Nanoparticles as drug delivery systems in the treatment of oral squamous cell carcinoma: current status and recent progression.

Oral squamous cell carcinoma (OSCC) is a common human malignancy with an estimated incidence of around 377,713 new cases worldwide in 2020. Despite the advance in clinical management, some of OSCC patients still miss the opportunity of completable resection of tumor, and have to accept medical therapies, e.g., chemotherapy, radiotherapy, or immunotherapy when the disease develops into the advanced stage. However, these therapies have been reported to be far from ideal due to the low efficiency of conventional delivery approaches. To obtain a better therapeutic effect, considerable attempts have been made toward to develop an effective drug delivery system (DDS). Nanoparticles (NPs) including inorganic NPs, polymer NPs, lipid NP, extracellular vesicles and cell membrane-based NPs have been evaluated as the better DDS candidates that can specifically accumulate in the tumor microenvironment along with a large amount of blood vessels. Emerging evidence suggested that NPs formulated with anticancer drugs including chemotherapeutic drugs, radiotherapy and immunotarget antibodies could remarkably improve the release and increase concentration of these drugs at the tumor site and show a better therapeutic efficacy, suggesting that NPs might serve as promising DDSs in the treatment of OSCC. Therefore, we have conducted this review to summarize recent progression and current status of diverse NPs as DDSs in this research field.

Differential profile of protumor immunological factors between the tumor site and the tumor-free site - predictive potential of IL-8 and COX2 for colorectal cancer and metastasis.

To study the role of host immune surveillance in the initiation and progression of colorectal cancer (CRC), a set of protumor immunological factors was determined by quantitative real-time PCR (q-PCR) between the primary tumor and the adjacent tumor-free site tissues in 63 patients with colorectal neoplasms. Results showed that expression levels of interleukin (IL)-1ß, IL-6, IL-8, IL-17A, IL-23, and cyclooxygenase 2 (COX2) mRNAs, except transforming growth factor beta (TGFß), in adenoma tissues were significantly higher than that in relative adjacent tissues. Difference of immunological factor levels between adenoma and adjacent tissues (Δ values) was in an order of ΔIL-8 > ΔIL-6 > ΔIL-17A > ΔIL-1ß > ΔCOX2 > ΔIL-23; Analysis showed that the value of ΔCOX2 correlated to the grade of dysplastic degree in patients with adenoma. Notably, levels of all these immunological factors in CRC tissues were continuously increased, the order of values of Δ immunological factors was ΔIL-8 > ΔCOX2 > ΔIL-6 > ΔIL-1ß > ΔIL-17A > ΔIL-23 > ΔTGFß. Further analysis revealed that increased value of Δ IL-1ß was associated with advanced TNM stage, a higher value of Δ COX2 tended to predicate a deeper degree of tumor invasion; and higher values of Δ IL-1ß, IL-6 and COX2 closely correlated to lymph node metastasis in patients with CRC. In addition, the ratio of ΔIL-8/ΔTGFß was most obvious changed factor and associated with node metastasis in patients with CRC. Therefore, we concluded that the difference of protumor immunological factor levels between the primary tumor site and tumor-free site along the adenoma-carcinoma sequence reflects the change of protumor/antitumor force balance, which is associated with CRC initiation and invasion.

IL-33-expressing microvascular endothelial cells in human esophageal squamous cell carcinoma: Implications for pathological features and prognosis.

