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Experimental preclinical models have been a cornerstone of lung cancer translational research. Work in these model systems has provided insights into the biology of lung cancer subtypes and their origins, contributed to our understanding of the mechanisms that underlie tumor progression, and revealed new therapeutic vulnerabilities. Initially patient-derived lung cancer cell lines were the main preclinical models available. The landscape is very different now with numerous preclinical models for research each with unique characteristics. These include genetically engineered mouse models (GEMMs), patient-derived xenografts (PDXs) and three-dimensional culture systems ("organoid" cultures). Here we review the development and applications of these models and describe their contributions to lung cancer research.

Phylogenetic methods are emerging as a useful tool to understand cancer evolutionary dynamics, including tumor structure, heterogeneity, and progression. Most currently used approaches utilize either bulk whole genome sequencing (WGS) or single-cell DNA sequencing (scDNA-seq) and are based on calling copy number alterations and single nucleotide variants (SNVs). Here we explore the potential of single-cell RNA sequencing (scRNA-seq) to reconstruct cancer evolutionary dynamics. scRNA-seq is commonly applied to explore differential gene expression of cancer cells throughout tumor progression. The method exacerbates the single-cell sequencing problem of low yield per cell with uneven expression levels. This accounts for low and uneven sequencing coverage and makes SNV detection and phylogenetic analysis challenging. In this paper, we demonstrate for the first time that scRNA-seq data contains sufficient evolutionary signal and can be utilized in phylogenetic analyses. We explore and compare results of such analyses based on both expression levels and SNVs called from our scRNA-seq data. Both techniques are shown to be useful for reconstructing phylogenetic relationships between cells, reflecting the clonal composition of a tumor. Without an explicit error model, standardized expression values appear to be more powerful and informative than the SNV values at a lower computational cost, due to being a by-product of standard expression analysis. Our results suggest that scRNA-seq can be a competitive alternative or useful addition to conventional scDNA-seq phylogenetic reconstruction. Our results open up a new direction of somatic phylogenetics based on scRNA-seq data. Further research is required to refine and improve these approaches to capture the full picture of somatic evolutionary dynamics in cancer.

Background Non-small cell lung cancer (NSCLC) is the most common type of lung cancer with a high mortality rate and poor prognosis. miR-637 has been reported to regulate tumor progression and act as a prognosis biomarker of various cancers. Its functional role in NSCLC was investigated in this study. Methods The expression level of miR-637 in NSCLC tissues and adjacent normal tissues of 123 NSCLC patients was analyzed by qRT-PCR. The association between miR-637 and clinical pathological features in the prognosis of patients was analyzed. Cell transfection was performed to overexpress or knockdown miR-637 in H1299 and HCC827. The proliferation, migration, and invasion of H1299 and HCC827 were evaluated by CCK8 and Transwell assay. Results miR-637 expression was significantly decreased in NSCLC tissues and cell lines relative to normal tissues and cells. The survival rate of NSCLC patients with low miR-637 expression was lower than that of patients with high miR-637 expression. Additionally, miR-637 served as a tumor suppressor that inhibited cell proliferation, migration, and invasion of NSCLC. Conclusion Downregulation of miR-637 in NSCLC was associated with TNM stage and poor prognosis of patients and served as a tumor suppressor in NSCLC. These results provide a potential strategy to control NSCLC.

The chaperonins CCT and Hsp60 are molecular chaperones, members of the chaperone system (CS). Chaperones are cytoprotective but if abnormal in quantity or quality they may cause diseases, the chaperonopathies. Here, recent advances in the understanding of CCT and Hsp60 in cancerology are briefly discussed, focusing on breast and brain cancers. CCT subunits, particularly CCT2, were increased in breast cancer cells and this correlated with tumor progression. Experimental induction of CCT2 increase was accompanied by an increase of CCT3, 4, and 5, providing another evidence for the interconnection between the members of the CS and the difficulties expected while manipulating one member with therapeutic purposes. Another in silico study demonstrated a direct correlation between the increase in the tumor tissue of the mRNA levels of all CCT subunits, except CCTB6, with bad prognosis. Studies with glioblastomas demonstrated an increase in the CCT subunits in the tumor tissue and in extracellular vesicles (EVs) derived from them. Expression levels of CCT1, 2, 6A, and 7 were the most increased and markers of bad prognosis, particularly CCT6A. A method for measuring Hsp60 and related miRNA in exosomes from blood of patients with glioblastomas or other brain tumors was discussed, and the results indicate that the triad Hsp60-related miRNAs-exosomes has potential regarding diagnosis and patient monitoring. All these data provide a strong foundation for future studies on the role played by chaperonins in carcinogenesis and for fully developing their theranostics applications along with exosomes.

Accumulating evidence has demonstrated that cancer stem cells (CSCs) play an essential role in tumor progression and reoccurrence and drug resistance. Multiple signaling pathways have been revealed to be critically participated in CSC development and maintenance. Emerging evidence indicates that numerous chemopreventive compounds, also known as nutraceuticals, could eliminate CSCs in part via regulating several signaling pathways. Therefore, in this review, we will describe the some natural chemopreventive agents that target CSCs in a variety of human malignancies, including soy isoflavone, curcumin, resveratrol, tea polyphenols, sulforaphane, quercetin, indole-3-carbinol, 3,3'-diindolylmethane, withaferin A, apigenin, etc. Moreover, we discuss that eliminating CSCs by nutraceuticals might be a promising strategy for treating human cancer via overcoming drug resistance and reducing tumor reoccurrence.

Slow-cycling/dormant cancer cells (SCCs) have pivotal roles in driving cancer relapse and drug resistance. A mechanistic explanation for cancer cell dormancy and therapeutic strategies targeting SCCs are necessary to improve patient prognosis, but are limited because of technical challenges to obtaining SCCs. Here, by applying proliferation-sensitive dyes and chemotherapeutics to non-small cell lung cancer (NSCLC) cell lines and patient-derived xenografts, we identified a distinct SCC subpopulation that resembled SCCs in patient tumors. These SCCs displayed major dormancy-like phenotypes and high survival capacity under hostile microenvironments through transcriptional upregulation of regulator of G protein signaling 2 (RGS2). Database analysis revealed RGS2 as a biomarker of retarded proliferation and poor prognosis in NSCLC. We showed that RGS2 caused prolonged translational arrest in SCCs through persistent eukaryotic initiation factor 2 (eIF2α) phosphorylation via proteasome-mediated degradation of activating transcription factor 4 (ATF4). Translational activation through RGS2 antagonism or the use of phosphodiesterase 5 inhibitors, including sildenafil (Viagra), promoted ER stress-induced apoptosis in SCCs in vitro and in vivo under stressed conditions, such as those induced by chemotherapy. Our results suggest that a low-dose chemotherapy and translation-instigating pharmacological intervention in combination is an effective strategy to prevent tumor progression in NSCLC patients after rigorous chemotherapy.

