Collection on reports of molecules linked to epithelial-mesenchymal transition in the process of treating metastasizing cancer: a narrative review

Introduction

Cancer metastasis, which is the process by which precancerous lesions spread from primary tumors to distal organs, is the leading contributing factor to cancer lethality (1). Over 90% of cancer-related deaths are caused by distant metastasis. Recently, epithelial-mesenchymal transition (EMT)-targeted treatment has become a popular area of research. The metastasis process is reported to be influenced and regulated by various mechanisms, including EMT. EMT can be targeted to prevent cancer metastasis in the early stage or eliminate metastatic cells in the advanced stage. We present the following article in accordance with the Narrative Review reporting checklist (available at http://dx.doi.org/10.21037/atm-20-7002).

Introduction: metastasis in cancer

Cancers share the same basic mechanism of cancer metastasis. In this paper, we examine cancer metastasis in the condition of adrenal cancer.

Mechanisms of adrenal metastasis in cancer

In 2011, Valastyan et al. reviewed the “seed and soil” hypothesis and put forward the invasion-metastasis cascade (2) whereby cancer cells detach from primary tumors and then move to distant organ sites via the vasculature. Cancer cells successfully extravasate into distant tissues through their parenchyma. The blood supply in the adrenal sinuses is abundant, and the reticular capillary network endothelium is beneficial to the adhesion of cancer cells. After blood vessels have formed, cancer cells proliferate to form metastasis.

Venous, arterial, and blood capillary systems are the principal processes of adrenal metastasis, and early lung cancer cells are likely to metastasize to the ipsilateral adrenal gland via the lymphatic system. The invasion of cancer cells in the bone stimulates the self-renewal capacity of tumor-initiating cells (TICs). The transcription factors (TFs), such as Twist, Snail, and c-Ets1, promote EMT and facilitate TICs. These factors boost early invasion and have self-renewal properties (3).

Detection of adrenal metastasis

The main methods for diagnosing metastases are computerized tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) (4). Usually, detection methods include both a CT and a B-ultrasonic examination, both of which are ultrasound imaging methods. The B-ultrasonic examination is convenient and acceptable. The negative sonogram is characterized by uneven echo distribution in the mass and is usually hypoechoic. However, it is difficult to determine whether a cancer is primary or metastatic due to the similarity of the results and the internal echo's low sensitivity. CT can be used to conduct a further examination. Small lesions that the B-ultrasound can barely detect can be found through CT, the localizations of which are more accurate than those of the B-ultrasound. In a CT examination, the results of a metastatic tumor and non-functional adenoma are significantly different, but it is difficult to differentiate them from non-functional sebaceous adenocarcinoma and pheochromocytoma. If necessary, a CT and B-ultrasound biopsy can be used for a histological examination, but it could induce traumas (5). PET scanning can image a primary tumor, which is useful for detecting an unknown primary cancer and detecting other small metastases. PET scans are sensitive and specific (6).

Treatment of metastasis

Treatments of metastases (Table 1) include surgical resection, interventional therapy, local ablation, immunotherapy, radiotherapy, and chemotherapy (10).

Table 1 Therapies for metastases
Full table

EMT-targeted treatment—a promising treatment

Introduction of EMT

EMT is a biological process whereby a special process turns epithelial cells into cells with an interstitial phenotype. It plays a vital role in developing embryonic tissue reconstruction, cancer metastasis, chronic inflammation, and multiple fibrosis diseases. A decrease embodies it in cell adhesion molecules' expression, the morphological characteristics in mesenchymal cells, and the transition from keratin cytoskeleton into vimentin cytoskeleton (11). Many articles in different fields targeting different types of cancer have noted that some genes have a unique effect in the process in EMT, including those in the Snail family, Twist, and c-Ets1. Some of these produce direct changes in the EMT process, while others act by changing how deoxyribonucleic acid (DNA) and protein bind. Thus, understanding the mechanism of EMT provides insights into targeted treatments for cancer.

Involvement of EMT in cancer metastasis

As a result of EMT, cells show a loss of polarity, decreased adhesion, and enhanced migration, which are tumor cell characteristics. EMT has various molecular factors, phenotypic changes, and genetic changes in multi-step transmission (12). Conversely, metastatic lesions, such as cancer, cell proliferation, and proliferation, also require stroma to epithelial transition (13). In cancer, malignant epithelial cells acquire mesenchymal properties to promote migration, invasiveness, anti-apoptotic ability, and the production of extracellular matrix (ECM) components. Large amounts of genetic and epigenetic variation are also associated with type 3 EMT.

