Role of the IL-33/ST2L axis in colorectal cancer progression.

Interleukin-33 (IL-33) has been identified as a natural ligand of ST2L. IL-33 primarily acts as a key regulator of Th2 responses through binding to ST2L, which is antagonized by soluble ST2 (sST2). The IL-33/ST2L axis is involved in various inflammatory pathologies, including ulcerative colitis (UC). Several recent investigations have also suggested that the IL-33/ST2L axis plays a role in colorectal cancer (CRC) progression. In CRC, tumor- and stroma-derived IL-33 may activate ST2L on various cell types in an autocrine and paracrine manner. Although several findings support the hypothesis that the IL-33/ST2L axis positively regulates CRC progression, other reports do not; hence, this hypothesis remains controversial. At any rate, recent studies have provided overwhelming evidence that the IL-33/ST2L axis plays important roles in CRC progression. This review summarizes the role of the IL-33/ST2L axis in the UC and CRC microenvironments.

Pro-Tumoral Inflammatory Myeloid Cells as Emerging Therapeutic Targets.

Since the observation of Virchow, it has long been known that the tumor microenvironment constitutes the soil for the infiltration of inflammatory cells and for the release of inflammatory mediators. Under certain circumstances, inflammation remains unresolved and promotes cancer development. Here, we review some of these indisputable experimental and clinical evidences of cancer related smouldering inflammation. The most common myeloid infiltrate in solid tumors is composed of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). These cells promote tumor growth by several mechanisms, including their inherent immunosuppressive activity, promotion of neoangiogenesis, mediation of epithelial-mesenchymal transition and alteration of cellular metabolism. The pro-tumoral functions of TAMs and MDSCs are further enhanced by their cross-talk offering a myriad of potential anti-cancer therapeutic targets. We highlight these main pro-tumoral mechanisms of myeloid cells and give a general overview of their phenotypical and functional diversity, offering examples of possible therapeutic targets. Pharmacological targeting of inflammatory cells and molecular mediators may result in therapies improving patient condition and prognosis. Here, we review experimental and clinical findings on cancer-related inflammation with a major focus on creating an inventory of current small molecule-based therapeutic interventions targeting cancer-related inflammatory cells: TAMs and MDSCs.

The upregulation of TGM2 is associated with poor prognosis and the shaping of the inflammatory tumor microenvironment in lung squamous cell carcinoma.

Tissue transglutaminase (TGM2) is a member of the glutamine transferase superfamily, located within cells and their membranes. When secreted, it catalyzes the cross-linking of extracellular matrix proteins and promotes the formation of extracellular matrix scaffolds. To determine the function of TGM2 in the tumorigenesis of lung squamous cell carcinoma (LUSC), we conducted a comprehensive bioinformatics analysis of TGM2. Our findings indicate that high expression of TGM2 in LUSC was associated with a poorer prognosis. Additionally, we found that high expression of TGM2 is closely related to tumor-promoting inflammation and may increase sensitivity to immunotherapy. We further confirmed the cancer-promoting effect of TGM2 in LUSC through in vitro overexpression and knockdown experiments and showed that TGM2 primarily affects cancer cell proliferation, apoptosis, and invasion. In summary, TGM2 promoted the progression of LUSC, and targeting TGM2 is expected to become a new therapeutic approach for LUSC treatment.

Envoplakin Inhibits Macrophage Polarization by Altering the Inflammatory Tumor Microenvironment of Melanoma Through the RAS / ERK Signaling Pathway.