Prostate cancer (PCa) is a prevalent malignancy that occurs primarily in old males. Prostate tumors in different patients manifest significant inter-patient heterogeneity with respect to histo-morphological presentations and molecular architecture. An individual patient tumor also harbors genetically distinct clones in which PCa cells display intra-tumor heterogeneity in molecular features and phenotypic marker expression. This inherent PCa cell heterogeneity, e.g., in the expression of androgen receptor (AR), constitutes a barrier to the long-term therapeutic efficacy of AR-targeting therapies. Furthermore, tumor progression as well as therapeutic treatments induce PCa cell plasticity such that AR-positive PCa cells may turn into AR-negative cells and prostate tumors may switch lineage identity from adenocarcinomas to neuroendocrine-like tumors. This induced PCa cell plasticity similarly confers resistance to AR-targeting and other therapies. In this review, I first discuss PCa from the perspective of an abnormal organ development and deregulated cellular differentiation, and discuss the luminal progenitor cells as the likely cells of origin for PCa. I then focus on intrinsic PCa cell heterogeneity in treatment-naïve tumors with the presence of prostate cancer stem cells (PCSCs). I further elaborate on PCa cell plasticity induced by genetic alterations and therapeutic interventions, and present potential strategies to therapeutically tackle PCa cell heterogeneity and plasticity. My discussions will make it clear that, to achieve enduring clinical efficacy, both intrinsic PCa cell heterogeneity and induced PCa cell plasticity need to be targeted with novel combinatorial approaches.

Background: Although few patients with breast cancer experience tumor progression during neoadjuvant systemic therapy (NST), their extremely poor outcomes are similar to patients who fail to achieve pathological complete response (pCR). No reports have compared patients with pCR, non-pCR, and progression during NST to determine the survival outcomes.Methods: This retrospective chart review of patients with stage I–III breast cancer was conducted between January 2001 and December 2018. pCR was defined as no invasive cancer or in situ residuals in the breast and lymph nodes (ypT0 ypN0). Disease-free survival (DFS) and overall survival (OS) were estimated using Kaplan–Meier methods.Results: Of the 595 patients who received NST, 167 (29.2%) had pCR (pCR group), 404 (70.8%) responded to NST but did not have pCR (non-pCR group), and 24 (4.0%) experienced tumor progression during NST (PD group). The median DFS was 6.0 months, 154.0 months, and not reached in the PD, non-pCR, and pCR groups, respectively. The PD group had significantly shorter DFS than patients without tumor progression in the pCR and non-pCR groups [hazard ratios (HR) 13.0, 95% CI: 8.1–21.0, p < 0.01]. The median OS was 13.6 months (95% CI: 10.4–35.5) in the PD group and was not reached in the pCR and non-pCR (non-PD) groups. The OS was significantly poorer in the PD group than in the non-PD group (HR 15.8, 95% CI: 9.2–27.1, p < 0.01).Conclusion: The PD group had the poorest survival outcomes even after recurrence, thus warranting new treatment targets.

Abstract: Brain tissue is known to have elevated citrate levels, necessary to regulate ion chelation, neuron excitability, and are also necessary for the supply of necessary energy substrates to neurons. Importantly, citrate also acts as a central substrate in cancer metabolism. Recent studies have shown that extracellular citrate levels in the brain undergo significant changes during tumor development and may play a dual role in tumor progression, as well as cancer cell aggressiveness. In the present article, we review available literature describing changes of citrate levels in brain tissue, blood, and cerebrospinal fluid, as well as intracellular alterations during tumor development before and after metastatic progression. Based on the available literature and our recent findings, we hypothesize that changes in extracellular citrate levels may be related to the increased consumption of this metabolite by cancer cells. Interestingly, cancerassociated cells, including reactive astrocytes, might be a source of citrate. Extracellular citrate uptake mechanisms, as well as potential citrate synthesis and release by surrounding stroma, could provide novel targets for anti-cancer treatments of primary brain tumors and brain metastases.

The histone demethylase KDM6A controls gene expression by the epigenetic regulation of H3K27 methylation and functions in diverse processes, including differentiation, development, and cancer. Here, we investigated the role of KDM6A in prostate cancer. Specific deletion of KDM6A in the adult mouse prostate epithelium strongly inhibited tumor progression initiated by the loss of PTEN. Mechanistically, KDM6A promoted prostate tumorigenesis and lipid metabolism by binding to the SREBP1c promoter to increase SREBP1c transcription. USP7 deubiquitinated KDM6A to increase its expression. KDM6A was significantly upregulated in prostate cancer and positively associated with USP7 expression. Furthermore, targeting KDM6A stability by inhibiting USP7 in conditional knockout mice and xenograft models markedly suppressed prostate cancer growth and significantly enhanced KDM6A inhibitor efficacy. Collectively, these findings indicate that KDM6A regulates prostate lipid metabolism and is essential for prostate tumorigenesis initiated by PTEN loss. Targeting USP7/KDM6A could be a valuable strategy to ameliorate prostate cancer progression and therapeutic resistance. Significance: These findings show that KDM6A supports prostate tumorigenesis by promoting SREBP1c-mediated lipid metabolism, proposing targeting the USP7/KDM6A axis as a therapeutic strategy for treating prostate cancer.

Among the growing family of inhibitory receptors regulating immunity, sialic acid-binding immunoglobulin domain-containing lectins (Siglecs) have recently emerged as immunoregulatory receptors recognizing sialylated ligands on tumor cell surface. However, their role in the immunoregulation of bladder cancer (BCa) remains unknown. Here, we determined the presence of eight Siglec ligands (SLs) on bladder nontumor and tumor cell lines. S2L, S3L, and S6L were not expressed, and few bladder tumor cell lines expressed S5L and S14L. In contrast, S7L and S10L were upregulated on all bladder tumor cell lines. We found a discrepency in S9L expression by nontumor cell lines, which is however highly expressed by bladder tumor cell lines. Notably, expression of S5L, S6L, and S14L was increased upon bacillus Calmette-Guerin (BCG) infection. Furthermore, we analyzed the expression of Siglecs on T cells from healthy donors and BCa patients. Circulating T cells only expressed Siglec-6, which is upregulated in non-muscle-invasive BCa patients. In addition, BCG therapy induced the overexpression of Siglec-6 by urinary CD8+ T cells. In vitro functional assays suggested that Siglecs may decrease cytotoxic functions of effector CD8+ T cells. Finally, analyses from two BCa datasets (The Cancer Genome Atlas and UROMOL cohorts) showed that Siglec-6 is associated with tumor progression and poor survival. Our findings indicate that Siglec-6 might be a new target for BCa treatments. PATIENT SUMMARY: We investigated the expression of Siglecs, a family of immunoregulatory receptors, in bladder cancer patients. We observed that the expression of Siglec-6 is increased on circulating and urinary T cells of non-muscle-invasive bladder cancer patients. We also showed that Siglec-6 is associated with lower survival in bladder cancer patients and might contribute to bladder cancer recurrence.

