Esophageal squamous cell carcinoma (ESCC) is the main prevalent histological type of esophageal cancer, predominantly constituting 90% of cases worldwide. Despite the development of multidisciplinary ...therapeutic approaches, its prognosis remains unfavorable. Recently, the development of monoclonal antibodies inhibiting programmed death 1 (PD‐1) or programmed death‐ligand 1 (PD‐L1) has led to marked therapeutic responses among multiple malignancies including ESCC. However, only a few patients achieved clinical benefits due to resistance. Therefore, precise and accurate predictive biomarkers should be identified for personalized immunotherapy in clinical settings. Because the tumor immune microenvironment can potentially influence the patient's response to immune checkpoint inhibitors, tumor immunity, such as PD‐L1 expression on tumors, tumor‐infiltrating lymphocytes, tumor‐associated macrophages, and myeloid‐derived suppressor cells, in ESCC should be further investigated. In this review, accumulated evidence regarding the tumor immune microenvironment and immune checkpoint inhibitors in ESCC are summarized.
Because the tumor immune microenvironment can potentially influence the patient's response to immune checkpoint inhibitors, tumor immunity, such as PD‐L1 expression on tumors, tumor‐infiltrating lymphocytes, tumor‐associated macrophages, and myeloid‐derived suppressor cells, in ESCC should be further investigated. In this review, accumulated evidence regarding the tumor immune microenvironment and immune checkpoint inhibitors in ESCC are summarized.
Increasing lines of evidence show that the malignant behavior of cancer is not exclusively attributable to cancer cells but also radically influenced by cancerous stroma activity and controlled ...through various mechanisms by the microenvironment. In addition to structural components, such as the extracellular matrix, stromal cells, such as macrophages, endothelial cells, and specifically cancer-associated fibroblasts (CAFs), have attracted substantial attention over recent decades. CAFs provide routes for aggressive carcinomas and contribute to invasion and metastasis through the biochemical alteration and regulation of cancer-related pathways. However, another facet of CAFs that has been neglected by numerous studies is that CAFs might serve as a negative regulator of cancer progression under certain circumstances. The various origins of CAFs, the diverse tissues in which they reside and their interactions with different cancer cells appear to be responsible for this inconsistency. This review summarizes the latest knowledge regarding CAF heterogeneity and offers a novel perspective and a beneficial approach for obtaining an improved understanding of CAFs.
Cellular senescence in cancer development is known to have tumor‐suppressive and tumor‐promoting roles. Recent studies have revealed numerous molecular mechanisms of senescence followed by ...senescence‐associated secretory phenotype induction and showed the significance of senescence on both sides. Cellular senescence in stromal cells is one of the reasons for therapeutic resistance in advanced cancer; thus, it is an inevitable phenomenon to address while seeking an effective cancer treatment strategy. This review summarizes the molecular mechanisms regarding cellular senescence, focusing on the dual roles played by senescence, and offers some direction toward successful treatments targeting harmful senescent cells.
From noncancerous to precancerous stages, immune cells act as senescent surveillance agents by eliminating premalignant senescent cells. On the other hand, in advanced stages of cancer, senescent stromal cells secrete senescence‐associated secretory phenotype factors to promote cancer cell proliferation, metastasis, and angiogenesis through interactions with tumor cells. We focus on the dual nature of senescence depending on the surrounding circumstances and offer some proposals toward successful senolytic strategies targeting harmful senescent cells.
The effectiveness of current chemotherapies for cancer is gradually progressing; however achieving a complete cure through chemotherapy is still difficult and has been the main goal in treatment of ...advanced cancer. Drug resistance is an issue in cancer therapy, therefore increasing numbers of investigations into drug resistance have focused on the characteristics of the cancer cells themselves. The interaction between the tumor microenvironment (TME) and cancer cells is also intimately involved in the development of drug resistance. Cancer‐associated fibroblasts (CAFs) are a predominant component of the TME and affect tumor progression by secreting soluble factors. This review summarizes the most up‐to‐date knowledge of CAFs and drug resistance in cancer, with a focus on factors secreted from CAFs including proteins, cytokines, extracellular vesicles, and metabolites. A perspective on the potential role of anti‐CAF therapies in overcoming CAF‐induced drug resistance is also discussed.
Drug resistance is a main issue for anticancer therapies. Cancer‐associated fibroblasts (CAFS) have a huge effect in promoting drug resistance. This review summarizes the current perspectives on the role of CAFs in chemoresistance.
Epidemiological surveys indicate that the incidence of inflammatory bowel disease (IBD) is increasing rapidly with the continuous growth of the economy. A large number of studies have investigated ...the relationship between the genetic factors related to the susceptibility to IBD and the gut microbiota of patients by using high-throughput sequencing. IBD is considered the outcome of the interaction between host and microorganisms, including intestinal microbial factors, abnormal immune response, and a damaged intestinal mucosal barrier. The imbalance of microbial homeostasis leads to the colonization and invasion of opportunistic pathogens in the gut, which increases the risk of the host immune response and promotes the development of IBD. It is critical to identify the specific pathogens related to the pathogenesis of IBD. An in-depth understanding of various pathogenic factors is of great significance for the early detection of IBD. This review highlights the role of gut microbiota in the pathogenesis of IBD and provides a theoretical basis for the personalized approaches that modulate the gut microbiota to treat IBD.
Inflammation-Induced Tumorigenesis and Metastasis Hibino, Sana; Kawazoe, Tetsuro; Kasahara, Hidenori ...