Accumulating evidence suggests that interleukin (IL)-33 plays a critical role in regulating angiogenesis and cancer progression. In this study, we characterized the pathological importance of IL-33 deployed by tumor microvascular endothelial cells (ECs) in human esophageal squamous cell carcinoma (ESCC). The expression of IL-33 in microvascular ECs in 80 cases of ESCC was examined with immunohistochemistry (IHC) and double immunofluorescence. IHC results showed that strong IL-33-immunoreactivity (IR) in microvessels, which were confirmed to be ECs by double immunofluorescence staining with IL-33/CD31 antibodies. Moreover, high proliferative activity was shown in IL-33-positive ECs, and the IL-33 functional receptor ST2 was expressed in microvascular ECs. Clinicopathological analysis revealed that IL-33-positive microvessel density (MVD) was positively correlated with node involvement in patients with ESCC. A log rank test showed a highly significant inverse correlation between the densities of IL-33-positive MVDs and overall survival rate, and patients with higher IL-33-positive MVDs tended to have a lower survival rate (both p < 0.05). Therefore, we concluded that IL-33 deployed by microvascular ECs correlates with advanced pathological features and the long-term survival rate, which provides new insights into the regulatory mechanisms of tumor angiogenesis in the tumor microenvironment and might serve as a promising target in patients with ESCC.

Endothelial cells-directed angiogenesis in colorectal cancer: Interleukin as the mediator and pharmacological target.

Enhanced angiogenesis is a cancer hallmark and critical for colorectal cancer (CRC) invasion and metastasis. Upon exposure to proangiogenic factors, therefore, targeting tumor-associated proangiogenic factors/receptors hold great promise as a therapeutic modality to treat CRC, particularly metastatic CRC. Accumulating evidence from numerous studies suggests that tumor endothelial cells (ECs) are not only the target of proangiogenic factors, but also function as the cellular source of proangiogenic factors. Studies showed that ECs can produce different proangiogenic factors to participate in the regulation of angiogenesis process, in which ECs-derived interleukins (ILs) show a potential stimulatory effect on angiogenesis via either an direct action on their receptors expressed on progenitor of ECs or an indirect way through enhanced production of other proangiogenic factors. Although a great deal of attention is given to the effects of tumor-derived and immune cell-derived ILs, few studies describe the potential effects of vascular ECs-derived ILs on the tumor angiogenesis process. This review provides an updated summary of available information on proangiogenic ILs, such as IL-1, IL-6, IL-8, IL-17, IL-22, IL-33, IL-34, and IL-37, released by microvascular ECs as potential drivers of the tumor angiogenesis process and discusses their potential as a novel candidate for antiangiogenic target for the treatment of CRC patients.

Cytokine-mediated crosstalk between cancer stem cells and their inflammatory niche from the colorectal precancerous adenoma stage to the cancerous stage: Mechanisms and clinical implications.

The majority of colorectal cancers (CRCs) are thought to arise from precancerous adenomas. Upon exposure to diverse microenvironmental factors, precancerous stem cells (pCSCs) undergo complex genetic/molecular changes and gradually progress to form cancer stem cells (CSCs). Accumulative evidence suggests that the pCSC/CSC niche is an inflammatory dominated milieu that contains different cytokines that function as the key communicators between pCSCs/CSCs and their niche and have a decisive role in promoting CRC development, progression, and metastasis. In view of the importance and increasing data about cytokines in modulating pCSCs/CSC stemness properties and their significance in CRC, this review summarizes current new insights of cytokines, such as interleukin (IL)-4, IL-6, IL-8, IL-17A, IL-22, IL-23, IL-33 and interferon (IFN)-γ, involving in the modulation of pCSC/CSC properties and features in precancerous and cancerous lesions and discusses the possible mechanisms of adenoma progression to CRCs and their therapeutic potential.

Towards a precision immune checkpoint blockade immunotherapy in patients with colorectal cancer: Strategies and perspectives.

To date, immune checkpoint blockade (ICB) immunotherapy has become one of promise strategies in the management of patients with unresectable or metastatic colorectal cancer (CRC). However, clinical observations showed that not all the patients responded equally to ICBs, certain group of CRC patients with microsatellite-instability-low (MSI-L) phenotype was not sensitive to ICB immunotherapy. In addition, some primary responders might lose their sensitivity and become resistant to ICBs overtime. To obtain a better response rate and therapeutic efficacy, considerable attempts have been made toward to a precision medicine algorithm. Studies showed that multiple strategies based on the patient's individual condition might improve the response and therapeutic efficacy to ICBs. Therefore, we focused on and discussed precision strategies and perspectives e.g., how to early define candidates who will benefit from ICB immunotherapy prior treatment, overcome the primary and acquired resistance and improve the therapeutic response to ICBs in CRC patients with different microsatellite-instability statuses within the context of precision medicine algorithm in this review.

