Markers In Tumor Tissue Research Articles

Altingia chinensis petroleum ether extract suppresses NSCLC via induction of apoptosis, attenuation of EMT, and downregulation of PI3K/Akt pathway

BackgroundNon-small-cell lung cancer (NSCLC) is the primary type of lung cancer with the leading cause of fatalities from cancer, and the effective treatment is minimal. Altingia chinensis is a medicinal plant utilized as a traditional folk remedy to alleviate rheumatism, punch injury and paralysis. APE is the petroleum ether extract from A. Chinensis, whose antitumor effects are rarely studied. PurposeTo explore the antitumor effects of APE on NSCLC and its molecular mechanism. MethodsLLC and H1299 cells were used to explore the anticancer effect of APE on NSCLC in vitro. MTT assay and colony formation were employed to evaluate cell viability. Flow cytometry was used to evaluate apoptosis. Wound healing and transwell were employed to evaluate cell migration and invasive capacity. Meanwhile, an LLC tumor-bearing C57BL/6 mice model was established for assessing the anticancer effect of APE on NSCLC in vivo. H&E staining was used to assess histopathology. TUNEL assay was performed to assess apoptosis in tumor tissue. Network pharmacology, CESTA, and kinase assay were employed to analyze potential molecular mechanisms. Western blots were performed to detect proteins involved in apoptosis, EMT, and the PI3K/Akt pathway. ResultsThis is the first investigation to identify APE's antitumor potential in both NSCLC cells and tumor-bearing mice models. Significantly, APE dose-dependently decreased cell viability and caused morphological changes both in LLC and H1299 cells. Furthermore, APE (31.25, 62.5, and 125 μg/ml) induced apoptosis in NSCLC cells, as demonstrated by increased Annexin V-FITC/PI-stained cells, the cleaved-caspase 3 levels, and the Bax/Bcl-2 ratio. Additionally, APE suppressed cell migration and invasion by the increase of E-cadherin expression and the downregulation of vimentin, implying that APE inhibited cell metastasis via attenuation of EMT. Importantly, intragastric administration of 100 mg/kg APE significantly inhibited tumor growth without apparent side effects. TUNEL assay confirmed the apoptosis in tumor tissue. Western blots validated the alteration of EMT and apoptotic markers in tumor tissue, which matched the in vitro findings. Moreover, APE directly bound to PI3Kα and inhibited its activity, leading to inhibition of the PI3K-Akt pathway. ConclusionOverall, APE exhibits anti-tumor effects on NSCLC via induction of apoptosis, attenuation of EMT, and its mechanism involves the suppression of the PI3K/Akt pathway. Our study offers new insights for the identification of novel drug development for NSCLC.

Melatonin downregulates angiogenesis and lymphangiogenesis by regulating tumor-associated macrophages via NLRP3 inflammasomes in lung adenocarcinoma.

Tumor-associated macrophages (TAMs), present within the tumor microenvironment (TME), strictly modulate tumor angiogenesis and lymphangiogenesis. Nevertheless, the associated signaling networks and candidate drug targets for these events remains to be elucidated. Given its antioxidative activities, we speculated that melatonin may reduce pyroptosis, and thereby modulate both angiogenesis and lymphangiogenesis. We revealed that a co-culture of A549 cells and THP-1 macrophages strongly enhanced expressions of the NLRP3 inflammasome axis members, and augmented angiogenesis and lymphangiogenesis. Next, we overexpressed NLRP3 in the A549 cells, and demonstrated that excess NLRP3 expression substantially upregulated VEGF and CXCL cytokine expressions, and enhanced lymphatic endothelial cells (LECs) tube formation. In contrast, NLRP3 inhibition produced the opposite effect. In addition, relative to controls, melatonin administration strongly inhibited the NLRP3 inflammasome axis, as well as angiogenesis and lymphangiogenesis in the co-culture system. Subsequent animal experiments using a Lewis Lung Carcinoma (LLC) subcutaneous tumor model in mice corroborate these findings. Melatonin treatment and NLRP3 knockdown significantly inhibit tumor growth and downregulate NLRP3 and IL-1β expression in tumor tissues. Furthermore, melatonin downregulates the expression of angiogenic and lymphangiogenic markers in tumor tissues. Taken together, the evidence suggested that a THP-1 macrophage and A549 cell co-culture stimulates angiogenesis and lymphangiogenesis via the NLRP3 axis. Melatonin protected against the TAMs- and NLRP3 axis-associated promotion of the aforementioned events in vitro and in vivo. Hence, melatonin is a promising candidate for managing for tumor-related angiogenesis and lymphangiogenesis in lung adenocarcinoma.

