Chemokines and Their Receptors: Predictors of Therapeutic Potential in Tumor Microenvironment on Esophageal Cancer.

Esophageal carcinoma (ESCA) is an aggressive solid tumor. The 5-year survival rate for patients with ESCA is estimated to be less than 20%, mainly due to tumor invasion and metastasis. Therefore, it is urgent to improve early diagnostic tools and effective treatments for ESCA patients. Tumor microenvironment (TME) enhances the ability of tumor cells to proliferate, migrate, and escape from the immune system, thus promoting the occurrence and development of tumor. TME contains chemokines. Chemokines consist of four major families, which are mainly composed of CC and CXC families. The main purpose of this review is to understand the CC and CXC chemokines and their receptors in ESCA, to improve the understanding of tumorigenesis of ESCA and determine new biomarkers for the diagnosis and prognosis of ESCA. We reviewed the literature on CC and CXC chemokines and their receptors in ESCA identified by PubMed database. This article introduces the general structures and functions of CC, CXC chemokines and their receptors in TME, as well as their roles in the progress of ESCA. Chemokines are involved in the development of ESCA, such as cancer cell invasion, metastasis, angiogenesis, and radioresistance, and are key determinants of disease progression, which have a great impact on patient prognosis and treatment response. In addition, a full understanding of their mechanism of action is essential to further verify that these chemokines and their receptors may serve as biomarkers or therapeutic targets of ESCA.

Understanding PI3K/Akt/mTOR signaling in squamous cell carcinoma: mutated PIK3CA as an example.

Compared with those in adenocarcinoma, PIK3CA mutations are more common in squamous cell carcinoma (SCC), which arises from stratified squamous epithelia that are usually exposed to adverse environmental factors. Although hotspot mutations in exons 9 and 20 of PIK3CA, including E542K, E545K, H1047L and H1047R, are frequently encountered in the clinic, their clinicopathological meaning remains to be determined in the context of SCC. Considering that few reviews on PIK3CA mutations in SCC are available in the literature, we undertook this review to shed light on the clinical significance of PIK3CA mutations, mainly regarding the implications and ramifications of PIK3CA mutations in malignant cell behavior, prognosis, relapse or recurrence and chemo- or radioresistance of SCC. It should be noted that only those studies regarding SCC in which PIK3CA was mutated were cherry-picked, which fell within the scope of this review. However, the role of mutated PIK3CA in adenocarcinoma has not been discussed. In addition, mutations occurring in other main members of the PI3K-AKT-mTOR signaling pathway other than PIK3CA were also excluded.

In silico analyses of pan-squamous cell carcinoma unveiled the immunological implications of MRPL13, which had previously been under-recognized.

The involvement of the mitochondrial ribosomal protein 13 (MRPL13) gene in the development of adenocarcinoma has been previously reported. However, the clinicopathological significance of MRPL13 in squamous cell carcinoma (SCC) remains poorly understood. To gain insight into the clinicopathological and immunological implications of MRPL13 expression in SCC, we conducted a bioinformatic analysis utilizing various available databases, including TIMER 2.0, Xiantao academic tool and TISIDB, attempting to evaluate the abnormal expression, prognosis and immunological correlation of MRPL13 in the pan-SCC setting. Subsequently, we conducted experimental verification using an esophageal squamous cell carcinoma (ESCC) tissue array subjected to multiplexed immunofluorescent (mIF) staining. The ESCC tissue array we used consists of 93 dots of ESCC and 86 dots of matched adjacent normal tissues (ANT). Data from in silico analyses showed that MRPL13 mRNA is significantly up-regulated and correlated with infiltration of CD8+ T cells in pan-SCC. However, in silico analyses did not support the prognostic role of MRPL13 in SCC. Consistently, data from the ESCC tissue array showed that MRPL13 was remarkably elevated in ESCC tissues relative to ANT in stroma, which was controlled by pan-cytokeratin (pan-CK) staining. In the epithelia, no significant difference was identified between ESCC and ANT. Furthermore, MRPL13 expression markedly correlated with the infiltration of CD8+ T cells in the stromal region but not in the epithelial region. Prognostically, no significant association was observed between MRPL13 expression and overall survival, regardless of epithelial or stromal section. Through these pan-SCC analyses, we have expanded the understanding of MRPL13 previously reported, in particular, underscoring the immunological involvement of MRPL13 in the tumor microenvironment of SCC that has been under-recognized before, suggesting that MRPL13 may regulate the infiltration of CD8+ T cells into the SCC microenvironment.