The presentation and regulation of the IL-8 network in the epithelial cancer stem-like cell niche in patients with colorectal cancer.

BACKGROUND: Accumulative evidence suggests that the biological behavior of cancer stem-like cells (CSCs) is regulated by their surrounding niche, in which cytokines function as one of the main mediators for the interaction between CSCs and their microenvironment in the colorectal cancer (CRC). METHODS: We characterized the presentation of CSCs and the interleukin (IL)- 8 network in the adenoma/CRC epithelium using quantitative real-time PCR (q-PCR), immunohistochemistry (IHC) and double immunofluorescence. In addition, the capacity of IL-1ß to stimulate epithelial IL-8 production in colon cancer Caco-2 cells was examined in vitro and the IL-8 product was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: IHC observation showed increased expression of both CSCs and IL-8 in the adenoma and CRC epithelium, and q-PCR results revealed that increased expression of IL-1ß transcript was strongly correlated with increased IL-8 transcript levels in both adenoma and CRC tissues. Double immunofluorescence images demonstrated the coexpression of the IL-8 receptors IL-8RA and IL-8RB with LGR5 labeled CSCs in CRC tissue sections. Consistently, in vitro experiments showed that coculture of Caco-2 cells with IL-1ß at concentrations of 1, 5, 10 and 20 ng/ml resulted in a dose-dependent release of IL-8, which could be specifically inhibited by cotreatment with the IL-1ß receptor antagonist. CONCLUSIONS: These results demonstrate activation of the IL-8 network in the niche of CSCs from the precancerous adenoma stage to the CRC stage, which is potentially stimulated by IL-1ß in CRC cells.

Could Mucosal TNF Transcript as a Biomarker Candidate Help Optimize Anti-TNF Biological Therapy in Patients With Ulcerative Colitis?

Anti-tumor necrosis factor (TNF) biological therapy has generally been accepted as a standard therapeutic option in inflammatory bowel disease (IBD) patient who are refractory to steroids or immunomodulators. However, the primary and secondary nonresponse rates to anti-TNF bioagents in patients with IBD are high. To improve the response rate, anti-TNF bioagents must be offered to the appropriate IBD patients, and the withdrawal of anti-TNF bioagents needs to be done at the right time. In this context, reliable and reproducible biomarkers can provide important supportive information for clinicians to make correct decisions based on the patient's individual situation. In this review, we summarized the current understanding of using mucosal TNF transcript (TNF) to improve the precision of anti-TNF biological therapy strategies in patients with ulcerative colitis (UC). Analysis of published literature showed that mucosal TNF could affect the precision of the early identification of candidates who will benefit from anti-TNF therapy prior to treatment, the assessment of response and mucosal healing, and the prediction of discontinuation of anti-TNF biological therapy and relapse after drug withdrawal. Challenges and limitations of using mucosal TNF as a biomarker in applying individualized anti-TNF biological therapy in patients with UC still remain and need to be further investigated.

Occurrences and phenotypes of RIPK3-positive gastric cells in Helicobacter pylori infected gastritis and atrophic lesions.

