articles

Chemokine/GPCR Signaling-Mediated EMT in Cancer Metastasis.

Metastasis, the chief cause of cancer-related deaths, is associated with epithelial-mesenchymal transition (EMT). In the tumor microenvironment, EMT can be triggered by chemokine/G-protein-coupled receptor (GPCR) signaling, which is closely associated with tumor progression. However, the functional links between chemokine/GPCR signaling-mediated EMT and metastasis remain unclear. Herein, we summarized the mechanisms of chemokine/GPCR signaling-mediated EMT with an insight into facilitating metastasis and clarified the role of chemokine in the local invasion, intravasation, circulation, extravasation, and colonization, respectively. Moreover, several potential pathways that might contribute to EMT based on the latest studies on GPCR signaling were proposed, including signaling mediated by G protein, β-arrestin, intracellular, dimerization activation, and transactivation. However, there is still limited evidence to support the EMT programme functional contribution to metastasis, which keeps a key question still open whether we should target EMT programme of cancer cells. Answers to that question might help develop an anticancer strategy or guide new directions for anticancer metastasis therapy.

COMP Gene Coexpresses With EMT Genes and Is Associated With Poor Survival in Colon Cancer Patients

BackgroundAbout 1.2 million new cases of colon cancer (CC) and 0.6 million deaths are reported every year, establishing CC as an important contributor to worldwide cancer morbidity and mortality. Although the overall incidence and mortality of CC have declined over the past 3 decades, the number of early-onset colon cancer ([EOCC], patients <50 y old) continues to rise alarmingly. These young patients are often diagnosed at a more advanced stage and tend to have poor survival. Our recently published data showed that the cartilage oligomeric matrix protein (COMP) is overexpressed in early-onset colon cancer patients. COMP is also reported in several cancers to coexpress with epithelial-mesenchymal transition (EMT) transcription factors. Given the role of EMT in cancer metastasis and cell invasion, we assessed the correlation between COMP gene expression and EMT gene expression in CC, and COMP's relationship to patient survival. MethodsmRNA expression of COMP was compared to that of EMT markers using the UCSC Cancer Genomics Browser. Survival analysis was performed using the UCSC Xena Browser for cancer genomics. ResultsExpression analysis revealed coexpression of COMP with the EMT markers CDH2, FN1, VIM, TWIST1, TWIST2, SNAI1, SNAI2, ZEB1, ZEB2, POSTN, MMP2, MMP9, and COL1A1. Samples that were more mesenchymal had higher expression levels of COMP and EMT markers, thus suggesting a potential role of COMP in EMT. Patients with increased COMP expression presented with poorer overall survival compared to patients with no change or reduced COMP expression (P = 0.02). ConclusionsThese findings reveal COMP as a potential biomarker for CC especially in more aggressive CC and CC in young patients, with a likely role in EMT during tumor metastasis and invasion, and a contributing factor to patient survival.

Epithelial-mesenchymal transition in cancer metastasis through the lymphatic system.

It was already in the 18th century when the French surgeon LeDran first noted that breast cancer patients with spread of tumor cells to their axillary lymph nodes had a drastically worse prognosis than patients without spread (LeDran et al., 1752). Since then, metastatic spread of cancer cells to regional lymph nodes has been established as the most important prognostic factor in many types of cancer (Carter et al., 1989; Elston and Ellis, 1991). However, despite its clinical importance, lymph metastasis remains an underexplored area of tumor biology. Fundamental questions, such as when, how, and perhaps most importantly, why tumor cells disseminate through the lymphatic system, remain largely unanswered. Accordingly, no treatment strategies exist that specifically target lymph metastasis. The identification of epithelial‐mesenchymal transition (EMT) as a mechanism, which allows cancer cells to dedifferentiate and acquire enhanced migratory and invasive properties, has been a game changer in cancer research. Conceptually, EMT provides an explanation for why epithelial cancers with poor differentiation status are generally more aggressive and prone to metastasize than more differentiated cancers. Inflammatory cytokines, such as TGF‐β, which are produced and secreted by tumor‐infiltrating immune cells, are potent inducers of EMT. Thus, reactivation of EMT also links cancer‐related inflammation to invasive and metastatic disease. Recently, we found that breast cancer cells undergoing TGF‐β‐induced EMT acquire properties of immune cells allowing them to disseminate in a targeted fashion through the lymphatic system similar to activated dendritic cells during inflammation. Here, we review our current understanding of the mechanisms by which cancer cells spread through the lymphatic system and the links to inflammation and the immune system. We also emphasize how imaging techniques have the potential to further expand our knowledge of the mechanisms of lymph metastasis, and how lymph nodes serve as an interface between cancer and the immune system.