There is increasing evidence that micro ribonucleic acid (miRNA) is a key regulator of the EMT signaling pathway and TFs. Changes in miRNA expression affect the plan and metastasis of EMT. The regulation of miRNA expression in EMT has not yet been clearly identified; however, more and more signaling pathways and mechanisms have been explored and elucidated. The 3 encoding TFs of the Snail gene family (i.e., SNAI1, SNAI2, and SNAI3) perform unique functions. Their activation downregulates the expression of the epithelial gene and upregulates the expression of the mesenchymal gene. Various miRNAs regulate EMT by directly acting on the Snail family. Additionally, many genes promote or resist EMT through different targets and signaling pathways, affecting the migration and invasion of non-small-cell lung carcinoma (NSCLC) cells (14). For example, Snail is reported to promote EMT by activating transforming growth factor-beta (TGF-β), Smad, mitogen-activated protein kinase (MAPK), Wnt/βcatenin, PI3/AKT, etc.

Research progress in EMT

Gene and EMT

EMT is regulated by genes greatly and here are some of the genes (Table 2) that matter.

Table 2 Gene and EMT
Full table

miRNAs and EMT

Here we have listed some EMT-related miRNAs (Table 3).

Table 3 miRNAs and EMT
Full table

The main methods by which miRNAs regulate EMT processes target TFs and components with epithelial or mesenchymal characteristics. Three families of TFs primarily control EMT; that is, ZEB (ZEB1/ZEB2), the zinc finger Snail (Snail/Slug), and the basic helix-loop-helix (e.g., the Twist). To date, only a few studies have sought to examine the role of miRNAs in adrenal metastasis in lung cancer; however, similar research has shown that miRNAs have a controlling role in other kinds of cancer. Thus, we assumed that specific miRNAs would be found in adrenal metastasis and decided to make this the focus of our future research. The targeting of signaling pathways affected by miRNAs could help to define appropriate cancer treatments. Additionally, it could attenuate cancer progression in clinical treatments by preventing oncogenic miRNAs expression or by re-introducing miRNAs that can inhibit tumor metastasis (36).

Signaling pathways and EMT

In gene expression, signaling pathways (Table 4) in molecules function as connections and are synergistically involved in EMT.

Table 4 Signaling pathways and EMT
Full table

As the key point of invasion and metastasis, EMT remarkably influences the development of various cancers, including lung cancer (55). In gene expression, the hallmark of EMT is the loss of specific markers for epithelial cell (e.g., E-cadherin, cytokeratin, and ZO-1), the gain of specific markers for mesenchymal cells (e.g., N-cadherin, vimentin, and FSP1), the rebuild of actin cytoskeletal, and the presence of adhesion and polarity between cells. Signaling pathways in EMT function as inhibitors of epithelial cell markers and promotors of mesenchymal cell markers. Usually, many signaling pathways work together to induce EMT.

To suppress the EMT process, signaling pathways must be blocked to bring about inhibition and reverse the EMT process. Sotetsuflavone can reverse EMT by blocking PI3K/AKT and TNF-α/NF-κB pathways, thus inhibiting the migration and invasion of NSCLC cells (43). Glaucocalyxin A can inhibit EMT by blocking the TGF-β1/Smad2/3 signaling pathway, holding back the metastasis of cancer (56).

Cancer targeted therapy of EMT

We found numerous examples of and projects examining the targeted therapy of various kinds of cancer, many of which could be applied to targeted symptoms (Table 5). However, the mechanism of epigenetic therapy is still not thoroughly understood, and its use should be carefully evaluated. Additionally, EMT mechanisms broaden cancer therapies.

Table 5 Cancer targeted therapy of EMT
Full table

Prospects and challenges of EMT-targeted treatment

EMT is closely related to all aspects of tumor metastasis. As stated above, the design of a targeted intervention strategy for the key regulatory mechanism of EMT has recently become a popular area of research. One strategy to do this would be to block or reverse EMT, restoring epithelial cell features directly. However, research has shown that after the intervention of EMT, the same-time mesenchymal characteristics of cells in acquiring epithelial characteristics were often not fully reversed, and the reversal of EMT may promote the formation of large metastases (66). Under another strategy, the mesenchymal phenotype of metastatic tumor cells could be retained by a MET inhibitor to control metastasis progression (67). This strategy is promising, as it could convert invasive cancer cells into other types of cells to inhibit cancer metastasis (68). The potential value of EMT-targeted treatment for metastasis in cancer should be noted.

However, there are still many difficulties in this field. Extensive research needs to be conducted to identify the EMT mechanism. As the EMT mechanism is extremely complex, there is no reliable way to predict which key TF works in different tumors. Further, it is still unclear how TFs interact with each other in different tumor types to mediate EMT in tumor cells. Further, various intracellular and extracellular signaling pathways work together on tumor cells and activate the EMT process. However, it is still unknown how intracellular and extracellular signaling pathways regulate the EMT process in tumor cells.