BACKGROUND: Research evidences suggest that diverse forms of programmed cell death (PCD) are involved in the helicobacter pylori (H. pylori)-induced gastric inflammation and disorders. AIMS: To characterize occurrences and phenotypes of necroptosis in gastric cells in H. pylori infected gastritis and atrophic specimens. METHODS: Occurrences and phenotypes of necroptosis in gastric cells were immunohistochemically characterized with receptor-interacting protein kinase 3 (RIPK3) antibody in both human H. pylori infected gastric gastritis, atrophic specimens, and transgenic mice. RESULTS: Increased populations of RIPK3-positive cells were observed in both gastric glands and lamina propria in H. pylori infected human oxyntic gastritis and atrophic specimens. Phenotypic analysis revealed that many RIPK3-positive cells were H + K+ ATPase-positive parietal cells in the gastric glands and were predominantly CD3-positive T lymphocytes, CD68-positive macrophages, and SMA-alpha-positive stromal cells in the lamina propria. Furthermore, we found an increased expression of RIPK3-positive gastric glandular cells along with the histological process of hyperplasia-atrophy-dysplasia progression in hypergastrinemic INS-GAS mice. CONCLUSIONS: An increased population of RIPK3-positive cells was observed in several types of gastric cells, future studies that define the effects and mechanisms of PCD implicated in the development of H. pylori induced gastric disorders are needed.

Chlorpromazine Efficiently Treats the Crisis of Pheochromocytoma: Four Case Reports and Literature Review.

Pheochromocytoma multisystem crisis (PMC) is a potentially lethal emergency due to catecholamine secretion. The condition manifests as severe hypertension to intractable cardiogenic shock and has a high mortality rate. This study explored the efficacy and safety of applying chlorpromazine on PMC patients. The study included seven patients (median age, 42 years; range, 14-57 years) diagnosed with pheochromocytoma. Four consecutive PMC patients were admitted to our critical care unit between 2016 and 2020 due to abdominal or waist pain, nausea, and vomiting. Their blood pressure (BP) fluctuated between 200-330/120-200 and 40-70/30-50 mmHg. Chlorpromazine (25 or 50 mg) was injected intramuscularly, followed by continuous intravenous infusion (2-8 mg/h). The patients' BP decreased to 100-150/60-100 mmHg within 1-3 h and stabilized within 3-5 days. Two weeks later, surgical tumor resection was successfully performed in all four patients. Similar clinical outcomes were also obtained in three patients with sporadic PMC reported in the literature who received chlorpromazine treatment, which reduced their BP readings from >200/100 mmHg to 120/70 mmHg. Our observations, combined with sporadic reports, showed that chlorpromazine efficiently controlled PMC. Thus, future studies on the use of chlorpromazine are warranted.

Association of exposure to ethylene oxide with risk of diabetes mellitus: results from NHANES 2013-2016.

Animal studies suggested that exposure to ethylene oxide (EO) might induce hepatic lipid peroxidation and inflammatory lesions in various organs. However, the association between EO exposure and diabetes risk in humans is unknown. This study aimed to examine the association of EO exposure with the prevalence of diabetes mellitus in a general population of US adults. This study consisted of 3448 participants aged 20 years and older from the National Health and Nutrition Examination Survey (NHANES) 2013-2014 cycle and 2015-2016 cycle. Circulating levels of EO biomarker (hemoglobin adducts of EO (HbEO)) was measured by using high-performance liquid chromatography coupled with tandem mass spectrometry. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariate logistic regression. The weighted median level of HbEO was 29.9 (95% CI: 21.8, 56.0) pmol/g Hb. Elevated levels of HbEO were associated with higher HbA1c and lower high-density lipoprotein cholesterol (both Ptrend <0.01). After multivariate adjustment including demographics, lifestyle factors, and body mass index (BMI), higher HbEO levels were significantly associated with an increased prevalence of diabetes mellitus. The OR (95% CI) of diabetes across increasing quartiles of HbEO was 1.00 (reference), 1.45 (1.08, 1.96), 1.76 (1.31, 2.36), and 1.77 (1.22, 2.57), respectively (Ptrend <0.001). Similar results were observed when analyses were stratified by smoking status, age, sex, race/ethnicity, and BMI. In a nationally representative sample of US adults, higher levels of HbEO were significantly associated with an increased prevalence of diabetes mellitus. Further prospective studies are needed to confirm these findings.