Purpose: Tumor growth induces the tumor margin to become a transition zone rich in immune cells. EVPL is a potential prognostic biomarker for melanoma. Melanoma is difficult to cure because of its high metastasis, so it is urgent to find effective genes to inhibit tumor progression and regulate tumor microenvironment. Methods: Firstly, differentially expressed genes (DEGs) among normal skin, nevus and melanoma samples in GSE3189 were screened. Bioinformatics was used to further explore the hub genes and enriched pathways closely related to the inflammatory response of DEGs in melanoma. We selected EVPL, which is associated with the Ras/Raf signaling pathway, for in vitro study. CCK-8, colony formation, wound healing, Transwell and flow cytometry assays were respectively used to evaluate the proliferation, migration, invasion, and apoptosis of cancer cells. Enzyme-linked immunosorbent assay was conducted for the monitoring of changes in the tumor microenvironment. To evaluate the effect of EVPL on macrophage recruitment, we established a co-culture system in a Transwell chamber. The polarization of macrophages was examined after treatment of cells with RAS/ERK signaling inhibitors SCH772984 and sh-EVPL. Additionally, changes in the expression of pathway proteins were measured by Western blot. Results: Among the screened hub genes, EVPL was associated with the Ras/Raf pathway, a key signaling pathway in melanoma, and may be involved in regulating the inflammatory microenvironment of melanoma. Oe-EVPL was proved to suppress melanoma cell malignant progression. By inhibiting EVPL expression, the inhibitory effects on melanoma progression induced by the addition of SCH772984 were reversed. Furthermore, EVPL was found to inhibit the expression of chemokines, the recruitment of macrophages, and the polarization of macrophages through the Ras/Raf/ERK signaling pathway. Conclusion: EVPL can inhibit the progression of melanoma through the RAS/ERK signaling pathway, change the inflammatory tumor microenvironment of melanoma, and inhibit the recruitment of macrophages.

Immune Cell-Derived Exosomes in Inflammatory Disease and Inflammatory Tumor Microenvironment: A Review.

Inflammation is a common feature of many inflammatory diseases and tumors, and plays a decisive role in their development. Exosomes are extracellular vesicles unleashed by assorted types of cells, and it is widely known that exosomes of different immune cell sources play different functions. Exosome production has recently been reported for immune cells comprising macrophages, T cells, B cells, and dendritic cells (DCs). Immune cell-derived exosomes are involved in a variety of inflammatory responses.Herein, we summarize and review the role of macrophages, T cells, B cells, and dendritic cells (DC) in inflammatory diseases, with a focus on the role of immune cell-derived exosomes in osteoarthritis, rheumatoid arthritis, and the inflammatory tumor microenvironment (TME).These findings are expected to be important for developing new treatments for inflammatory diseases and ameliorating tumor-related inflammation.

JAK3/STAT5 signaling-triggered upregulation of PIK3CD contributes to gastric carcinoma development.

Gastric cancer (GC) is one of the most common solid cancers with high incidence and mortality worldwide. Chronic gastritis and consequent inflammatory microenvironment is known as a major cause leading to gastric carcinogenesis. Here we report that PIK3CD that encodes p110δ, a catalytic subunit of the class IA PI3Ks, is overexpressed and tumorigenic in GC and associated with tumor inflammatory microenvironment. By investigating the data from TCGA database and our immunohistochemical staining and quantitative real-time PCR results from clinical samples, we found PIK3CD exhibits higher expression level in GC tissues compared with adjacent non-tumorous stomach tissues. Genetic silencing of PIK3CD in GC cells retards proliferation and migration in vitro and tumorigenicity and metastasis in vivo. In contrast, enhanced expression of PIK3CD promotes these phenotypes in vitro. Furthermore, pharmacological inhibition of PIK3CD could reduce GC cell viability and colony formation capacities. More importantly, we reveal a relevant mechanism that PIK3CD, but not PIK3CA and PIK3CB, is transcriptionally regulated by the pro-inflammatory IL2/JAK3/STAT5 axis and tumor-infiltrating immune cells such as lymphocytes. These observations may setup a new crosstalk between tumor inflammatory microenvironment, IL2/JAK3/STAT5 signaling and PI3K/AKT signaling. Targeting PIK3CD may be a promising therapy strategy for GC.

The Application of Single-Cell RNA Sequencing in the Inflammatory Tumor Microenvironment.