Positioning determines function: Wandering PKM2 performs different roles in tumor cells.

Short for pyruvate kinase M2 subtype, PKM2 can be said of all-round player that is notoriously known for its metabolic involvement in glycolysis. Holding a dural role as a metabolic or non-metabolic (kinase) enzyme, PKM2 has drawn extensive attention over its biological roles implicated in tumor cells, including proliferation, migration, invasion, metabolism, and so on. wandering PKM2 can be transboundary both intracellularly and extracellularly. Specifically, PKM2 can be nuclear, cytoplasmic, mitochondrial, exosomal, or even circulate within the body. Importantly, PKM2 can function as an RNA-binding protein (RBP) to self-support its metabolic function. Despite extensive investigations or reviews available surrounding the biological roles of PKM2 from different angles in tumor cells, little has been described regarding some novel role of PKM2 that has been recently found, including, for example, acting as RNA-binding protein, protection of Golgi apparatus, and remodeling of microenvironment, and so forth. Given these findings, in this review, we summarize the recent advancements made in PKM2 research, mainly from non-metabolic respects. By the way, PKM1, another paralog of PKM2, seems to have been overlooked or under-investigated since its discovery. Some recent discoveries made about PKM1 are also preliminarily mentioned and discussed.

miR-133b Promotes Esophageal Squamous Cell Carcinoma Metastasis.

Background: Evaluation of biological changes at the molecular level has important clinical implications for improving the survival rate of esophageal squamous cell carcinoma (ESCC). Therefore, we plan to analyze and elucidate the expression of microRNA-133b (miR-133b), M2 pyruvate kinase (PKM2), and signal transducer and activator of transcription 3 (STAT3) in ESCC and their associated clinicopathological significance. Methods: The 72 patients with ESCC were selected as the experimental study group. Normal adjacent tissues (NAT) were matched as the control group. In this study, in situ hybridization was used to detect the expression of miR-133b in ESCC, and tissue expressions of PKM2 and STAT3 were detected by immunohistochemistry, and literature review was conducted. Results: Studies had shown that the positive expression of miR-133b in NAT was significantly higher than that in ESCC (χ2 = 9.007, P = .003). PKM2 and STAT3 in ESCC had a significantly higher positive expression levels than those of NAT (χ2 = 56.523, P = .000; χ2 = 72.939, P = .000). From correlation analysis, there was a negative correlation between miR-133b and PKM2(r = -0.515, P < .001), a negative correlation between miR-133b and STAT3(r = -0.314, P = .007), and a positive correlation between PKM2 and STAT3(r = 0.771, P < .001). Conclusions: In ESCC, our study demonstrated that downregulation of miR-133b and upregulation of PKM2 and STAT3. We predict that miR-133b may inhibit the STAT3 pathway by downregulating PKM2.

SLC1A5, unrelated to prognosis, was associated with CD8+ T-cell exclusion in the tumor microenvironment of squamous cell carcinoma.

SLC1A5, short for solute carrier family 1 member 5, is a neutral amino acid transporter whose expression has been reported to be upregulated in various cancers, including esophageal squamous cell carcinoma (ESCC). Despite this, little has been described regarding the immunological involvement of SLC1A5 expression in the tumor microenvironment of ESCC. Given this, we adopted in silico analyses together with a wet lab strategy to investigate the prognostic and clinicopathological meaning of SLC1A5 expression in ESCC. In silico analyses of SLC1A5 expression data available from The Cancer Genome Atlas (TCGA) database revealed that SLC1A5 expression was unrelated to the prognosis of ESCC, which holds true when extended to other types of squamous cell carcinoma (SCC), including head and neck squamous cell carcinoma (HNSC) and lung squamous cell carcinoma (LUSC). Further analyses revealed that SLC1A5 expression correlated markedly with the infiltration density of effector CD8+ T cells in ESCC, and the same was true for HNSC and LUSC when extrapolated. As experimental confirmation, multiplexed immunofluorescent staining was undertaken to verify the correlation between SLC1A5 expression and infiltration of CD8+ T cells in a tissue microarray prepared from ESCC and matched normal control tissues. Our data confirmed that SLC1A5 expression was not associated with prognosis but was associated with the exclusion of CD8+ T cells. Taken together, all the data we curated strongly support the notion that SLC1A5 expression is associated with CD8+ T-cell exclusion in the tumor microenvironment of SCC.