The expression of RIPK3 is associated with cell turnover of gastric mucosa in the mouse and human stomach.

Necroptosis is a novel manner of programmed cell death and important for tissue development, homeostasis, damage, and repair. Activation of receptor-interacting protein kinase 3 (RIPK3), a key member of receptor-interacting protein family in contributing significantly to necroptosis, in tissues is a hallmark of cells dying by necroptosis. However, there are few studies that examine the expression of RIPK3 in the glandular cells of stomachs under physiological condition. We have therefore conducted this study to immunohistochemically characterize the key element of necroptosis, RIPK3, in the mouse and human stomach. Results showed that RIPK3 positive cells could be observed in the surface mucosal cells, granular cells, and lamina propria cells in both mouse and human stomach tissues. Ratios of PCNA/RIPK3 positive cells in the glandular cells were ~ 2.1 in mouse and ~ 4.15 in human sections respectively. Morphological and double immunofluorescence analysis confirmed that these RIPK3 positive cells were mucous, parietal and lamina propria cells. Our results indicate that the expression of RIPK3 in different cell types might contribute to cell turnover of gastric mucosa in the mouse and human stomach under physiological condition.

Dynamic stromal cellular reaction throughout human colorectal adenoma-carcinoma sequence: A role of TH17/IL-17A.

BACKGROUND: Accumulating data suggest that the tumour stroma rapidly undergoes dynamic mechanical and cellular changes by which creates a supportive milieu to promote disease progression and metastasis. Cytokines are reported to play a key role in the modulation of tumour stromal response. METHODS: The activation of TH17/interleukin (IL)-17A network in association with tumour stromal proliferative and cellular response in samples from 50 patients with colorectal adenoma, 45 with colorectal cancer (CRCs) were elucidated with quantitative real-time PCR (q-PCR), immunohistochemistry and double immunofluorescence. RESULTS: q-PCR results showed that retinoic acid-receptor-related orphan receptor-C, a critical transcriptional factor for TH17 cell differentiation, was significantly increased at the adenoma stage and slightly decreased at the CRC stage, but was still higher than that at normal controls. The level of TH17 signature cytokine IL-17A was shown in an increasing gradient throughout the adenoma-carcinoma sequence. Immunohistochemistry revealed an activated proliferative rate evaluated by Ki67 and population expansion of myofibroblasts in the adenoma/CRC stroma. Notably, densities of IL-17A-expressing cells were associated with populations of Ki67-positive cells and myofibroblasts in the adenoma/CRC stroma. Finally, CD146-positive stromal cells are an important participator for stroma remodelling, double immunofluorescence image demonstrated that IL-17 receptor C, one of the key elements for IL-17 receptor complex, was highly expressed in CD146-positive adenoma/CRC stromal cells. CONCLUSIONS: An activated TH17/IL-17A network in the tumour microenvironment is significantly associated with dynamic stromal cellular response throughout the adenoma-carcinoma sequence, which might provide a supportive environment for the initiation and progression of CRC.

Evaluation of anti-TNF therapeutic response in patients with inflammatory bowel disease: Current and novel biomarkers.

Neutralizing tumour necrosis factor (TNF) antibodies have been widely used to treat inflammatory bowel disease (IBD) in the clinical practice. In this review, the principal biomarker analysis revealed that faecal calprotectin, C-reactive protein, serum or mucosal concentrations of anti-TNF monoclonal antibodies (mAbs) and antibodies to anti-TNF mAbs are commonly used as current biomarkers in the evaluation of anti-TNF therapeutic efficacy. However, mucosal cytokine transcripts. microRNAs, proteomics and faecal and mucosal gut microbiota profile and mucosal histological features are reported to be novel candidates of biomarkers with high clinical utility in the evaluation of anti-TNF therapeutic efficacy in patients with IBD. Therefore, a robust validation of novel promising biomarkers and comparison studies between current used and novel biomarkers are urgently required to improve their value in the evaluation of therapeutic efficacy and optimization of personalized medicine and identification of IBD candidates for anti-TNF therapy in future clinical practice.