The initiation and progression of tumors are complex. The cancer evolution-development hypothesis holds that the dysregulation of immune balance is caused by the synergistic effect of immune genetic factors and environmental factors that stimulate and maintain non-resolving inflammation. Throughout the cancer development process, this inflammation creates a microenvironment for the evolution and development of cancer. Research on the inflammatory tumor microenvironment (TME) explains the initiation and progression of cancer and guides anti-cancer immunotherapy. Single-cell RNA sequencing (scRNA-seq) can detect the transcription levels of cells at the single-cell resolution level, reveal the heterogeneity and evolutionary trajectory of infiltrated immune cells and cancer cells, and provide insight into the composition and function of each cell group in the inflammatory TME. This paper summarizes the application of scRNA-seq in inflammatory TME.

Hotspots and Frontiers in Inflammatory Tumor Microenvironment Research: A Scientometric and Visualization Analysis.

Methods: Articles on inflammatory tumor microenvironment were retrieved from the Web of Science Core Collection, and the characteristics of the articles were analyzed by CiteSpace software. Background: The inflammatory tumor microenvironment is an essential feature of the tumor microenvironment. The way in which it promotes or inhibits tumor progression plays an important role in the outcome of a tumor treatment. This research aims to explore a scientific collaboration network, describe evolution of hotspots, and predict future trends through bibliometric analysis. Results: A total of 3,534 papers published by 390 institutions in 81 countries/regions were screened, and the annual quantity has been increasing rapidly in the past decades. United States was the leading country and has the most productive institutions in this field. The research topics were mainly focused on inflammation and immunity mediated by crucial factors as well as the mechanisms of angiogenesis. Additionally, the development and application of nanoparticles is currently a novel research frontier with bright prospect. Conclusion: The present scientometric study provides an overview of inflammatory tumor microenvironment research over the previous decades using quantitative and qualitative methods, and the findings of this study can provide references for researchers focusing on tumor treatment.

Inflammatory Cytokine: An Attractive Target for Cancer Treatment.

The relationship between inflammation and cancer has attracted attention for a long time. The inflammatory tumor microenvironment consists of inflammatory cells, chemokines, cytokines, and signaling pathways. Among them, inflammatory cytokines play an especially pivotal role in cancer development, prognosis, and treatment. Interleukins, tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-ß), interferons, and vascular endothelial growth factor (VEGF) are the representative inflammatory cytokines in various cancers, which may promote or inhibit cancer progression. The pro-inflammatory cytokines are associated with advanced cancer stages, resistance to immunotherapy, and poor prognoses, such as in objective response and disease control rates, and progression-free and overall survival. In this review, we selected colorectal, pancreatic, breast, gastric, lung, and prostate cancers, which are well-reported for an association between cancer and inflammatory cytokines. The related cytokines and their effects on each cancer's development and prognosis were summarized. In addition, the treatment strategies targeting inflammatory cytokines in each carcinoma were also described here. By understanding the biological roles of cancer-related inflammatory cytokines, we may modulate the inflammatory tumor microenvironment for potential cancer treatment.

DCLK1 promotes colorectal cancer stemness and aggressiveness via the XRCC5/COX2 axis.

Rationale: Doublecortin-like kinase 1 (DCLK1) is a serine/threonine kinase that selectively marks cancer stem-like cells (CSCs) and promotes malignant progression in colorectal cancer (CRC). However, the exact molecular mechanism by which DCLK1 drives the aggressive phenotype of cancer cells is incompletely determined. Methods: Here, we performed comprehensive genomics and proteomics analyses to identify binding proteins of DCLK1 and discovered X-ray repair cross-complementing 5 (XRCC5). Thus, we explored the biological role and downstream events of the DCLK1/XRCC5 axis in human CRC cells and CRC mouse models. Results: The results of comprehensive bioinformatics analyses suggested that DCLK1-driven CRC aggressiveness is linked to inflammation. Mechanistically, DCLK1 bound and phosphorylated XRCC5, which in turn transcriptionally activated cyclooxygenase-2 expression and enhanced prostaglandin E2 production; these events collectively generated the inflammatory tumor microenvironment and enhanced the aggressive behavior of CRC cells. Consistent with the discovered mechanism, inhibition of DCLK1 kinase activity strongly impaired the tumor seeding and growth capabilities in CRC mouse models. Conclusion: Our study illuminates a novel mechanism that mediates the pro-inflammatory function of CSCs in driving the aggressive phenotype of CRC, broadening the biological function of DCLK1 in CRC.