Small Tweaks, Major Changes: Post-Translational Modifications That Occur within M2 Macrophages in the Tumor Microenvironment.

The majority of proteins are subjected to post-translational modifications (PTMs), regardless of whether they occur in or after biosynthesis of the protein. Capable of altering the physical and chemical properties and functions of proteins, PTMs are thus crucial. By fostering the proliferation, migration, and invasion of cancer cells with which they communicate in the tumor microenvironment (TME), M2 macrophages have emerged as key cellular players in the TME. Furthermore, growing evidence illustrates that PTMs can occur in M2 macrophages as well, possibly participating in molding the multifaceted characteristics and physiological behaviors in the TME. Hence, there is a need to review the PTMs that have been reported to occur within M2 macrophages. Although there are several reviews available regarding the roles of M2 macrophages, the majority of these reviews overlooked PTMs occurring within M2 macrophages. Considering this, in this review, we provide a review focusing on the advancement of PTMs that have been reported to take place within M2 macrophages, mainly in the TME, to better understand the performance of M2 macrophages in the tumor microenvironment. Incidentally, we also briefly cover the advances in developing inhibitors that target PTMs and the application of artificial intelligence (AI) in the prediction and analysis of PTMs at the end of the review.

Proteomic profiling of plasma exosomes reveals CD82 involvement in the development of esophageal squamous cell carcinoma.

The Xinjiang Uygur autonomous region has a high incidence of esophageal cancer. For the early diagnosis of patients with esophageal squamous cell carcinoma (ESCC), exosomes were isolated and quantified by liquid chromatography tandem mass spectrometry ((LC-MS/MS) with data independent acquisition (DIA) from the peripheral blood of patients with benign esophageal disease (BED), esophageal intraepithelial neoplasia (EIN) and ESCC. A total of 1117 proteins were identified in the above 9 samples. The proteomic results showed that the quantity of CD82 in exosomes of EIN was significantly higher than that in patients with BED and ESCC. Meanwhile, our ELISA test verified our proteomic results. In addition, the immunohistochemical results showed high CD82 expression in adjacent normal tissues and low expression in ESCC tissues. CD82 expression in ESCC tissues was negatively correlated with tumor stage and the expression of PKM2, and the high expression of CD82 combined with low expression of PKM2 in ESCC tissues suggested a good prognosis. To further clarify the tumor suppressive mechanism of CD82, the TIMER and TISDB databases were analyzed, and CD82 expression in tumor tissues was found to be related to the infiltration of immune cells. CD82 in exosomes is involved in the development of ESCC. SIGNIFICANCE: Xinjiang is a high incidence area of ESCC. When diagnosed in the middle and late stages of the disease, the prognosis of patients is poor. Exosomes provide the possibility of relatively noninvasive and early detection of esophageal carcinogenesis. To the best of our knowledge, this was the first study using the DIA technique to analyze the exosomal proteins of patients with different stages of ESCC. The proteins identified in the exosomes in these three groups could provide insights for understanding how exosomes promote the occurrence of ESCC, the antitumour mechanism of humans and the early diagnosis of ESCC.

Revisiting the Old Data of Heat Shock Protein 27 Expression in Squamous Cell Carcinoma: Enigmatic HSP27, More Than Heat Shock.

Initially discovered to be induced by heat shock, heat shock protein 27 (HSP27, also called HSPB1), a member of the small HSP family, can help cells better withstand or avoid heat shock damage. After years of studies, HSP27 was gradually found to be extensively engaged in various physiological or pathophysiological activities. Herein, revisiting the previously published data concerning HSP27, we conducted a critical review of the literature regarding its role in squamous cell carcinoma (SCC) from the perspective of clinicopathological and prognostic significance, excluding studies conducted on adenocarcinoma, which is very different from SCC, to understand the enigmatic role of HSP27 in the tumorigenesis of SCC, including normal mucosa, dysplasia, intraepithelial neoplasm, carcinoma in situ and invasive SCC.