Background: WWP1 (WW domain-containing E3 ubiquitin protein ligase 1) is increased in several kinds of carcinomas, but the influence of WWP1 in papillary thyroid cancer (PTC) is not well understood...

Objective The multimode ablation of liver cancer, which uses radio-frequency heating after a pre-freezing process to treat the tumor, has shown significantly improved therapeutic effects and enhanced anti-tumor immune response. Unlike open surgery, the ablated lesions remain in the body after treatment, so it is critical to assess the immediate outcome and to monitor disease status over time. Here we propose a novel tumor progression prediction method for simultaneous postoperative evaluation and prognosis analysis. Methods We propose to leverage the intraoperative therapeutic information extracted from thermal dose distribution. For tumors with specific sensitivity reflected in medical images, different thermal doses implicitly indicate the degree of instant damage and long-term inhibition excited under specific ablation energy. We further propose a survival analysis framework for the multimode ablation treatment. It extracts carefully designed features from clinical, preoperative, intraoperative, and postoperative data, then uses random survival forest for feature selection and deep neural networks for survival prediction. Results We evaluated the proposed methods using clinical data. The results show that our method outperforms the state-of-the-art survival analysis methods with a C-index of 0.8550.090. The thermal dose information contributes significantly to the prediction accuracy by taking up 21.7% of the overall feature importance. Conclusion The proposed methods have been demonstrated to be a powerful tool in tumor progression prediction of multimode ablation therapy. Significance This kind of data-driven prognosis analysis may benefit personalized medicine and simplify the follow-up process.

Objective To compare the differences in adverse effects and efficacy profile between bacillus Calmette-Guerin (BCG) Danish 1331 and BCG Moscow-I strain in management of non-muscle invasive bladder cancer (NMIBC). Methods Clinical data of 188 cases of NMIBC treated with BCG between 2008 and 2018 in our institute were collected prospectively and analysed retrospectively, and 114 patients who completed a minimum of 12 months of follow-up were analysed. Patient and tumor characters, strain of BCG, adverse effects and tumor progression were included for analysis. Intravesical BCG was instilled in intermediate and high-risk patients. Six weeks of induction BCG, followed by three weekly maintenance BCG at 3,6,12, 18 and 24 months was advised in high-risk patients. Results Overall 68 patients received BCG Danish 1331 strain and 46 patients received Moscow-I strain. Patient and tumor characteristics were well balanced between the two groups. The median follow-up period was 42.5 months and 34.5 months in Danish-1331 and Moscow groups, respectively. Adverse events like dropout rate, anti-tubercular treatment requirement and need of cystectomy were higher in Moscow group (n = 31, 67.4%) when compared to Danish 1331 strain (n = 33, 48.5%) (p = 0.046). On direct comparison between Danish-1331 and Moscow strain, there was similar 3-year recurrence-free survival (RFS) (80% vs. 72.9%) and 3-year progression-free survival (PFS) (96.5% vs. 97.8%). Conclusion Study results suggest no significant differences between Danish 1331 and Moscow strain in RFS and PFS, but a significantly higher incidence of moderate to severe adverse events in BCG Moscow strain.

OBJECTIVE Resection of meningiomas in direct contact with the anterior optic apparatus carries risk of injury to the visual pathway. Stereotactic radiosurgery (SRS) offers a minimally invasive alternative. However, its use is limited owing to the risk of radiation-induced optic neuropathy. Few SRS studies have specifically assessed the risks and benefits of treating meningiomas in direct contact with the optic nerve, chiasm, or optic tract. The authors hypothesized that SRS is safe for select patients with meningiomas in direct contact with the anterior optic apparatus. METHODS The authors performed an international multicenter retrospective analysis of 328 patients across 11 institutions. All patients had meningiomas in direct contract with the optic apparatus. Patients were followed for a median duration of 56 months after SRS. Neurological examinations, including visual function evaluations, were performed at follow-up visits. Clinical and treatment variables were collected at each site according to protocol. Tumor volumes were assessed with serial MR imaging. Variables predictive of visual deficit were identified using univariable and multivariable logistic regression. RESULTS SRS was the initial treatment modality for 64.6% of patients, and 93% of patients received SRS as a single fraction. Visual information was available for 302 patients. Of these patients, visual decline occurred in 29 patients (9.6%), of whom 12 (41.4%) had evidence of tumor progression. Visual decline in the remaining 17 patients (5.6%) was not associated with tumor progression. Pre-SRS Karnofsky Performance Status predicted visual decline in adjusted analysis (adjusted OR 0.9, 95% CI 0.9–1.0, p < 0.01). Follow-up imaging data were available for 322 patients. Of these patients, 294 patients (91.3%) had radiographic evidence of stability or tumor regression at last follow up. Symptom duration was associated with tumor progression in adjusted analysis (adjusted OR 1.01, adjusted 95% CI 1.0–1.02, adjusted p = 0.02). CONCLUSIONS In this international multicenter study, the vast majority of patients exhibited tumor control and preservation of visual function when SRS was used to treat meningioma in direct contact with the anterior optic pathways. SRS is a relatively safe treatment modality for select patients with perioptic meningiomas in direct contact with the optic apparatus.

The spatial organization of immune cells within the tumor microenvironment (TME) largely determines the anti-tumor immunity and also highly predicts tumor progression and therapeutic response. Tim-3 is a well-accepted immune checkpoint and plays multifaceted immunoregulatory roles via interaction with distinct Tim-3 ligands (Tim-3L), showing great potential as an immunotherapy target. However, the cell sociology mediated by Tim-3/Tim-3L and their contribution to tumor development remains elusive. Here, we analyzed the spatial distribution of Tim-3/Tim-3L in TME using multiplex fluorescence staining and revealed that despite the increased Tim-3 expression in various tumor-infiltrated lymphocytes, Tim-3(+)CD4(+) cells were more accumulated in parenchymal/tumor region compared with stromal region and exhibited more close association with patient survival. Strikingly, CD4 T cells surrounding Tim-3L(+) cells expressed higher Tim-3 than other cells in cancerous tissues. In vivo studies confirmed that depletion of CD4 T cells completely abrogated the inhibition of tumor growth and metastasis, as well as the functional improvement of CD8 T and NK, mediated by Tim-3 blockade, which was further validated in peripheral lymphocytes from patients with hepatocellular carcinoma. In conclusion, our findings unravel the importance of CD4 T cells in Tim-3/Tim-3L-mediated immunosuppression and provide new thoughts for Tim-3 targeted cancer immunotherapy.