Noninvasive Lung Cancer Subtype Classification Using Tumor-Derived Signatures and cfDNA Methylome.

This study explores the use of cfDNA methylomes for the classification of lung cancer subtypes, vital for effective treatment. By identifying specific methylation markers in tumor tissues, we developed a robust classification model achieving high accuracy for noninvasive subtype detection. This cfDNA methylome approach offers promising avenues for early detection and monitoring.

F127/chlorin e6-nanomicelles to enhance Ce6 solubility and PDT-efficacy mitigating lung metastasis in melanoma.

Photodynamic Therapy (PDT) is a promising paradigm for treating cancer, especially superficial cancers, including skin and oral cancers. However, the effectiveness of PDT is hindered by the hydrophobicity of photosensitizers. Here, chlorin e6 (Ce6), a hydrophobic photosensitizer, was loaded into pluronic F127 micelles to enhance solubility and improve tumor-specific targeting efficiency. The resulting Ce6@F127 Ms demonstrated a significant increase in solubility and singlet oxygen generation (SOG) efficiency in aqueous media compared to free Ce6. The confocal imaging and fluorescence-activated cell sorting (FACS) analysis confirmed the enhanced internalization rate of Ce6@F127 Ms in murine melanoma cell lines (B16F10) and human oral carcinoma cell lines (FaDu). Upon laser irradiation (666nm), the cellular phototoxicity of Ce6@F127 Ms against B16F10 and FaDu was approximately three times higher than the free Ce6 treatment. The in vivo therapeutic investigations conducted on a murine model of skin cancer demonstrated the ability of Ce6@F127 Ms, when combined with laser treatment, to penetrate solid tumors effectively, which resulted in a significant reduction in tumor volume compared to free Ce6. Further, the Ce6@F127 Ms demonstrated upregulation of TUNEL-positive cells, downregulation of proliferation markers in tumor tissues, and prevention of lung metastasis with insignificant levels of proliferating cells and collagenase, as validated through immunohistochemistry. Subsequent analysis of serum and blood components affirmed the safety and efficacy of Ce6@F127 Ms in mice. Consequently, the developed Ce6@F127 Ms exhibits significant potential for concurrently treating solid tumors and preventing metastasis. The photodynamic formulation holds great clinical translation potential for treating superficial tumors.

Subcellular expression of MTA1, HIF1A and p53 in primary tumor predicts aggressive triple negative breast cancers: a meta-analysis based study.

The prevalence of TNBC in India is higher compared to western countries. There is a multitude of biomarkers associated with different clinical outcomes of TNBC with contradictory reports. Identification of a set of specific biomarkers from the very many number of proteins reported in the literature to predict prognosis of TNBC is an urgent clinical need. A systematic review of key molecular biomarkers in cohort studies that have been investigated for their role in breast cancer prognosis was conducted. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology was followed. A meta-analysis was used to evaluate their pooled hazard ratio (HR) and the corresponding 95% confidence interval (95% CI) statistically. Immunohistochemical characterization of the meta-analyzed markers were performed in a cohort of 200 retrospective TNBC and 100 non TNBC patient tissues. Kaplan-Meier plot were used to evaluate disease free survival (DFS), and overall survival (OS). Cox regression models were used to evaluate predictors of DFS and OS. Using a meta-analytical approach, we consolidated the biomarker signatures associated with survival outcomes in breast cancers. The promising markers that emerged for the prediction of DFS and OS included E-Cadherin, Survivin, p53, MTA1, HIF1A, CD133, Vimentin and CK5/6. Evaluation of these markers in tumor tissue revealed that subcellular localization of p53, MTA1 and HIF1A had a significant association in predicting TNBC prognosis. Kaplan Meier plot revealed that p53 (OS p = 0.007, DFS p = 0.004), HIF 1A (OS p = 0.054, DFS p = 0.009) and MTA1 (OS p = 0.043, DFS = p = 0.001) expression in the primary tumor tissue were found to be significantly correlated with poor OS and DFS, whereas expression of Survivin (DFS p = 0.024) and E Cadherin (DFS p = 0.027) correlated with DFS alone in TNBC. Univariate analysis revealed that p53, HIF1A and MTA1 could be independent prognostic markers. Our study suggests cytoplasmic over expression of HIF1A, nuclear over expression of MTA1 and mutated p53 in the primary tumor tissue of TNBC have significance as markers predicting survival of TNBC patients.