Combination of mitochondria impairment and inflammation blockade to combat metastasis.

Targeted induction of mitochondria impairment has emerged as a promising strategy for anti-metastasis therapy. However, problems such as limited mitochondria targeting efficiency, undesired drug leakage and insufficient drug release inside mitochondria remain crucial challenges for mitochondria-targeting therapy. Here, we constructed an N-(2-hydroxypropyl) methacrylamide (HPMA) polymer based cationic system that could target to mitochondria and facilitate on demand drug release in response to excessive mitochondrial reactive oxygen species. Whereas, this drug delivery system is still challenged by limitations of (1) in vivo application, and (2) inflammatory tumor microenvironment (TME). On one aspect, to prolong blood circulation and increase tumor targeting, we designed a nanocomposite (PDT-NCs) that assembled from the cationic HPMA polymer and anionic hyaluronic acid via electrostatic interaction. On another aspect, a celecoxib loaded liposome (Lip-Cel) was further fabricated to alleviate inflammation in TME by downregulating various metastasis-associated factors. Ultimately, PDT-NCs and Lip-Cel led to a drastic improvement in the suppression of primary tumor growth and distant lung metastasis. Our work provided a generalizable approach of mitochondria dysfunction and inflammation blockade to combat metastatic tumors.

The role of FKBP51 in the prognosis of ulcerative colitis-associated colorectal cancer.

PURPOSE: Ulcerative colitis (UC) carries a high risk of developing colorectal cancer (CRC). FK506-binding protein 51 (FKBP51) is a key regulator of glucocorticoid resistance and inflammatory tumor microenvironment. This study aimed to investigate the role of FKBP51 in UC-CRC prognosis. MATERIALS AND METHODS: The FKBP51 expression was measured by immunohistochemistry, qRT-PCR and western blot in control and tumor-containing tissues from UC-CRC patients. H&E staining was used to analyze the inflammatory status of each sample. The relationship between FKBP51 expression and UC-CRC prognosis was assessed by Kaplan-Meier curves and Mann-Whitney U test, and receiver-operating characteristic curves were generated to clarify the role of FKBP51 in predicting survival period and recurrence of UC-CRC patients. RESULTS: The FKBP51 expression was significantly (p â€‹< â€‹0.01) increased by 36.3% in tumor-containing tissues compared to control tissues in UC-CRC patients. Nuclear enrichment of FKBP51 in tumor-containing tissues was significantly (p â€‹< â€‹0.001) increased by 78.5%. The UC-CRC patients with higher levels of FKBP51 expression ratio between tumor-containing tissues and control tissues had shorter survival periods, but greater neutrophil invasion and neutrophils to lymphocytes ratio (NLR) in peripheral blood. Moreover, the FKBP51 expression ratio was more helpful in predicting the survival periods and recurrence in the UC-CRC patients than the NLR in peripheral blood. CONCLUSIONS: The FKBP51 expression ratio between tumor-containing tissue and control tissue may be an important biomarker of inflammatory tumor microenvironment and more helpful for the UC-CRC prognosis.

Tryptanthrin exerts anti-breast cancer effects both in vitro and in vivo through modulating the inflammatory tumor microenvironment.