Background Spontaneous rupture of hepatocellular carcinoma (HCC) is a potentially fatal complication and the third leading cause of death in patients with HCC after tumor progression and liver failure. Previous studies suggested that improved HCC surveillance has decreased the incidence of rupture. This study aims to characterize patients with ruptured HCC over time and identify predictors of rupture. Methods We retrospectively reviewed a prospectively collected database of 1451 HCC patients to identify cases with rupture and predictors of rupture. Data were divided into three 9-year eras to compare and trend patient/tumor characteristics and rupture. Results Fifty-seven patients (3.9%) presented with spontaneous HCC rupture and the following characteristics: mean age 62.6 years, 73.7% males, 41% cirrhosis, and mean tumor size of 8.0 cm. On multivariate analyses, predictors of rupture included obesity, tumor >5 cm, and single tumors, whereas the presence of cirrhosis was a negative predictor for rupture. Across three eras, there were changes in disease etiology and decreases in tumor size, and more HCCs were found with surveillance. However, more patients were noncirrhotic, and the incidence of spontaneous rupture was unchanged over time. Conclusion Despite improved early detection of HCC over time, the incidence of rupture has been unchanged. The persistent incidence of rupture may possibly be attributed to increasing proportion of fatty liver–related HCC patients who lack traditional risk factors for surveillance and may not have cirrhosis. Better identification of fatty liver disease and determining which patients need HCC surveillance may be needed in the future to prevent spontaneous rupture.

In recent years, there has been an increasing interest in understanding the mysterious functions of nitric oxide (NO) and how this pleiotropic signaling molecule contributes to tumorigenesis. This review attempts to expose and discuss the information available on the immunomodulatory role of NO in cancer and recent approaches to the role of NO donors in the area of immunotherapy. To address the goal, the following databases were searched to identify relevant literature concerning empirical evidence: The Cochrane Library, Pubmed, Medline, and EMBASE from 1980 through March 2020. Valuable attempts have been made to develop distinctive NO-based cancer therapy. Although the data do not allow generalization, the evidence seems to indicate that low/moderate levels may favor tumorigenesis, while higher levels would exert antitumor effects. In this sense, the use of NO donors could have an important therapeutic potential within immunotherapy, although there are still no clinical trials. The emerging understanding of NO-regulated immune responses in cancer may help unravel the recent features of this “doubleedged sword” in cancer physiological and pathologic processes and its potential use as a therapeutic agent for cancer treatment. In short, in this review, we discuss the complex cellular mechanism in which NO, as a pleiotropic signaling molecule, participates in cancer pathophysiology. We also debate the dual role of NO in cancer and tumor progression and clinical approaches for inducible nitric oxide synthase (iNOS) based therapy against cancer.

The mammalian target of rapamycin (mTOR) pathway is abnormally activated in lung cancer. However, the anti-lung cancer effect of mTOR inhibitors as monotherapy is modest. Here, we identified that ginsenoside Rh2, an active component of Panax ginseng C. A. Mey., enhanced the anti-cancer effect of the mTOR inhibitor everolimus both in vitro and in vivo. Moreover, ginsenoside Rh2 alleviated the hepatic fat accumulation caused by everolimus in xenograft nude mice models. The combination of everolimus and ginsenoside Rh2 (labeled Eve-Rh2) induced caspase-independent cell death and cytoplasmic vacuolation in lung cancer cells, indicating that Eve-Rh2 prevented tumor progression by triggering paraptosis. Eve-Rh2 up-regulated the expression of c-MYC in cancer cells as well as tumor tissues. The increased c-MYC mediated the accumulation of tribbles homolog 3 (TRIB3)/P62+ aggresomes and consequently triggered paraptosis, bypassing the classical c-MYC/MAX pathway. Our study offers a potential effective and safe strategy for the treatment of lung cancer. Moreover, we have identified a new mechanism of TRIB3/P62+ aggresomes-triggered paraptosis and revealed a unique function of c-MYC.

Endoscopic resection (ER) is the preferred treatment for superficial esophageal cancer; however, a safe time frame for performing ER has not been established. This study evaluated the period in which ER can be performed for patients with stage I esophageal adenocarcinoma without compromising outcomes.The 2004-2015 National Cancer Database was used to identify patients with cT1 N0 M0 esophageal adenocarcinoma who underwent upfront ER. The primary outcome was overall survival, which was evaluated using Kaplan-Meier and multivariable Cox proportional hazards methods. The secondary outcome was rate of margin-positive resection, which was evaluated using a multivariable logistic regression.A total of 983 patients met study criteria. The median time from diagnosis to ER was 34 days (interquartile range, 5-70 days). Patients in the highest quartile of time to ER were more likely to be treated at a high-volume center and at a center different from that of diagnosis compared with those in the lowest quartile. Increasing time to ER was not independently associated with survival (adjusted hazard ratio per 10 days, 1.02; 95% confidence interval, 0.98-1.05; P = .32) or margin-positive resection (odds ratio per 10 days 1.01; 95% confidence interval, 0.96-1.06; P = .60).In this National Cancer Database analysis, increasing time to endoscopic resection, up to 180 days from diagnosis, was not associated with worsened survival or increased odds of margin-positive resection in patients with cT1 N0 M0 esophageal adenocarcinoma. Given these findings, patients may be afforded time to be seen in specialty centers without risk of tumor progression.

The frequency of human suffering from cancer is increasing annually across the globe. This has fueled numerous investigations aimed at the prevention and cure of various cancers. Long non-coding RNA (lncRNA) are known to play a crucial role in cancer. For instance, cancer susceptibility candidate 11 (CASC11), as one of the long non-coding RNAs, has been reported to be overexpressed in various tumors. This review elucidates the mechanism by which lncRNA CASC11 regulates tumors' biological processes and affirms its value as a therapeutic target for tumors. Through systematic analysis and review of relevant articles in PubMed, we revealed the pathophysiological mechanism of CASC11 on the tumor by regulating the biological processes of tumor such as proliferation, autophagy, apoptosis, thereby promoting tumor metastasis. We also revealed the regulatory pathways of CASC11 in different tumors, for instance by acting on a variety of microRNAs, oncogenic proteins, carcinogens, and transcription factors. Consequently, CASC11 regulates cancer proliferation, apoptosis, and invasion by altering the WNT/β-catenin signaling pathway and epithelial–mesenchymal transition (EMT). Furthermore, CASC11 expression has a high pertinence with clinical prognosis, suggesting that it is a potential marker for malignant tumors or a clinical adjuvant therapy in the future.