Abstract 3405: CT-assessed body composition and tumor immunologic characteristics in patients with non-small-cell lung cancer

Abstract Objectives: Obesity is associated with higher immunotherapy efficacy, but body mass index is a convoluted marker of adipose and muscle tissue. We conducted a discovery scale study to assess the association of skeletal muscle and adipose tissue areas annotated on computed tomography (CT) scan images with selected tumor immunologic characteristics among patients with non-small-cell lung cancer (NSCLC). Methods: We analyzed publicly available data from 102 patients (mean age = 67.2, 47.1% female, and 70.6% stage I-II) who had diagnostic CT images in The Cancer Image Archive. All patients had the 12th thoracic vertebra (T12) image, and a subset (62 patients) had the 3rd lumber vertebra (L3) image. Paravertebral muscle areas on T12 and skeletal muscle and adipose tissue areas on L3 were annotated using Slice-O-Matic. RNA-seq data were provided by The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium; percentages of CD8, regulatory T cells, and activated NK cells were identified using the CIBERSORT. ESTIMATE algorithm was used to derive the stromal score and the immune score. Differences in the immune markers were examined using ANOVA adjusting for stage, histology, and study. Results and Conclusion: Patients with higher paravertebral muscle area (3rd tertile) had the lowest stromal scores, compared to the 2nd and 1st tertile (P<0.05). Patients in the 2nd tertile of paravertebral muscle areas had the highest immune score and CD274 (PD-L1) gene expression. Among the body composition types classified using L3 images, low muscle/high adiposity was associated with lower stromal scores, and low muscle was associated with lower immune scores, compared to high adiposity and high muscle/low adiposity types. Other immunological markers did not differ across the body composition types. Significance: These findings suggest associations between deconvoluted skeletal and adipose tissue components and tumor markers relevant to immune checkpoint inhibitor efficacies in NSCLC. Further validation using immune phenotyping in a large patient sample is warranted. Funding: The study is in part supported by NIH/NCI R37CA248371 and OSU Comprehensive Cancer Center - James. Citation Format: Ting-Yuan David Cheng, Cuthbert Mario Mahenge, Rand T. Akasheh, Ayse Selen Yilmaz, Ben Kinder, Xuan Nguyen, Maciej Pietrzak, Carolyn J. Presley, Peter G. Shields. CT-assessed body composition and tumor immunologic characteristics in patients with non-small-cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3405.

Etomidate inhibits tumor growth of glioblastoma by regulating M1 macrophage polarization.

Glioblastoma (GBM) is a common primary central nervous system tumor. Although the multimodal integrated treatment for GBM has made great progress in recent years, the overall survival time of GBM is still short. Thus, novel treatments for GBM are worth further investigation and exploration. This study aimed to investigate the effects of etomidate on GBM tumor growth and the underlying mechanism. A xenograft tumor model was established and treated with etomidate to assess tumor growth. Immunohistochemistry (IHC) assay evaluated the positive rate of Ki67 cells in tumor tissues. Cell counting kit (CCK)-8 and EdU assays accessed the cell viability and proliferation. Immunofluorescence (IF) staining detected the distribution of macrophage markers in tumor tissues. The percentages of M1- and M2-like macrophages in tumor-associated macrophages (TAMs) and co-culture system (macrophages and GBM cells) were detected using flow cytometry. Macrophage polarization-related genes were measured using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Etomidate treatment inhibited the tumor growth, and increased the CD86+ cells but decreased the CD206+ cells in TAMs. The gene expression of M1 markers was increased in TAMs of etomidate-treated mice, whereas that of M2 markers was decreased. Moreover, etomidate treatment increased the number of CD86+ M1-like macrophages co-cultured with tumor cells but decreased that of CD206+ M2-like macrophages, with the upregulation of M1 markers and downregulation of M2 markers. Etomidate inhibited GBM tumor growth by promoting M1 macrophage polarization, suggesting a new insight into the clinical treatment of GBM.

Colon-targeted S100A8/A9-specific peptide systems ameliorate colitis and colitis-associated colorectal cancer in mouse models.

