Epithelial-to-Mesenchymal Transition (EMT) has been shown to be crucial in tumorigenesis where the EMT program enhances metastasis, chemoresistance and tumor stemness. Due to its emerging role as a pivotal driver of tumorigenesis, targeting EMT is of great therapeutic interest in counteracting metastasis and chemoresistance in cancer patients. The hallmark of EMT is the upregulation of N-cadherin followed by the downregulation of E-cadherin, and this process is regulated by a complex network of signaling pathways and transcription factors. In this review, we summarized the recent understanding of the roles of E- and N-cadherins in cancer invasion and metastasis as well as the crosstalk with other signaling pathways involved in EMT. We also highlighted a few natural compounds with potential anti-EMT property and outlined the future directions in the development of novel intervention in human cancer treatments. We have reviewed 287 published papers related to this topic and identified some of the challenges faced in translating the discovery work from bench to bedside.

https://www.mdpi.com/2073-4409/8/10/1118/pdf

The E-Cadherin and N-Cadherin Switch in Epithelial-to-Mesenchymal Transition: Signaling, Therapeutic Implications, and Challenges.

China is one of the countries with the highest incidence of gastric cancer. There are differences in epidemiological characteristics, clinicopathological features, tumor biological characteristics, treatment patterns, and drug selection between gastric cancer patients from the Eastern and Western countries. Non-Chinese guidelines cannot specifically reflect the diagnosis and treatment characteristics for the Chinese gastric cancer patients. The Chinese Society of Clinical Oncology (CSCO) arranged for a panel of senior experts specializing in all sub-specialties of gastric cancer to compile, discuss, and revise the guidelines on the diagnosis and treatment of gastric cancer based on the findings of evidence-based medicine in China and abroad. By referring to the opinions of industry experts, taking into account of regional differences, giving full consideration to the accessibility of diagnosis and treatment resources, these experts have conducted experts’ consensus judgement on relevant evidence and made various grades of recommendations for the clinical diagnosis and treatment of gastric cancer to reflect the value of cancer treatment and meeting health economic indexes. This guideline uses tables and is complemented by explanatory and descriptive notes covering the diagnosis, comprehensive treatment, and follow-up visits for gastric cancer.

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The Chinese Society of Clinical Oncology (CSCO): clinical guidelines for the diagnosis and treatment of gastric cancer.

Although many kinds of therapies are applied in the clinic, drug-resistance is a major and unavoidable problem. Another disturbing statistic is the limited number of drug targets, which are presently only 20–25% of all protein targets that are currently being studied. Moreover, the focus of current explorations of targets are their enzymatic functions, which ignores the functions from their scaffold moiety. As a promising and appealing technology, PROteolysis TArgeting Chimeras (PROTACs) have attracted great attention both from academia and industry for finding available approaches to solve the above problems. PROTACs regulate protein function by degrading target proteins instead of inhibiting them, providing more sensitivity to drug-resistant targets and a greater chance to affect the nonenzymatic functions. PROTACs have been proven to show better selectivity compared to classic inhibitors. PROTACs can be described as a chemical knockdown approach with rapidity and reversibility, which presents new and different biology compared to other gene editing tools by avoiding misinterpretations that arise from potential genetic compensation and/or spontaneous mutations. PRTOACs have been widely explored throughout the world and have outperformed not only in cancer diseases, but also in immune disorders, viral infections and neurodegenerative diseases. Although PROTACs present a very promising and powerful approach for crossing the hurdles of present drug discovery and tool development in biology, more efforts are needed to gain to get deeper insight into the efficacy and safety of PROTACs in the clinic. More target binders and more E3 ligases applicable for developing PROTACs are waiting for exploration.

PROTACs: great opportunities for academia and industry.

Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling mediates almost all immune regulatory processes, including those that are involved in tumor cell recognition and tumor-driven immune escape. Antitumor immune responses are largely driven by STAT1 and STAT2 induction of type I and II interferons (IFNs) and the downstream programs IFNs potentiate. Conversely, STAT3 has been widely linked to cancer cell survival, immunosuppression, and sustained inflammation in the tumor microenvironment. The discovery of JAK-STAT cross-regulatory mechanisms, post-translational control, and non-canonical signal transduction has added a new level of complexity to JAK-STAT governance over tumor initiation and progression. Endeavors to better understand the vast effects of JAK-STAT signaling on antitumor immunity have unearthed a wide range of targets, including oncogenes, miRNAs, and other co-regulatory factors, which direct specific phenotypical outcomes subsequent to JAK-STAT stimulation. Yet, the rapidly expanding field of therapeutic developments aimed to resolve JAK-STAT aberrations commonly reported in a multitude of cancers has been marred by off-target effects. Here, we discuss JAK-STAT biology in the context of immunity and cancer, the consequences of pathway perturbations and current therapeutic interventions, to provide insight and consideration for future targeting innovations.

JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

Targeting DNA Methylation and EZH2 Activity to Overcome Melanoma Resistance to Immunotherapy

Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and a catalytic component of PRC2, catalyzes tri-methylation of histone H3 at Lys 27 (H3K27me3) to regulate gene expression through epigenetic machinery. EZH2 also functions both as a transcriptional suppressor and a transcriptional co-activator, depending on H3K27me3 or not and on the different cellular contexts. Unsurprisingly, numerous studies have highlighted the role of EZH2 in cancer development and progression. Through modulating critical gene expression, EZH2 promotes cell survival, proliferation, epithelial to mesenchymal, invasion, and drug resistance of cancer cells. The tumor suppressive effects of EZH2 are also identified. What is more, EZH2 has decisive roles in immune cells (for example, T cells, NK cells, dendritic cells and macrophages), which are essential components in tumor microenvironment. In this review, we aim to discuss the molecular functions of EZH2, highlight recent findings regarding the physiological functions and related regulation of EZH2 in cancer pathogenesis. Furthermore, we summarized and updated the emerging roles of EZH2 in tumor immunity, and current pre-clinical and clinical trials of EZH2 inhibitors in cancer therapy.

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Epigenetic regulation of cancer progression by EZH2: from biological insights to therapeutic potential.

Purpose
Gastric cancer with para-aortic lymph node (PAN) involvement is regarded as advanced disease, and only chemotherapy is recommended from the guidelines. In unresectable cases, neoadjuvant chemotherapy could prolong survival if conversion to resectability could be achieved.

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A phase II trial of Xeloda and oxaliplatin (XELOX) neo-adjuvant chemotherapy followed by surgery for advanced gastric cancer patients with para-aortic lymph node metastasis

The reported incidence of synchronous multiple primary cancer (SMPC) is rare, and it is even less common to observe synchronous solid tumor with a hematological malignancy. We report five cases of solid tumor presented synchronously with hematological malignancy, all observed within a 2 year period at the oncology department of a university hospital in Shanghai, China. These individual cases included lung adenocarcinoma with chronic myelogenous leukemia, colon cancer with solitary plasmocytoma, gastric adenocarcinoma with diffuse large B cell non-Hodgkin's lymphoma, lung adenocarcinoma with multiple myeloma, and colon cancer with diffuse large B cell non-Hodgkin's lymphoma. It is challenging to therapeutically control the biological behavior of concurrent multiple primary tumors, and there is no standard treatment for such rare conditions. In this paper we discuss these five cases of SMPC and their treatments.

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Five cases report of solid tumor synchronously with hematologic malignancy.