Background PIK3CA is associated with tumor progression, and the prevalence of its mutation is high in breast cancer. Liquid biopsy offers convenient, non-invasive, and real-time insight into genetic alternation. In this study, we attempted to detect PIK3CA mutations in breast cancer patients through liquid biopsy. Methods We recruited patients with histologically confirmed breast cancer with distant metastases between April 2020 and September 2020. Circulating DNA was extracted from plasma (ctDNA) and exosomes (exoDNA). PIK3CA mutations (exons 9 and 20) were analyzed by droplet digital PCR. Results Of a total of 52 patients recruited, 16 had PIK3CA mutations in their tumor tissue or blood, which comprised 9 with exon 9 mutations (E542K and E545K) and 8 with exon 20 mutations (H1047L and H1047R). In 8 (15%) of the 52 patients, PIK3CA mutations were detected by liquid biopsies using ctDNA in 5 (9%), exoDNA in 6 (11%), and both ctDNA and exoDNA in 3 (6%). Of the 8 patients with PIK3CA mutations detected by liquid biopsies, 3 had no PIK3CA mutations in the primary tumors. Conclusions PIK3CA mutations can be detected using liquid biopsy even in patients with no PIK3CA mutations in their primary tumors; thus, combination analysis using tissue and liquid biopsies can provide clinically useful information for patients with breast cancer.

OBJECTIVE Widespread use of modern neuroimaging has led to a surge in diagnosing pediatric brain incidentalomas. Thalamic lesions have unique characteristics such as deep location, surgical complexity, and proximity to eloquent neuronal structures. Currently, the natural course of incidental thalamic lesions is unknown. Therefore, the authors present their experience in treating such lesions. METHODS A retrospective, international multicenter study was carried out in 8 tertiary pediatric centers from 5 countries. Patients were included if they had an incidental thalamic lesion suspected of being a tumor and were diagnosed before the age of 20 years. Treatment strategy, imaging characteristics, pathology, and the outcome of operated and unoperated cases were analyzed. RESULTS Overall, 58 children (23 females and 35 males) with a mean age of 10.8 ± 4.0 years were included. The two most common indications for imaging were nonspecific reasons (n = 19; e.g., research and developmental delay) and headache unrelated to small thalamic lesions (n = 14). Eleven patients (19%) underwent early surgery and 47 were followed, of whom 10 underwent surgery due to radiological changes at a mean of 11.4 ± 9.5 months after diagnosis. Of the 21 patients who underwent surgery, 9 patients underwent resection and 12 underwent biopsy. The two most frequent pathologies were pilocytic astrocytoma and WHO grade II astrocytoma (n = 6 and n = 5, respectively). Three lesions were high-grade gliomas. CONCLUSIONS The results of this study indicate that pediatric incidental thalamic lesions include both low- and high-grade tumors. Close and long-term radiological follow-up is warranted in patients who do not undergo immediate surgery, as tumor progression may occur.

Cancer‐associated fibroblasts (CAF) are the most abundant stromal cells in tumor and exert a pro‐tumoral effect in cancer progression. Numerous evidence shows long non‐coding RNA (lncRNA) abnormally regulates gene expression in various cancers. However, little is known about the role of lncRNA in the interaction between CAF and cancer cells. Here, we first identify an uncharacterized lncRNA, LOC100506114, which is significantly upregulated in CAF and is involved in the functional transformation of normal fibroblasts (NF) and CAF. Expression of LOC100506114 enhances the expression of fibroblast activation protein alpha and α‐smooth muscle actin in NF and promotes malignant characteristics of NF and CAF in vivo and in vitro. The profile of gene co‐expression analysis shows that growth differentiation factor 10 (GDF10) is positively correlated with the expression of LOC100506114. CAF promote stromal fibroblast activation and the proliferation and migration of tumor cells by secreting GDF10. Our data demonstrate that lncRNA plays a critical role in the interplay of stromal fibroblasts and tumor cells in oral squamous cell carcinoma., Abnormal expression of lncRNA LOC100506114 in oral squamous cell carcinoma (OSCC) induced normal fibroblasts (NF) to transform into CAF by upregulating growth differentiation factor 10 (GDF10) expression and secretion. The interaction of GDF10 with the transcription factor RUNX family transcription factor 2 further enhanced the growth and migration of OSCC tumor cells by activating the TGFβRI/Smad3/ERK pathway. Our results demonstrate that lncRNA play an important role in the functional transformation of human NF into CAF and promote OSCC tumorigenesis.

Although overall survival (OS) has improved in patients with brain metastases (BMs), control of recurrent BMs remains a therapeutic challenge. Salvage surgery may achieve acceptable control rates in the setting of progression after previous stereotactic radiosurgery (SRS), yet it remains a question how additional adjuvant therapies may affect outcomes and how patient selection for salvage surgery may be optimized.Patients receiving salvage surgery for BM progression after previous SRS were retrospectively reviewed from a single center. Outcomes of interest included local tumor progression, leptomeningeal dissemination, and OS. Cox proportional hazard models and nominal logistic regression were applied to determine factors associated with outcomes of interest.A total of 43 patients with 50 BMs were included. After salvage surgery, local progression was observed for 17 BMs (34%), leptomeningeal dissemination was observed in 17 patients (39.5%), and censored median OS was 17.9 months. On multivariate analysis, use of brachytherapy was associated with improved local control (hazard ratio [HR], 0.15; 95% confidence interval [CI], 0.04-0.6; P = 0.008). For patients treated with SRS ≥4.5 months before salvage surgery, both brachytherapy (HR, 0.07; 95% CI, 0.01-0.39; P = 0.002) and postoperative adjuvant SRS (HR, 0.14; 95% CI, 0.02-1.00; P = 0.05) were associated with improved local control compared with no adjuvant radiation therapy. Presence of extracranial malignancy (HR, 6.70; 95% CI, 2.58-17.42; P0.0001) was associated with shorter survival. Graded prognostic assessment underestimated survival in 79.1% of patients, with a mean difference of 18.9 months between graded prognostic assessment-estimated and actual OS.In properly selected patients, salvage surgery may be an appropriate therapy for BM progression after previous SRS. Adjuvant brachytherapy and repeat SRS can offer significant benefit for local control with salvage resection.

Tumor-associated macrophages (TAM) play a crucial role in promoting cancer progression. Upon cytokine stimulation, TAM preferentially polarize to the anti-inflammatory and pro-tumor M2 subtype. The mechanism underlying such preferential polarization remains elusive. Here, we report that macrophage-specific deletion of the SUMO-specific protease Sentrin/SUMO-specific protease 3 promotes macrophage polarization towards M2 in bone marrow-derived macrophage (BMDM) induced by interleukin 4 (IL-4)/IL-13 and in an ex vivo model (murine Py8119 cell line), as well as in a mouse orthotopic tumor model. Notably, Sentrin/SUMO-specific protease 3 (SENP3) loss in macrophages accelerated breast cancer malignancy in ex vivo and in vivo models. Mechanistically, we identified Akt Serine/threonine kinase 1 (Akt1) as the substrate of SENP3 and found that the enhanced Akt1 SUMOylation upon SENP3 loss resulted in Akt1 hyper-phosphorylation and activation, which facilitates M2 polarization. Analysis of clinical data showed that a lower level of SENP3 in TAM has a strong negative correlation with the level of the M2 marker CD206, as well as with a worse clinical outcome. Thus, increased Akt1 SUMOylation as a result of SENP3 deficiency modulates polarization of macrophages to the M2 subtype within a breast cancer microenvironment, which in turn promotes tumor progression.