Tryptanthrin is an indole quinazoline alkaloid from the indigo-bearing plants, such as Isatis indigotica Fort. Typically, this natural compound shows a variety of pharmacological activities such as antitumor, antibacterial, anti-inflammatory and antioxidant effects. This study was conducted to assess the antitumor activity of tryptanthrin in breast cancer models both in vitro and in vivo, and to explore the important role of the inflammatory tumor microenvironment (TME) in the antitumor effects of tryptanthrin. Human breast adenocarcinoma MCF-7 cells were used to assess the antitumor effect of tryptanthrin in vitro. MTT assay and colony formation assay were carried out to monitor the antiproliferative effect of tryptanthrin (1.56~50.0 µmol L-1) on inhibiting the proliferation and colony formation of MCF-7 cells, respectively. The migration and invasion of MCF-7 cells were evaluated by wound healing assay and Transwell chamber assay, respectively. Moreover, the 4T1 murine breast cancer model was established to examine the pharmacological activity of tryptanthrin, and three groups with different doses of tryptanthrin (25, 50 and 100 mg kg-1) were set in study. Additionally, tumor volumes and organ coefficients were measured and calculated. After two weeks of tryptanthrin treatment, samples from serum, tumor tissue and different organs from tumor-bearing mice were collected, and the enzyme-linked immunosorbent assay (ELISA) was performed to assess the regulation of inflammatory molecules in mouse serum. Additionally, pathological examinations of tumor tissues and organs from mice were evaluated through hematoxylin and eosin (H&E) staining. The expression of inflammatory proteins in tumor tissues was measured by immunohistochemistry (IHC) and Western blotting. Tryptanthrin inhibited the proliferation, migration and invasion of MCF-7 cells, up-regulated the protein level of E-cadherin, and down-regulated those of MMP-2 and Snail, as suggested by the MCF-7 cell experiment. According to the results from in vivo experiment, tryptanthrin was effective in inhibiting tumor growth, and it showed favorable safety without inducing the fluctuations of body mass and organ coefficient (p > 0.05). In addition, tryptanthrin also suppressed the expression levels of NOS1, COX-2 and NF-κB in mouse tumor tissues, and regulated those of IL-2, IL-10 and TNF-α in the serum of tumor cells-transplanted mice. Tryptanthrin exerted its anti-breast cancer activities through modulating the inflammatory TME both in vitro and in vivo.

The Bromodomain Inhibitor, INCB057643, Targets Both Cancer Cells and the Tumor Microenvironment in Two Preclinical Models of Pancreatic Cancer.

In pancreatic cancer the tumor microenvironment (TME) can account for up to 90% of the tumor mass. The TME drives essential functions in disease progression, invasion and metastasis. Tumor cells can use epigenetic modulation to evade immune recognition and shape the TME toward an immunosuppressive phenotype. Bromodomain inhibitors are a class of drugs that target BET (bromodomain and extra-terminal) proteins, impairing their ability to bind to acetylated lysines and therefore interfering with transcriptional initiation and elongation. INCB057643 is a new generation, orally bioavailable BET inhibitor that was developed for treating patients with advanced malignancies. KrasG12D/+; Trp53R172H/+; Pdx-1-Cre (KPC) mice mimic human disease, with similar progression and incidence of metastasis. Treatment of established tumors in KPC mice with INCB057643 increased survival by an average of 55 days, compared to the control group. Moreover, INCB057643 reduced metastatic burden in these mice. KPC mice treated with INCB057643, starting at 4 weeks of age, showed beneficial changes in immune cell populations in the pancreas and liver. Similarly, INCB057643 modified immune cell populations in the pancreas of KrasG12D/+; Pdx-1-Cre (KC) mice with pancreatitis, an inflammatory process known to promote pancreatic cancer progression. The data presented here suggest that the bromodomain inhibitor INCB057643 modulates the TME, reducing disease burden in two mouse models of pancreatic cancer. Furthermore, this work suggests that BRD4 may play a role in establishing the TME in the liver, a primary metastatic site for pancreatic cancer.