The Mechanisms Leading to Distinct Responses to PD-1/PD-L1 Blockades in Colorectal Cancers With Different MSI Statuses.

Current clinical studies showed distinct therapeutic outcomes, in which CRC patients with mismatch repair-deficient (dMMR)/microsatellite instability high (MSI-H) seem to be relatively more "sensitive" in response to anti-programmed death-1 receptor (PD-1)/programmed death-1 receptor ligand 1 (PD-L1) therapy than those with mismatch repair-proficient (pMMR)/microsatellite instability-low (MSI-L). The mechanisms by which the same PD-1/PD-L1 blockades lead to two distinct therapeutic responses in CRC patients with different MSI statuses remain poorly understood and become a topic of great interest in both basic research and clinical practice. In this review of the potential mechanisms for the distinct response to PD-1/PD-L1 blockades between dMMR/MSI-H CRCs and pMMR/MSI-L CRCs, relevant references were electronically searched and collected from databases PubMed, MEDLINE, and Google scholar. Sixty-eight articles with full text and 10 articles by reference-cross search were included for final analysis after eligibility selection according to the guidelines of PRISMA. Analysis revealed that multiple factors e.g. tumor mutation burden, immune cell densities and types in the tumor microenvironment, expression levels of PD-1/PD-L1 and cytokines are potential determinants of such distinct response to PD-1/PD-L1 blockades in CRC patients with different MSI statuses which might help clinicians to select candidates for anti-PD-1/PD-L1 therapy and improve therapeutic response in patients with CRC.

Case Report: COVID-19 Vaccination Associated Fulminant Myocarditis.

Herein, we describe a novel finding of fulminant myocarditis (FM) in two subjects the day after administration of the first dose of the currently available inactivated SARS-CoV-2 vaccine (Vero cell). Cardiac magnetic resonance imaging revealed extensive myocardial edema and necrosis. A pathologic evaluation of the endocardial biopsy tissues revealed inflammatory cell (lymphocytes) infiltration and interstitial edema, myocyte necrosis, and focal areas of fibrosis. A life-support-based comprehensive treatment regimen comprising mechanical circulatory support using intra-aortic balloon pulsation and immunomodulatory therapy-glucocorticoids and intravenous immunoglobulin-was used to treat the patients with FM; eventually, the patients recovered and were discharged. To our knowledge, these are the first two reported cases of FM, with no other identified cause or associated illness, after receiving the inactivated SARS-CoV-2 vaccine (Vero cell). These findings suggest a novel pathogenesis of myocarditis which mentions to pay more attention to this rare, but lethal complication of COVID-19 vaccination.

Immune battle at the premalignant stage of colorectal cancer: focus on immune cell compositions, functions and cytokine products.

It is now widely accepted that most human cancers, including colorectal cancers (CRCs), develop from premalignant lesions through a long-term multistep process. Host immunity is a key determinant that maintains most premalignant lesions in a stable state via immunosurveillance. However, premalignant cells use diverse strategies to escape host immunosurveillance. A switch in the immune function from immunosurveillance to immunosuppression facilitates the progression of premalignant lesions to established CRCs. This review summarizes the recent progress in understanding alterations in the immune landscape, including immune cell compositions, functions and cytokine products, in the premalignant stage of CRC and provides an updated discussion on its translational significance along the colorectal adenoma-carcinoma sequence.

ST2 and regulatory T cells in the colorectal adenoma/carcinoma microenvironment: implications for diseases progression and prognosis.