Focal Adhesion Kinase (FAK) is a 125-kDa cytoplasmic protein kinase that is implicated in several cellular functions. This protein is an attractive molecular target for cancer therapy because a wide variety of studies have demonstrated associations between the activation or elevated expression of FAK and tumor progression, invasion, and drug resistance in malignant tumors. Here, we review the strategies used to inhibit FAK activity in solid tumors. We also include an overview of the preclinical (in vitro and in vivo) and clinical studies on FAK inhibitors.

Gliomas are the most common and recalcitrant intracranial tumors, approximately a quarter of which are classified as lower-grade gliomas (WHO II–III). Although the prognosis of lower-grade gliomas (LGGs) is significantly better than that of higher-grade gliomas, as a highly heterogeneous tumor type, the prognosis of LGGs varies greatly based on the molecular diagnosis. IDH wild-type used to be regarded as a dismal prognostic biomarker in LGGs; however, several studies revealed that IDH wild-type LGGs might not always be equivalent to glioblastoma (WHO IV). Hence, we hypothesize that underlying biological events in LGGs can result in different prognosis. In our study, transcriptome profiling was performed in 24 samples of LGG, and the results showed that the expression of phospholipase Cγ1 (PLCG1) was significantly correlated with IDH1/2 status and patients’ clinical outcome. Furthermore, the cancer genome atlas (TCGA) and the Chinese glioma genome atlas (CGGA) databases verified that elevated PLCG1 expression was associated with tumor progression and poor survival in LGG patients. Moreover, PLCG1-targeted siRNA dramatically affected the growth, migration and invasiveness of IDH wild-type LGG cell lines. In in vitro and in vivo experiments, the PLC-targeted drug significantly suppressed the tumor growth of IDH wild-type LGG cell lines in vitro and tumors in mouse models. Taken together, our results demonstrated that higher PLCG1 expression was associated with tumor growth and worse prognosis in IDH wild-type LGGs and PLCG1 could serve as a potential therapeutic target for IDH wild-type LGG patients., The mRNA expression levels of phospholipase Cγ1 (PLCG1) are much higher in IDH wild-type (IDHwt) lower-grade gliomas (LGGs) than in that of IDH mutant (IDHmut) LGGs. Higher PLCG1expression in IDHwt LGGs indicates poor clinical outcome. PLCG1 amplification may act as the key mechanism of PLCG1 upregulation. Depletion of PLCG1 expression can inhibits proliferation and invasion of IDHwt LGG cell lines in vitro and in vivo. The PLC inhibitor U73122 may therefore be a potential therapeutical agent for IDHwt LGGs.

EBV-encoded circular RNA LMP2A (ebv-circLMP2A) was found to be expressed in EBV-associated gastric carcinoma (EBVaGC) and associated with distant metastasis and poor prognosis. Angiogenesis is a key step in tumor invasion and metastasis and plays a crucial role in tumor progression. However, it is unclear whether and how ebv-circLMP2A is involved in angiogenesis. In this study, we showed that MVD, HIF1α, and VEGFA expression was increased in EBVaGC mouse xenografts with high expression of ebv-circLMP2A. The expression of ebv-circLMP2A was positively correlated with MVD, HIF1α, and VEGFA expression in clinical samples of EBVaGC. Knockdown of ebv-circLMP2A repressed tube formation and migration of HUVECs and decreased VEGFA and HIF1α expression in cancer cells under hypoxia, while ectopic expression of ebv-circLMP2A reversed these effects. Additionally, knockdown of HIF1α blocked the upregulation of ebv-circLMP2A by hypoxia, and ebv-circLMP2A interacted with KHSRP to enhance KHSRP-mediated decay of VHL mRNA, leading to the accumulation of HIF1α under hypoxia. There was a positive feedback loop between HIF1α and ebv-circLMP2A that promotes angiogenesis under hypoxia. ebv-circLMP2A was essential in regulating tumor angiogenesis in EBVaGC and might provide a valuable therapeutic target for EBVaGC.

Background Podoplanin (PDPN) is a sialylated membrane glycoprotein that binds to C-type lectin-like receptor 2 (CLEC-2) on platelets resulting in platelet activation. PDPN is expressed on lymphatic endothelial cells, perivascular fibroblasts/pericytes, cancer cells, cancer-associated fibroblasts, and tumor stromal cells. PDPN's expression on malignant epithelial cells plays a role in metastasis. Furthermore, the expression of PDPN in brain tumors (high-grade gliomas) was found to correlate with an increased risk of venous thrombosis. Objective We examined the expression of PDPN and its role in tumor progression and venous thrombosis in ovarian cancer. Methods We used mouse models of ovarian cancer and venous thrombosis. Results We showed that ovarian cancer cells express PDPN and release PDPN-rich extracellular vesicles (EVs) and that cisplatin and topotecan (chemotherapies commonly used in ovarian cancer) increase the expression of podoplanin in cancer cells. We also show that expression of PDPN in ovarian cancer cells promotes tumor growth in a murine model of ovarian cancer and that knockdown of PDPN gene expression results in smaller primary tumors. Both PDPN-expressing ovarian cancer cells and their EVs cause platelet aggregation. In a mouse model of venous thrombosis, PDPN-expressing EVs released from HeyA8 ovarian cancer cells produce more frequent thrombosis than PDPN-negative EVs derived from PDPN-knockdown HeyA8 cells. Blood clots induced by PDPN-positive EVs contain more platelets than those in blood clots induced by PDPN-negative EVs. Conclusions In summary, our findings demonstrate that the expression of PDPN by ovarian cancer cells promotes tumor growth and venous thrombosis in mice.

It is increasingly appreciated that cancer cell heterogeneity and plasticity constitute major barriers to effective clinical treatments and long-term therapeutic efficacy. Research in the past two decades suggest that virtually all treatment-naive human cancers harbor subsets of cancer cells that possess many of the cardinal features of normal stem cells. Such stem-like cancer cells, operationally defined as cancer stem cells (CSCs), are frequently quiescent and dynamically change and evolve during tumor progression and therapeutic interventions. Intrinsic tumor cell heterogeneity is reflected in a different aspect in that tumors also harbor a population of slow-cycling cells (SCCs) that are not in the proliferative cell cycle and thus are intrinsically refractory to anti-mitotic drugs. In this Perspective, we focus our discussions on SCCs in cancer and on various methodologies that can be employed to enrich and purify SCCs, compare the similarities and differences between SCCs, CSCs and cancer cells undergoing EMT, and present evidence for the involvement of SCCs in surviving anti-neoplastic treatments, mediating tumor relapse, maintaining tumor dormancy and mediating metastatic dissemination. Our discussions make it clear that an in-depth understanding of the biological properties of SCCs in cancer will be instrumental to developing new therapeutic strategies to prevent tumor relapse and distant metastasis.