Revisiting epithelial-mesenchymal transition in cancer metastasis: the connection between epithelial plasticity and stemness.

Epithelial‐mesenchymal transition (EMT) is an important process in embryonic development, fibrosis, and cancer metastasis. During cancer progression, the activation of EMT permits cancer cells to acquire migratory, invasive, and stem‐like properties. A growing body of evidence supports the critical link between EMT and cancer stemness. However, contradictory results have indicated that the inhibition of EMT also promotes cancer stemness, and that mesenchymal‐epithelial transition, the reverse process of EMT, is associated with the tumor‐initiating ability required for metastatic colonization. The concept of ‘intermediate‐state EMT’ provides a possible explanation for this conflicting evidence. In addition, recent studies have indicated that the appearance of ‘hybrid’ epithelial‐mesenchymal cells is favorable for the establishment of metastasis. In summary, dynamic changes or plasticity between the epithelial and the mesenchymal states rather than a fixed phenotype is more likely to occur in tumors in the clinical setting. Further studies aimed at validating and consolidating the concept of intermediate‐state EMT and hybrid tumors are needed for the establishment of a comprehensive profile of cancer metastasis.

Epithelial-mesenchymal transition mediates anoikis resistance and enhances invasion in pleural effusion-derived human lung cancer cells

Epithelial-mesenchymal transition (EMT) is implicated in cancer pathological processes, particularly cancer invasion and metastasis. The present study demonstrated that EMT was critical for the metastasic potential of lung cancer cells isolated from a patient. P1 primary lung cancer cells were found to exhibit increased anoikis resistance compared with established A549, H23 and H460 lung cancer cells. Results of migration and invasion assays revealed that the invasion capability of P1 and A549 cells was higher than that of H23 and H460 cells. However, the migration of P1 cells was similar to that of H23 and H460 cells while A549 demonstrated a superior migrating ability. Western blot analysis indicated that while E-cadherin levels in all lung cancer cells were identified as comparable, P1 cells expressed the highest levels of N-cadherin. In the present study, detachment of cells was demonstrated for the first time to stimulate further transition of E-cadherin to N-cadherin. In addition, this obervation was more pronounced in P1 cells. These observations highlight the importance of EMT in cancer metastasis. In order to study the effect of ethnicity on cancer cell behavior, in the future a large number of Thai patient-derived cell lines must be analyzed.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Detection of Differentially Expressed Basal Cell Proteins by Mass Spectrometry

The ability of cells to modulate interactions with each other and the substrate is essential for epithelial tissue remodeling during processes such as wound healing and tumor progression. However, despite strides made in the field of proteomics, proteins involved in adhesion have been difficult to study. Here, we report a method for the enrichment and analysis of proteins associated with the basal surface of the cell and its underlying matrix. The enrichment involves deroofing the cells with 20 mM ammonium hydroxide and the removal of cytosolic and organellar proteins by stringent water wash. Proteomic profiling was achieved by LC-FTMS, which allowed comparison of differentially expressed or shared proteins under different cell states. First, we analyzed and compared the basal cell components of mouse keratinocytes lacking the cell-cell junction molecule plakoglobin with their control counterparts. Changes in the molecules involved in motility and invasion were detected in plakoglobin-deficient cells, including decreased detection of fibronectin, integrin beta(4), and FAT tumor suppressor. Second, we assessed the differences in basal cell components between two human oral squamous cell carcinoma lines originating from different sites in the oral cavity (CAL33 and UM-SCC-1). The data show differences between the two lines in the type and abundance of proteins specific to cell adhesion, migration, and angiogenesis. Therefore, the method described here has the potential to serve as a platform to assess proteomic changes in basal cell components including extracellular and adhesion-specific proteins involved in wound healing, cancer, and chronic and acquired adhesion-related disorders.

Epithelial-Mesenchymal Transition and Cell Cooperativity in Metastasis

The role of epithelial-mesenchymal transition (EMT) in metastasis remains controversial. EMT has been postulated as an absolute requirement for tumor invasion and metastasis. Three different models including incomplete EMT, mesenchymal-epithelial transition (MET), and collective migration have been proposed for the role of EMT in cancer invasion and metastasis. However, skepticism remains about whether EMT truly occurs during cancer progression, and if it does, whether it plays an indispensible role in metastasis. Our recent findings suggest that EMT cells are responsible for degrading the surrounding matrix to enable invasion and intravasation of both EMT and non-EMT cells. Only non-EMT cells that have entered the blood stream are able to re-establish colonies in the secondary sites. Here, we discuss an alternative model for the role of EMT in cancer metastasis in which EMT and non-EMT cells cooperate to complete the entire process of spontaneous metastasis.