The link between chronic inflammation and cancer development is well acknowledged. Inflammatory bowel disease including ulcerative colitis and Crohn's disease frequently promotes colon cancer development. Thus, control of intestinal inflammation is a therapeutic strategy to prevent and manage colitis-associated colorectal cancer (CRC). Recently, gut mucosal damage-associated molecular patterns S100A8 and S100A9, acting via interactions with their pattern recognition receptors (PRRs), especially TLR4 and RAGE, have emerged as key players in the pathogenesis of colonic inflammation. We found elevated serum levels of S100A8 and S100A9 in both colitis and colitis-associated CRC mouse models along with significant increases in their binding with PRR, TLR4, and RAGE. In this study we developed a dual PRR-inhibiting peptide system (rCT-S100A8/A9) that consisted of TLR4- and RAGE-inhibiting motifs derived from S100A8 and S100A9, and conjugated with a CT peptide (TWYKIAFQRNRK) for colon-specific delivery. In human monocyte THP-1 and mouse BMDMs, S100A8/A9-derived peptide comprising TLR4- and RAGE-interacting motif (0.01, 0.1, 1 μM) dose-dependently inhibited the binding of S100 to TLR4 or RAGE, and effectively inhibited NLRP3 inflammasome activation. We demonstrated that rCT-S100A8/A9 had appropriate drug-like properties including in vitro stabilities and PK properties as well as pharmacological activities. In mouse models of DSS-induced acute and chronic colitis, injection of rCT-S100A8/A9 (50 μg·kg-1·d-1, i.p. for certain consecutive days) significantly increased the survival rates and alleviated the pathological injuries of the colon. In AOM/DSS-induced colitis-associated colorectal cancer (CAC) mouse model, injection of rCT-S100A8/A9 (50 μg·kg-1·d-1, i.p.) increased the body weight, decreased tumor burden in the distal colon, and significantly alleviated histological colonic damage. In mice bearing oxaliplatin-resistant CRC xenografts, injection of rCT-S100A8/A9 (20 μg/kg, i.p., every 3 days for 24-30 days) significantly inhibited the tumor growth with reduced EMT-associated markers in tumor tissues. Our results demonstrate that targeting the S100-PRR axis improves colonic inflammation and thus highlight this axis as a potential therapeutic target for colitis and CRC.

Fabrication of Antibody Conjugated Super Magnetic Oxide Nanoparticles for Early Detection of Prostate Cancer.

Prostate cancer is one of the most widespread cancers in the world. Early diagnosis is the most important factor in treatment efficiency. Furthermore, new methods for early diagnosis and treatment play an important role. In this study, we designed targeted conjugation of antibodies with iron nanoparticles and evaluated the binding properties of antibodies to prostate cancers and benign tissues. This method in addition to having a lower cost has high sensitivity and specificity. Anti- PSCA antibodies were purified and conjugated to super magnetic oxide nanoparticles (SPION). Then, iron staining on prostate adenocarcinoma tissues was performed. At the same time, immunohistochemically staining was performed on similar tissues to compare the results. In addition, benign prostatic hyperplasia (BPH) samples were used as a control sample. In adenocarcinoma tissues with iron staining, many blue spots are seen compared to benign tissues, and the number of these spots increases with increasing tumor grade. These findings indicate the characteristic of iron staining as a conjugate antibody to iron can be an appropriate approach to specific staining of tumor markers in cancer tissues and can be used to diagnose prostate cancer due to its safety, low cost, sensitivity, and specificity.

Associations between Etiologic or Prognostic Tumor Tissue Markers and Neighborhood Contextual Factors in Male Health Professionals Diagnosed with Prostate Cancer.

There is growing evidence that unfavorable neighborhood contexts may influence prostate cancer progression. Whether these associations may be explained in part by differences in tumor-level somatic alterations remain unclear. Data on tumor markers (PTEN, p53, ERG, and SPINK1) were obtained from 1,157 participants with prostate cancer in the Health Professionals Follow-up Study. Neighborhood greenness, socioeconomic status, and the income Index of Concentration at Extremes were obtained from satellite and census data and linked to participants' address at diagnosis and at study enrollment. Exposures were scaled to an interquartile range and modeled as tertiles. Bivariate associations between tertiles of neighborhood factors and tumor markers were assessed in covariate adjusted logistic regression models to estimate ORs and 95% confidence intervals. There was no association between any of the neighborhood contextual factors and PTEN, p53, ERG, or SPINK1 in bivariate or multivariable adjusted models. Results were generally consistent when modeling exposure using exposure at diagnosis or at study enrollment. In this multilevel study of men with prostate cancer, we found no evidence of associations between neighborhood context and tumor tissue markers. Our results provide some of the first empirical data in support of the hypothesis that prostate cancer risk conferred by tumor tissue markers may arise independently of underlying neighborhood context. Prospective studies in more diverse populations are needed to confirm these findings.