ST2 (also known as IL1RL1) is the critical functional receptor for interleukin (IL)-33 in stimulating regulatory T cell (Treg) expansion and function in physiological and pathological conditions. We examined the correlation between ST2 cell expression and FoxP3 positive Tregs in both colorectal adenoma and cancer (CRC) microenvironment by real-time PCR, immunohistochemistry (IHC) and double immunofluorescences. The clinicopathological and prognostic significance of cellular ST2-positive cells and FoxP3-positive Tregs in patients with adenoma and CRC were evaluated. Real-time PCR results revealed increased expression levels of ST2 and FoxP3 mRNAs in both adenoma and CRC tissues as compared with control tissues. IHC analysis confirmed increased densities of ST2-positive cells in both the adenoma/CRC epithelium and stroma, which show a close positive linear association with the densities of FoxP3-positive Tregs in respective compartments. Pathological feature analysis showed that densities of ST2-positive cells in the tumor stroma were notably associated with degree of dysplastic grading in patients with adenoma, and disease stages and lymph node metastasis in patients with CRC. Kaplan-Meier survival curves suggested that CRC patients with high densities of ST2-positive cells in the stroma tend to have a shorter overall survival. We therefore concluded that increased densities of ST2-postive cells relate to Treg accumulation within the adenoma/CRC microenvironment, suggesting the IL-33/ST2 pathway as a potential contributor for immunosuppressive milieu formation that impact disease stage and prognosis in patients with CRC.

Tumoral Expression of CD166 in Human Esophageal Squamous Cell Carcinoma: Implications for Cancer Progression and Prognosis.

Accumulating data showed that cancer stem cells (CSCs) identified by cell surface markers contribute to the initiation, progression, and prognosis of human cancers. In this study, the expression of CSC candidates CD166, CD44, and Lgr5 in 65 cases of esophageal squamous cell carcinoma (ESCC) and 16 cases of control esophageal tissues were examined with immunohistochemistry (IHC). The correlation between tumoral expression levels of these CSC candidates and clinicopathological variables was analyzed. IHC results showed that the expression of CD166 in esophageal control tissues was completely negative, but it was in 87.69% (57/65) ESCC tissues. The expression of CD44 and Lgr5 did not differ between esophageal control tissues and ESCC tissues (p > 0.05). In addition, there were not correlations found among the expression levels of CD166, CD44, and Lgr5 in ESCC tissues. Clinicopathological analysis revealed that the tumoral expression level of CD166 correlated with lymph node involvement and TNM staging in patients with ESCC, and lower tumoral expression of CD44 was found in patients with advanced TNM staging. Kaplan-Meier survival curves suggested that expression level of CD166 appeared to have a negative impact on overall survival rate after surgery in patients with ESCC. Such impact was not found in other two CSC candidates. The authors therefore conclude that CD166 is a potential prognostic biomarker and correlates with advanced progression features in patients with ESCC.

TH9, TH17, and TH22 Cell Subsets and Their Main Cytokine Products in the Pathogenesis of Colorectal Cancer.

In recent years, several newly identified T helper (TH) cell subsets, such as TH9, TH17, and TH22 cells, and their respective cytokine products, IL-9, IL-17, and IL-22, have been reported to play critical roles in the development of chronic inflammation in the colorectum. Since chronic inflammation is a potent driving force for the development of human colorectal cancer (CRC), the contributions of TH9/IL-9, TH17/IL-17, and TH22/IL-22 in the pathogenesis of CRC have recently become an increasingly popular area of scientific investigation. Extensive laboratory and clinical evidence suggests a positive relationship between these new TH subsets and the growth and formation of CRC, whereas, administration of IL-9, IL-17, and IL-22 signaling inhibitors can significantly alter the formation of colorectal chronic inflammation or CRC lesions in animal models, suggesting that blocking these cytokine signals might represent promising immunotherapeutic strategies. This review summarizes recent findings and currently available data for understanding the vital role and therapeutic significance of TH9/IL-9, TH17/IL-17, and TH22/IL-22 in the development of colorectal tumorigenesis.