It is also difficult to explore EMT-targeted treatment for a specific disease. EMT is known to be important in tumor cell metastasis; however, tumor metastasis is a multi-stage process in which EMT may play a different role. For example, due to the heterogeneity inherent in tumors, therapy for adrenal metastasis in lung cancer may differ. In clinical practice, we found that immunotherapy had a good therapeutic effect on all parts of patients’ bodies, except for the adrenal gland. The adrenal gland may have immune privilege, which adds to the difficulty of exploring EMT-targeted treatments for adrenal metastasis. Thus, it is necessary to explore the EMT mechanism by focusing on one specific disease, such as adrenal metastasis in lung cancer.

Methods

This paper sought to elucidate the role and therapeutic significance of EMT in metastatic tumors. Thus, we approached the article from two aspects. After gaining a specific understanding of the mechanism, we conducted in-depth research on the method and application of metastatic tumors and EMT. We then conducted further research on the related treatment of metastatic cancer by EMT in recent years.

First, “tumor metastasis” was used as the keyword to find relevant review articles to understand the familiar research methods and the difficulties of metastatic cancer. Also, secondary keywords (such as “detection” and “mechanism”) were added to gain a specific understanding of metastatic tumors. Then, starting from EMT, we searched for relevant literature to understand its mechanism, research methods, and relevant clinical applications. We then cross-checked the literature using “EMT” and “metastatic tumors” as bidirectional keywords. In our search, we found many current therapies for various types of cancer metastasis that are related to EMT. We found the basic research context and utilization means of EMT in tumor therapy by undertaking a year-by-year summary. According to the types of cancers, the differences among different cancers were analyzed, as were the different EMT therapy effects. Most of the relevant pieces of literature examined in this paper were retrieved from the Web of Science and China National Knowledge Internet. The above logic is the mainline supplemented by searching and summarizing, the paper-related extension as a supplement to complete the review’s writing.

Discussion

In this paper, we reorganized the literature about molecules linked to EMT in cancer metastasis. The studies examined in this review used cell experiments, animal experiments, biological information analysis technologies, and other reliable methods to explore cancer metastasis’s molecular mechanisms, which are based on related genes, miRNAs, proteins, and pathways. However, it should be noted that current treatments are still in their infancy, and an EMT-targeted treatment is still an ideal concept. Most of the research studies identified in this paper were limited to a single view and ignored any connection to genes, miRNAs, proteins, and biological function. However, a clear connection between microcosmic and macroscopic functions could be revealed to map the molecular changes to the corresponding changes in clinical symptoms. Further, the relationship among related genes should be explored to determine the holistic generality among them.

Despite its many challenges and difficulties, such as regulating EMT's multifactorial process, EMT-targeted treatment is a promising treatment for metastasis in cancer. Future research could eliminate these limitations and build a bridge between microcosmic and macroscopic functions, enabling metastasizing cancers to be more accurately detected and treated. With bioinformatic evidence, the study of the prognosis of cancer metastasis may be realized.

Conclusions

As we described in this paper, EMT appears to promote the malignancy and metastasis of epithelial tumors, including lung cancer. Many studies have shown that inhibiting EMT suppresses cancer metastasis, which appears to prove the correlation between EMT and cancer metastasis. Two promising strategies to prevent cancer metastasis have been put forward to block or reverse EMT in metastasizing cancers. Thus, EMT-targeted treatment is a novel and promising therapy in the treatment of cancer. However, there are still many difficulties in this field, including those related to its complexity and diversity. We are convinced that future research will clearly identify the mechanism of EMT in cancer metastasis and improve the EMT-targeted treatments that can be used to intervene in cancer metastasis.

Acknowledgments

Funding: This study was supported in part by a grant from the National Undergraduate Training Program for Innovation and Entrepreneurship, National Natural Science Foundation of China (81802255), Young Talents in Shanghai (2019QNBJ), ‘Dream Tutor’ Outstanding Young Talents Program (fkyq1901), Clinical Research Project of Shanghai Pulmonary Hospital (fk18005), Key Discipline in 2019 (oncology), Project of Shanghai Municipal Science and Technology Commission (Project of Municipal Science and Technology Commission), and Scientific research project of Shanghai Pulmonary Hospital (fkcx1903).

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at http://dx.doi.org/10.21037/atm-20-7002

Peer Review File: Available at http://dx.doi.org/10.21037/atm-20-7002

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-7002). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editors: L. Huleatt and J. Chapnick)