Xihuang Pill-destabilized CD133/EGFR/Akt/mTOR cascade reduces stemness enrichment of glioblastoma via the down-regulation of SOX2

BackgroundOur previous study found that XHP could induce GBM cells to undergo apoptosis. A lot of evidence suggests that glioma stem-like cells (GSCs) are key factors that contribute to disease progression and poor prognosis of glioblastoma multiforme (GBM). Traditional Chinese medicine has been applied in clinical practice as a complementary and alternative therapy for glioma. PurposeTo evaluate the effect and the potential molecular mechanism of Xihuang pill (XHP) on GSCs. MethodsUPLC-QTOF-MS analysis was used for constituent analysis of XHP. Using network pharmacology and bioinformatics methods, a molecular network targeting GSCs by the active ingredients in XHP was constructed. Cell viability, self-renewal ability, apoptosis, and GSC markers were detected by CCK-8 assay, tumor sphere formation assay and flow cytometry, respectively. The interrelationship between GSC markers (CD133 and SOX2) and key proteins of the EGFR/Akt/mTOR signaling pathway was evaluated using GEPIA and verified by western blot. A GBM cell line stably overexpressing Akt was constructed using lentivirus to evaluate the role of Akt signaling in the regulation of glioma stemness. The effect of XHP on glioma growth was analyzed by a subcutaneously transplanted glioma cell model in nude mice, hematoxylin-eosin staining was used to examine pathological changes, TUNEL staining was used to detect apoptosis in tumor tissues, and the expression of GSC markers in tumor tissues was identified by western blot and immunofluorescence. ResultsBioinformatics analysis showed that 55 matched targets were related to XHP targets and glioma stem cell targets. In addition to causing apoptosis, XHP could diminish the number of GBM 3D spheroids, the proportion of CD133-positive cells and the expression level of GSC markers (CD133 and SOX2) in vitro. Furthermore, XHP could attenuate the expression of CD133, EGFR, p-Akt, p-mTOR and SOX2 in GBM spheres. Overexpression of Akt significantly increased the expression level of SOX2, which was prohibited in the presence of XHP. XHP reduced GSC markers including CD133 and SOX2, and impeded the development of glioma growth in xenograft mouse models in vivo. ConclusionWe demonstrate for the first time that XHP down-regulates stemness, restrains self-renewal and induces apoptosis in GSCs and impedes glioma growth by down-regulating SOX2 through destabilizing the CD133/EGFR/Akt/mTOR cascade.

Exome sequencing analysis of gastric primary myeloid sarcoma with monocytic differentiation with altered immunophenotype after chemotherapy: case report

BackgroundMyeloid Sarcoma with monocytic differentiation is rare and quite likely is missed by surgical pathologists. However it is frequently misdiagnosed because of its non-specific imaging and histological pattern.Case presentationWe report the case of a 64-year-old woman with gastric primary myeloid sarcoma with monocytic differentiatio. Upper endoscopy revealed a neoplastic growth at the junction of the lesser curvature and gastric antrum. Except for a slightly increased peripheral monocyte count, no abnormalities were found on hematological and bone-marrow examination. Gastroscopic biopsy showed poorly differentiated atypical large cells with visible nucleoli and nuclear fission. Immunohistochemistry showed positive CD34, CD4, CD43, and CD56 expression, and weakly positive lysozyme expression. Immune markers for poorly differentiated adenocarcinoma, malignant melanoma, and lymphohematopoietic-system tumors were negative. The final diagnosis was myeloid sarcoma with monocytic differentiation. Chemotherapy did not shrink the tumor, so, radical surgery was performed. Although the tumor morphology did not change postoperatively, the immunophenotype did. CD68 and lysozyme expression (tumor tissue markers) changed from negative and weakly positive to strongly positive, AE1/3 expression (epithelial marker) changed from negative to positive, and CD34, CD4, CD43, and CD56 expression (common in naive hematopoietic cell-derived tumors) was greatly attenuated. Exome sequencing revealed missense mutations in FLT3 and PTPRB, which are associated with myeloid sarcoma, and in TP53, CD44, CD19, LTK, NOTCH2, and CNTN2, which are associated with lymphohematopoietic tumors and poorly differentiated cancers.ConclusionWe diagnosed myeloid sarcoma with monocytic differentiation after excluding poorly differentiated adenocarcinoma, common lymphohematopoietic-system tumors, epithelioid sarcoma, and malignant melanoma. We identified that the immunophenotypic of patient had alterations after chemotherapy, and FLT3 gene mutations. We hope that the above results will improve our understanding of this rare tumor.