Paclitaxel-induced peripheral neuropathy is a common reason for dose reduction or early cessation of therapy. Nab-paclitaxel was developed to provide additional clinical benefits and overcome the safety drawbacks of solvent-based paclitaxel. However, the incidence of peripheral neuropathy induced by nab-paclitaxel was reported higher than solvent-based paclitaxel but evidence remains inconsistent. Therefore, we conducted a meta-analysis to compare the incidence and severity of peripheral neuropathy between nab-paclitaxel and solvent-based paclitaxel mono-chemotherapy. In total, 24 articles were included in this meta-analysis. Results revealed the incidence of peripheral neuropathy induced by nab-paclitaxel was higher than solvent-based paclitaxel. The dosage and assessment method could influence the comparison of the incidence and severity of peripheral neuropathy between nab-paclitaxel and solvent-based paclitaxel. Current evidence suggests the incidence of peripheral neuropathy induced by nab-paclitaxel was higher than solvent-based paclitaxel among cancer patients received mono-chemotherapy. When received nab-paclitaxel, more attention should be paid to peripheral neuropathy.

Does nab-paclitaxel have a higher incidence of peripheral neuropathy than solvent-based paclitaxel? Evidence from a systematic review and meta-analysis.

The aim of this study was to evaluate the efficacy and toxicity of low dose of docetaxel in combination with standard dose of S-1 for patients with advanced or recurrent gastric cancer and to investigate whether the protein expression level of dihydropyrimidine dehydrogenase is a predictive factor of toxicities or responses. Between March 2010 and December 2011, 61 patients from the Department of Medical Oncology of Shanghai Zhong Shan Hospital, Fudan University, were enrolled in the study. Patients with advanced or recurrent gastric adenocarcinoma were treated with docetaxel of 40 mg/m2 intravenously on day 1 and S-1 of 80 mg/m2 orally on days 1–14 every 3 weeks as first-line chemotherapy. The chemotherapeutic effects were evaluated following every 3 cycles of chemotherapy using the Response Evaluation Criteria In Solid Tumors (RECIST). The serum of peripheral blood was obtained at the start of the study and at each evaluation point to analyze the protein expression level of DPD, which was estimated using an enzyme-linked immunosorbent assay. All the patients were followed-up until the time of progression, death, or the censor time, to calculate progression-free survival and overall survival (OS) time. In total, 61 patients [median age 60 years (range 28–76 years)] received a total of 318 treatment cycles [median 5 (range 2–9)], and 94 cycles of single S-1 maintenance treatment. One complete response (CR) and 25 partial responses (PR) were observed, with an overall response rate of 42.6 %. A total of 29 patients (47.5 %) had stable disease (SD) and 6 patients (9.8 %) had progressive disease (PD). The disease control rate (DCR, CR + PR + SD) was 90.2 %. Median overall survival was 13.0 months [95 % confidence interval (CI) 10.76–15.24 months], and median PFS was 6.0 months (95 % CI 4.61–7.39 months). Progression-free survival was far longer in peritoneal metastatic patients than that in patients with other metastases (7.3 ± 2. 6 vs. 5.4 ± 2.8 months; P < 0.05); however, this was not the case for OS. Grade 3–4 neutropenia was well controlled and grade 4 non-hematologic toxicities did not occur. Baseline expression level of DPD was not associated with efficacy. Lower expression level of DPD was correlated with high grade of toxicities (P < 0.05). This combination of standard dose of S-1 and low dose of docetaxel is effective and well tolerated in patients with advanced or recurrent gastric cancer. Peritoneal metastasis is treated more effectively by this regimen than other forms of metastases. Baseline DPD expression level in the serum is associated with toxicity, but not tumor response.

Combination of low-dose docetaxel and standard-dose S-1 for the treatment of advanced gastric cancer: efficacy, toxicity, and potential predictive factor.

Yi Feng

Papers

Epigenetic regulation of cancer progression by EZH2: from biological insights to therapeutic potential.

A phase II trial of Xeloda and oxaliplatin (XELOX) neo-adjuvant chemotherapy followed by surgery for advanced gastric cancer patients with para-aortic lymph node metastasis

Five cases report of solid tumor synchronously with hematologic malignancy.

Does nab-paclitaxel have a higher incidence of peripheral neuropathy than solvent-based paclitaxel? Evidence from a systematic review and meta-analysis.

Combination of low-dose docetaxel and standard-dose S-1 for the treatment of advanced gastric cancer: efficacy, toxicity, and potential predictive factor.