International journal of molecular sciences,
05/2021, Letnik:
22, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Inflammation, especially chronic inflammation, plays a pivotal role in tumorigenesis and metastasis through various mechanisms and is now recognized as a hallmark of cancer and an attractive ...therapeutic target in cancer. In this review, we discuss recent advances in molecular mechanisms of how inflammation promotes tumorigenesis and metastasis and suppresses anti-tumor immunity in various types of solid tumors, including esophageal, gastric, colorectal, liver, and pancreatic cancer as well as hematopoietic malignancies.
Background
The tumor proportion score (TPS) and combined positive score (CPS) have been developed to assess programmed death ligand 1 (PD-L1) expression in gastric cancer (GC). This study aimed to ...elucidate the role of TPS and CPS as prognostic biomarkers.
Methods
A total of 191 patients with GC who received curative gastrectomy were retrospectively enrolled. Double immunohistochemistry of PD-L1 and ionized calcium binding adaptor molecule 1 was performed to clearly distinguish PD-L1 expression between tumor cells and macrophages. Survival analysis for PD-L1 expression by TPS and CPS was performed.
Results
PD-L1 positivity was detected in 39 patients (20.4%) by TPS and in 137 patients (71.7%) by CPS. Patients with PD-L1 positivity by CPS experienced significantly shorter overall survival (OS) (
P
< 0.01) and relapse-free survival (RFS) (
P
= 0.01) than the other patients. In contrast, patients with either PD-L1 status by the TPS showed similar OS and RFS times. Multivariate Cox regression analysis for OS and RFS demonstrated that PD-L1 positivity by CPS was a significant independent factor for poor OS (hazard ratio HR 2.27, 95% confidence interval CI 1.27–4.37,
P
< 0.01) and RFS (HR 1.81, 95% CI 1.07–3.22,
P
= 0.03).
Conclusions
CPS was shown to be a more useful assessment method of determining PD-L1 expression than TPS as a prognostic biomarker. This suggests that the total number of PD-L1-expressing cells, including tumor and immune cells, is a more sensitive prognostic biomarker than the number of PD-L1-expressing tumor cells in GC.
Fusobacterium nucleatum (F. nucleatum) is a gut microbe implicated in gastrointestinal tumorigenesis. Predicting the chemotherapeutic response is critical to developing personalised therapeutic ...strategies for oesophageal cancer patients. The present study investigated the relationship between F. nucleatum and chemotherapeutic resistance in oesophageal squamous cell carcinoma (ESCC).
We examined the relationship between F. nucleatum and chemotherapy response in 120 ESCC resected specimens and 30 pre-treatment biopsy specimens. In vitro studies using ESCC cell lines and co-culture assays further uncovered the mechanism underlying chemotherapeutic resistance.
ESCC patients with F. nucleatum infection displayed lesser chemotherapeutic response. The infiltration and subsistence of F. nucleatum in the ESCC cells were observed by transmission electron microscopy and laser scanning confocal microscopy. We also observed that F. nucleatum modulates the endogenous LC3 and ATG7 expression, as well as autophagosome formation to induce chemoresistance against 5-FU, CDDP, and Docetaxel. ATG7 knockdown resulted in reversal of F. nucleatum-induced chemoresistance. In addition, immunohistochemical studies confirmed the correlation between F. nucleatum infection and ATG7 expression in 284 ESCC specimens.
F. nucleatum confers chemoresistance to ESCC cells by modulating autophagy. These findings suggest that targeting F. nucleatum, during chemotherapy, could result in variable therapeutic outcomes for ESCC patients.
Glucose transporter 1 (GLUT1) expression is a prognostic marker for esophageal squamous cell carcinoma (ESCC). Recent work on GLUT1 and development of specific inhibitors supports the feasibility of ...GLUT1 inhibition as a treatment for various cancers. The anti–proliferative effects of GLUT1‐specific small interfering RNA (siRNA) and a GLUT1 inhibitor were evaluated in ESCC cell lines. Expression of pro–proliferative and anti–proliferative signaling and effector molecules was examined by western blotting and quantitative RT‐PCR. GLUT1 expression in pretreatment clinical biopsy samples was measured by immunohistochemistry and correlated with various clinicopathological parameters and response to chemotherapy. The reduction in standardized uptake value (SUV) of 18F‐fluoro‐deoxyglucose was calculated using the formula: (pretreatment SUVmax – posttreatment SUVmax/pretreatment SUVmax) × 100. GLUT1‐specific siRNA expression in ESCC cells inhibited their proliferation, increased expression of p27kip, and decreased expression of cyclin‐dependent kinase 6, pyruvate kinase muscle isozyme M2, lactate dehydrogenase A and phospho‐ERK1/2. Suppression of GLUT1 by siRNA increased low‐dose cisplatin‐induced inhibition of proliferation of TE‐11 ESCC cells, which express high GLUT1 levels. Similarly, BAY‐876, a GLUT1 inhibitor, enhanced cisplatin‐mediated inhibition of ESCC cell proliferation. GLUT1 expression in pretreatment biopsy samples was associated with the response to chemotherapy as well as the pathological tumor stage and histological response grade after esophagectomy. Finally, GLUT1‐negative tumors showed a significantly larger reduction in SUVmax (61.2% ± 4.5%) compared with GLUT1‐positive tumors (46.2% ± 4.4%). GLUT1 expression may be a surrogate marker of response to chemotherapy, and inhibition of GLUT1 may be a potential novel therapy for ESCC patients.
Recent work on GLUT1 and development of specific inhibitors supports the feasibility of GLUT1 inhibition as a treatment for various cancers. This study demonstrated that downregulation of GLUT1 expression had a strong anti–proliferative effect in ESCC cells and also improved their sensitivity to cisplatin. GLUT1 expression may be a surrogate marker of response to chemotherapy, and inhibition of GLUT1 may be a potential novel therapy for ESCC patients.
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