A study of p53 and Bcl-2 genes expression and their relation to histopathological variables using DNA in situ hybridization in bladder cancer patients

Bladder carcinoma (BC) is one of the most common cancers worldwide, it accounts for 6.5% of all cancers, with highest incidence in industrialized countries. The investigation of p53 and bcl-2 expression by using in situ hybridization technique on the formalin fixed paraffin embedded sections and studying their relationships with the histopathological variables (type cells, grade, stage, and invasiveness) of bladder cancer was our aim of this work. In this study we have investigated p53 and bcl2 genes expression as tumor markers in BC. In situ hybridization technique was used to quantitate these markers in tumor tissues. A total of 50 bladder cancer tissues were examined compared with twelve cystitis tissue sections as control group. The results revealed significant differences between p53 and bcl2 overexpression (p=0.001) for both markers. A significant positive correlation between p53 and bcl-2 expression with grade) p=0.003, p=005 respectively) and invasiveness were found (p= 0.002, p= 0.007 respectively), while both gene expression were found to be negatively associated with other histological variables (histological type, stage, gender and age group). The intensity of p53 and bcl-2 overexpression revealed correlation with high grade (p=0.005, p=0.04) respectively, and invasive status (p = 0.01, p=0.05) respectively. In conclusion, this study confirms that p53 and bcl-2 play crucial roles in carcinogenesis process and BC management.

Predictors of residual disease after debulking surgery in advanced stage ovarian cancer.

Optimal debulking with no macroscopic residual disease strongly predicts ovarian cancer survival. The ability to predict likelihood of optimal debulking, which may be partially dependent on tumor biology, could inform clinical decision-making regarding use of neoadjuvant chemotherapy. Thus, we developed a prediction model including epidemiological factors and tumor markers of residual disease after primary debulking surgery. Univariate analyses examined associations of 11 pre-diagnosis epidemiologic factors (n=593) and 24 tumor markers (n=204) with debulking status among incident, high-stage, epithelial ovarian cancer cases from the Nurses' Health Studies and New England Case Control study. We used Bayesian model averaging (BMA) to develop prediction models of optimal debulking with 5x5-fold cross-validation and calculated the area under the curve (AUC). Current aspirin use was associated with lower odds of optimal debulking compared to never use (OR=0.52, 95%CI=0.31-0.86) and two tissue markers, ADRB2 (OR=2.21, 95%CI=1.23-4.41) and FAP (OR=1.91, 95%CI=1.24-3.05) were associated with increased odds of optimal debulking. The BMA selected aspirin, parity, and menopausal status as the epidemiologic/clinical predictors with the posterior effect probability ≥20%. While the prediction model with epidemiologic/clinical predictors had low performance (average AUC=0.49), the model adding tissue biomarkers showed improved, but weak, performance (average AUC=0.62). Addition of ovarian tumor tissue markers to our multivariable prediction models based on epidemiologic/clinical data slightly improved the model performance, suggesting debulking status may be in part driven by tumor characteristics. Larger studies are warranted to identify those at high risk of poor surgical outcomes informing personalized treatment.

Diagnosis and functional prediction of microbial markers in tumor tissues of sporadic colorectal cancer patients associated with the MLH1 protein phenotype.

Most patients with sporadic colorectal cancer (SCRC) develop microsatellite instability because of defects in mismatch repair (MMR). Moreover, the gut microbiome plays a vital role in the pathogenesis of SCRC. In this study, we assessed the microbial composition and diversity of SCRC tumors with varying MutL protein homolog 1 (MLH1) status, and the effects of functional genes related to bacterial markers and clinical diagnostic prediction. The tumor microbial diversity and composition were profiled using high-throughput sequencing of the 16S ribosomal RNA (rRNA) gene V4 region. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt2) software and BugBase tool were used to predict the functional roles of the microbiome. We aimed to construct a high-accuracy model to detect and evaluate the area under the receiver operating characteristic curve with candidate biomarkers. The study included 23 patients with negative/defective MLH1 (DM group) and 22 patients with positive/intact MLH1 (IM group). Estimation of alpha diversity indices showed that the Shannon index (p = 0.049) was significantly higher in the DM group than in the controls, while the Simpson index (p = 0.025) was significantly lower. At the genus level, we observed a significant difference in beta diversity in the DM group versus the IM group. Moreover, the abundance of Lachnoclostridium spp. and Coprococcus spp. was significantly more enriched in the DM group than in the IM group (q < 0.01 vs. q < 0.001). When predicting metagenomes, there were 18 Kyoto Encyclopedia of Genes and Genomes pathways and one BugBase function difference in both groups (all q < 0.05). On the basis of the model of diagnostic prediction, we built a simplified optimal model through stepwise selection, consisting of the top two bacterial candidate markers (area under the curve = 0.93). In conclusion, the genera Lachnoclostridium and Coprococcus as key species may be crucial biomarkers for non-invasive diagnostic prediction of DM in patients with SCRC in the future.

PD‑L1 mediates triple‑negative breast cancer evolution via the regulation of TAM/M2 polarization

Tumor-associated macrophages/M2-type (TAM/M2) play a key role in the metastasis and angiogenesis of cancer, and are considered to be critical targets for cancer treatment. However, it remains unclear whether α-programmed death-ligand 1 (αPD-L1; PD-L1 inhibitor) inhibits tumor progression via targeting TAMs. In the present study, it was demonstrated that αPD-L1 significantly inhibited IL-13-induced TAM/M2 polarization in vitro. Moreover, αPD-L1 inhibited the epithelial-mesenchymal transition (EMT) process and the stemness of triple-negative breast cancer (TNBC) cells, which were mediated via the reversal of TAM/M2 polarization. This therefore inhibited the migration and angiogenesis of TNBC cells. Furthermore, αPD-L1 prevented STAT3 phosphorylation and nuclear translocation, which resulted in the arrest of TAM/M2 polarization. In vivo experiments further demonstrated that αPD-L1 reduced the number of lung metastases without affecting tumor growth. Moreover, αPD-L1 reduced the expression levels of TAM/M2, EMT, stemness and vascular markers in tumor tissues. In summary, these data suggest that αPD-L1 plays a vital role in the anti-metastasis and anti-angiogenesis of TNBC in vitro and in vivo via the inhibition of TAM/M2 polarization. These findings may thus provide a novel therapeutic strategy for clinically refractory TNBC.

COL11A1 serves as a biomarker for poor prognosis and correlates with immune infiltration in breast cancer.

Breast cancer is the malignant tumor with the highest incidence rate at present, and its incidence rate ranks first in the female population. COL11A1 is an important component of collagen XI and is considered to play an important role in a variety of connective tissue diseases. Recent studies have shown that COL11A1 is associated with the occurrence and development of many kinds of malignant tumors. However, its prognostic value in breast cancer and its correlation with immune cell infiltration in tumor tissue are not clear. In this paper, we reveal the prognostic value of COL11A1 in breast cancer and its tumor immune-related function through in-depth bioinformatics analysis. The expression of COL11A1 is abnormally upregulated in breast cancer and is significantly related to the poor prognosis of breast cancer. In the analysis of the clinical characteristics of the patients, we found that the expression level of COLL11A1 was closely related to lymph node metastasis, PAM50 (Prediction Analysis of Microarray 50) expression, clinical stage and so on. Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) all suggest that COL11A1 is related to tumor immunity. Further study found that the COL11A1 expression was significantly correlated with the degree of immune infiltration and the expression of a variety of immune cell markers in tumor tissue. More importantly, COL11A1 can affect the prognosis of breast cancer patients by participating in the regulation of tumor immune infiltration. Therefore, we believe that COL11A1 is a very potential target for diagnosis and treatment of breast cancer.

IDH1 Mutation Induces HIF-1α and Confers Angiogenic Properties in Chondrosarcoma JJ012 Cells.

Chondrosarcoma is a group of primary bone cancers that arise from transformed cells of chondrocytic lineage. Tumor recurrence and metastasis are devastating for patients with chondrosarcoma since there are no effective treatment options. IDH mutations occur in over 50% of tumors from patients with conventional or dedifferentiated chondrosarcomas and represent an attractive target for therapy. However, their role in the pathogenesis of chondrosarcoma remains largely unknown. In this study, we sought to determine the association of IDH mutation and HIF-1α in chondrosarcoma. We used the chondrosarcoma JJ012 cell line and its derived CRISPR/Cas9 mutant IDH1 (IDH1mut) knockout (KO) cells. RNA-Seq data analysis revealed downregulation of several HIF-1α target genes upon loss of IDH1mut. This was associated with reduced HIF-1α levels in the IDH1mut KO cells and tumors. Loss of IDH1mut also attenuated the expression of angiogenic markers in tumor tissues and abrogated the angiogenic capacity of JJ012 cells. Moreover, we observed that exogenous expression of HIF-1α significantly promoted anchorage-independent colony-formation by IDH1mut KO cells. These results suggest IDH1 mutation confers angiogenic and tumorigenic properties of JJ012 cells by inducing HIF-1α. Thus, the HIF pathway represents a promising candidate for combinatorial regimens to target IDH1 mutated chondrosarcomas.

Molecular Markers in Guiding Lung Cancer Diagnosis and Treatment

Background: Lung cancer has the highest mortality rates and one of the lowest 5-year survival rates amongst cancer types in the world. Although there are constant advancements in treatment, the overall prognosis for lung cancer continues to be poor. In order to achieve early detection and personalized targeted treatment, an effective method is needed to make prognostic and treatment decisions. Methods: A thorough literature search was conducted to identify tumor tissue, blood, and expired breath markers that have been discovered in lung cancer. Articles were chosen by determining main markers holding promise for future clinical use. Results: Data suggests significance in using tumor tissue markers as promising diagnostic, prognostic and predictive of treatment response and outcome. Epidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma Kinase (ALK) and ROS-1 biomarkers can be used to decide to treat with EGFR-TKI and ALK-TKI, respectively. KRAS and p53 mutations suggest a likelihood of developing EGFR-TKI resistance. And c-MET is showing pertinence in predicting disease recurrence. Blood and expired breath markers are two more novel sources for biomarkers that is gaining more ground in lung cancer research. Circulating tumor cells (CTC) and DNA (ctDNA) were shown to be important markers in lung cancer prognosis and treatment response prediction. Circulating tumor cells suggest negative prognosis and increased likelihood of recurrence, while ctDNA data indicates use in treatment monitoring to help make decisions without keeping patients on disagreeable therapies. Volatile organic compounds (VOC) are the least studied, but investigators have noticed changes in VOC profiles between healthy and lung cancer patients. Blood and expired breath markers continue to be studied as these would be a welcome alternative to invasive biopsies. Recently there had been interest in using specific tumor biomarkers for imaging to localize tumors and determine disease progression. Conclusions: Years of research have elucidated multiple candidates as biomarkers found in tumor tissues, circulation, and even in exhaled air. Although more studies need to be performed on some markers mentioned in this review, such as EGFR, KRAS, ALK, and ROS-1, there is enough evidence for some use of these biomarkers to guide decisions in clinic, as well as evidence for promising future developments.

The Expression of Programmed Death Ligand 1 and Vimentin in Resected Non-Metastatic Non-Small-Cell Lung Cancer: Interplay and Prognostic Effects.

Programmed death ligand 1 (PD-L1) is an immune checkpoint with a role in cancer-related immune evasion. It is a target for cancer immunotherapy and its expression is detected for the use of some immune checkpoint inhibitors in advanced non-small cell lung cancer patients (NSCLC). Vimentin is a key component of the epithelial-to-mesenchymal transition phenotype. Its expression has negative prognostic effects in NSCLC. In this study, we retrospectively evaluated PD-L1 and vimentin expression in tumor cells, immune infiltrate and PD-L1 positive immune infiltrate via immunohistochemistry in tissue samples from resected non-metastatic NSCLC patients. We explored the interplay between PD-L1 and vimentin expression through Spearman’s correlation test. We performed univariate analysis through the Cox models for demographic and clinico-pathological variables, and also for dichotomized biomarkers, i.e., PD-L1 and vimentin in tumor cells, both with 1 and 50% cutoffs. We used Kaplan-Meier method to estimate the overall survival, comparing both vimentin and PD-L1 positive patients with all the others. We found a weak positive correlation between PD-L1 and vimentin expressions in tumor cells (r = 0.25; p = 0.001). We also observed a statistically not significant trend towards a shorter overall survival in patients with both PD-L1 and vimentin expression >1% (HR = 1.36; 95% CI: 0.96–1.93, p = 0.087). In conclusion, these findings suggest that interplay between PD-L1 and vimentin may exist in non-metastatic NSCLC patients and the positivity of both markers in tumor tissue is associated with a trend towards a worse prognosis.