Alcohol is a well-known risk factor for hepatocellular carcinoma. Autophagy plays a dual role in liver cancer, as it suppresses tumor initiation and promotes tumor progression. Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and autophagy, which is impaired in alcohol-related liver disease. However, the role of TFEB in alcohol-associated liver carcinogenesis is unknown. Liver-specific Tfeb knockout (KO) mice and their matched wild-type (WT) littermates were injected with the carcinogen diethylnitrosamine (DEN), followed by chronic ethanol feeding. We found that the numbers of both total and larger tumors increased significantly in DEN-treated mice fed with ethanol diet than in mice fed with control diet. Although the number of tumors was not different between WT and L-Tfeb KO mice fed either control or ethanol diet, the number of larger tumors was less in L-Tfeb KO mice than in WT mice. To our surprise, no differences were found in liver injury, steatosis, inflammation, ductular reaction, fibrosis, and tumor cell proliferation in DEN-treated mice fed ethanol. However, the levels of glypican 3, a marker of malignant hepatocellular carcinoma, markedly decreased in DEN-treated L-Tfeb KO mice fed ethanol in comparison to the WT mice. Our findings indicate that chronic ethanol feeding promotes DEN-initiated liver tumor development, which tends to be attenuated by genetic deletion of hepatic TFEB.

New approaches beyond PD-1/PD-L1 inhibition are required to target the immunologically diverse tumor microenvironment (TME) in high-grade serous ovarian cancer (HGSOC). In this study, we explored the immunosuppressive effect of B7-H3 (CD276) via the CCL2–CCR2–M2 macrophage axis and its potential as a therapeutic target. Transcriptome analysis revealed that B7-H3 is highly expressed in PD-L1–low, nonimmunoreactive HGSOC tumors, and its expression negatively correlated with an IFNγ signature, which reflects the tumor immune reactivity. In syngeneic mouse models, B7-H3 (Cd276) knockout (KO) in tumor cells, but not in stromal cells, suppressed tumor progression, with a reduced number of M2 macrophages and an increased number of IFNγ+CD8+ T cells. CCL2 expression was downregulated in the B7-H3 KO tumor cell lines. Inhibition of the CCL2–CCR2 axis partly negated the effects of B7-H3 suppression on M2 macrophage migration and differentiation, and tumor progression. In patients with HGSOC, B7-H3 expression positively correlated with CCL2 expression and M2 macrophage abundance, and patients with B7-H3–high tumors had fewer tumoral IFNγ+CD8+ T cells and poorer prognosis than patients with B7-H3–low tumors. Thus, B7-H3 expression in tumor cells contributes to CCL2–CCR2–M2 macrophage axis–mediated immunosuppression and tumor progression. These findings provide new insights into the immunologic TME and could aid the development of new therapeutic approaches against the unfavorable HGSOC phenotype.

DICER1 syndrome (OMIM 606241, 601200) is a rare autosomal dominant familial tumor predisposition disorder with a heterozygous DICER1 germline mutation. The most common tumor seen clinically is the pleuropulmonary blastoma (PPB), a lung neoplasm of early childhood which is classified on its morphologic features into four types (IR, I, II and III) with tumor progression over time within the first 4-5 years of life from the prognostically favorable cystic type I to the unfavorable solid type III. Following the initial report of PPB, its association with other cystic neoplasms was demonstrated in family studies. The detection of the germline mutation in DICER1 provided the opportunity to identify and continue to recognize a number seemingly unrelated extrapulmonary neoplasms: Sertoli-Leydig cell tumor, gynandroblastoma, embryonal rhabdomyosarcomas of the cervix and other sites, multinodular goiter, differentiated and poorly differentiated thyroid carcinoma, cervical-thyroid teratoma, cystic nephroma-anaplastic sarcoma of kidney, nasal chondromesenchymal hamartoma, intestinal juvenile-like hamartomatous polyp, ciliary body medulloepithelioma, pituitary blastoma, pineoblastoma, primary central nervous system sarcoma, embryonal tumor with multilayered rosettes-like cerebellar tumor, PPB-like peritoneal sarcoma, DICER1-associated presacral malignant teratoid neoplasm and other non-neoplastic associations. Each of these neoplasms is characterized by a second somatic mutation in DICER1. In this review, we have summarized the salient clinicopathologic aspects of these tumors whose histopathologic features have several overlapping morphologic attributes particularly the primitive mesenchyme often with rhabdomyoblastic and chondroid differentiation and an uncommitted spindle cell pattern. Several of these tumors have an initial cystic stage from which there is progression to a high grade, complex patterned neoplasm. These pathologic findings in the appropriate clinical setting should serve to alert the pathologist to the possibility of a DICER1-associated neoplasm and initiate appropriate testing on the neoplasm and to alert the clinician about the concern for a DICER1 mutation.

Recent advancements in the field of cancer have established that the process of metastasis is organ-specific with tumor cell dissemination occurring in the very early stages of disease. Pre-metastatic niches are actively remodeled and transformed by both primary tumor specific factors and by influences from the extracellular matrix.Although improvements in cancer therapies have significantly improved outcomes in patients with early stage disease, the risk of recurrence and relapse leading to mortality remains high. Recent studies have emerged highlighting the influence of dormant tumor cells and exosomes as key players in cancer relapse. In this review we discuss the critical mediators of tumor progression and their link to cancer dormancy, while also exploring possible therapeutics for targeting relapse.

RNA-binding motif protein 10 (RBM10), one of the members of the RNA-binding protein (RBP) family, has a tumor suppressor role in multiple cancers. However, the functional role of RBM10 in lung adenocarcinoma (LUAD) and the underlying molecular mechanism remains unclear. In this study, we observed that RBM10 is significantly downregulated in LUAD tissues compared with normal tissues. Low RBM10 expression is significantly associated with poor outcome of LUAD patients. In vitro and in vivo experiments show that RBM10 inhibits cell proliferation, metastasis and EMT progression in LUAD. Mechanistically, we demonstrate that RBM10 interacts with β-catenin interacting protein 1 (CTNNBIP1) and positively regulates its expression, disrupting the binding of β-catenin to the transcription factor TCF/LEF, thereby inactivating the Wnt/β-catenin pathway. In conclusion, this is the first study reporting the role of RBM10 in suppressing LUAD progression at least via partly inactivating the Wnt/β-catenin pathway, which provides new insights into the tumorigenesis and metastasis of LUAD. Thus, RBM10 may be a promising new therapeutic target or clinical biomarker for LUAD therapy in the future.

Prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer-related death among men in western countries. Androgen deprivation therapy (ADT) is considered the standard therapy for recurrent prostate cancer; however, this therapy may lead to ADT resistance and tumor progression, which seems to be regulated by epithelial-mesenchymal transition (EMT) and/or neuroendocrine differentiation (NED). In addition, recent data suggested the involvement of either adaptive or innate infiltrated immune cells in the initiation, progression, metastasis, and treatment of prostate cancer. In this review, we outlined the characteristics and roles of these immune cells in the initiation, progression, metastasis, and treatments of prostate cancer. We also summarized the current therapeutic strategies in targeting immune cells of the prostate tumor microenvironment.

Glioblastoma Multiforme (GBM) is a poorly curable brain tumor because of its extremely invasive nature. Curcuminoids, as potential phytochemicals extracted from Curcuma Longa L., have been documented for their chemopreventive and antitumor activities against several types of malignancies. These compounds exert these effects via modulation of multiple signaling pathways and molecular targets at different stages of tumor progression, proliferation, and metastasis. In experimental studies, curcuminoids have demonstrated promising therapeutic benefits to overcome GBM. Curcuminoids have been shown to exert their anti-GBM effects through regulation of angiogenesis, apoptosis, autophagy, metastasis, invasion, as well as potential molecular targets, including receptor tyrosine kinases, Sonic Hedgehog, and NF-κB. This study reviews the observations regarding the impact of curcumin and its derivatives on GBM and the potential of translating the research findings into the clinic.

Long-chain non-coding RNA ASB16-AS1 has been proven to be an oncogene for many cancer types. However, the relationship between ASB16-AS1 and immunity is still under studied. This study aims to explore the expression and prognostic potential of ASB16-AS1, and to visualize the relationship between ASB16-AS1 expression and immune infiltration in pan-cancer. We clarified ASB16-AS1 expression patterns in pan-cancer and its relationship with prognosis through multi-platform and multi-database sources (TCGA, GEO, GTEx, ArrayExpress, and SRA), and verified the function of ASB16-AS1 in liver hepatocellular carcinoma (LIHC). Then, a variety of immune cell content evaluation methods were used to mutually verify the correlation between ASB16-AS1 and immune infiltration. Finally, the relationships between ASB16-AS1 and some molecular characteristics (immune checkpoints, tumor mutation burden, microsatellite instability, oncogenic signaling pathways) were further explored. In terms of comprehensive analysis, compared with non-tumor tissues, ASB16-AS1 was highly expressed in tumor tissues, and indicated the value of poor prognosis in multiple cancer types. Functional assays, such as CCK8 assay, transwell assay and wound scratch assay, verified that high ASB16-AS1 expression promoted tumor progression in LIHC. ASB16-AS1 was positively correlated with B cells, T cell CD4+ and T cell CD8+ in most cancer types, and negatively correlated with macrophages, dendritic cells and neutrophils in some cancer types, especially in neutrophils. In addition, there were different interaction modes between ASB16-AS1 and molecular features, such as the relationship with oncogenic signaling pathways, showing that the high ASB16-AS1 expression was related to alterations in oncogenic signaling pathways. Our study emphasizes that ASB16-AS1 is a potential pan-cancer prognostic marker, whichs is associated with the immune infiltration in multiple cancer types.

Adult granulosa cells tumors (AGCTs) are typically low-grade indolent tumors. On rare occasions, they undergo high-grade/sarcomatous transformation and behave aggressively. This transformation is postulated to occur as the result of acquired genetic alterations, some of which may be eligible for targeted therapy. Here we report a rare case of AGCT with sarcomatous transformation that harbored distinct molecular alterations from those typically seen with AGCTs supporting a molecularly driven approach to these malignancies. The patient is a 56-yr-old G3P3 woman with a history of multiple recurrences of ovarian AGCT for which the first diagnosis was made at the age of 25 when she was evaluated for infertility. The ovarian tumor displayed typical features of AGCT with low-grade, bland morphology. The first extraovarian spread of tumor involving the cul-de-sac was reported at the age of 39. After that, recurrences occurred every 2 to 3 yr with involvement of multiple anatomic sites and repeated surgical resections. At the age of 55 she developed a symptomatic recurrence in the pelvis and underwent resection of an isolated lesion (specimen 1) to no gross residual disease. Within 4 wk of resection she developed significant pelvic pain and imaging showed recurrence of the mass. Therefore, in 5 mo after the initial resection she underwent repeat excision of the lesion (specimen 2) and associated bowel. The sections from specimen 1 showed a biphasic morphology: a low-grade component with morphology and immunophenotype consistent with a typical AGCT and a high-grade spindle cell component with features consistent with a high-grade sarcoma. Specimen 2 featured a pure high-grade sarcoma characterized by coagulative tumor cell necrosis, readily recognizable mitoses, highly atypical cells with vesicular nuclei and prominent nucleoli. SF-1 positivity and the presence of FOXL2 C134W mutation in the sarcomatous component support the notion of transformation of typical AGCT. While detected TERT promoter C228T mutation may play a role in this process, we further identified genetic alterations affecting PI3K/AKT/mTOR pathway, including mutations in PIK3CA , PIK3R1 , AKT1 , and NF2 , which may also contribute to tumor progression/transformation. These findings provide rationale for molecular/pathway-based targeted therapy for patients with advanced AGCT.

BACKGROUND Gastric cancer (GC) is one of the most prevalent malignancy around the world. Primary tumor cells are enabled to invade and migrate into adjacent normal tissues to form secondary tumors. Epithelial-mesenchymal transitions (EMT) plays a pivotal role in facilitating tumor progression. Abundant evidence suggested that the transforming growth factor-β1 (TGF-β1) triggered the process of EMT. Nonetheless, the precise molecular mechanisms underlying EMT requires further elucidation, and there still lacks effective specific therapeutic target. In our recent research, we demonstrated that the interferon (IFN)-induced transmembrane protein 2 (IFITM2) promoted the growth and metastasis of GC. However, it remains unclear whether IFITM2 involves in TGF-β1 mediated EMT in GC. METHODS AND RESULTS In the present research, we investigated the functional role of IFITM2 in EMT process and TGF-β1 signaling pathway in two GC cell lines. We noticed that silencing IFITM2 can effectively inhibit TGF-β1 signaling mediated EMT by regulating down stream small mother against decapentaplegic (SMAD) 2/3 and transcription factors.This finding was further determined in both tumor tissues from GC patients and normal tissues adjacent to cancer. Our data demonstrated the key role of IFITM2 in TGF-β1 signaling and EMT in GC. CONCLUSION The findings enriched our understanding of the underlying mechanism in EMT during the progression of GC. In addition, IFITM2 would be a potential target for treating GC and other malignant tumors.

Breast cancer is a neoplastic disease and is a cause of cancer-related mortality for women. Among cellular and molecular regulators of the microenvironment, mast cells and vascular endothelial growth factor (VEGF), are correlated with tumor progression and prognosis in breast cancer. Clinical and experimental studies on breast cancer have revealed a marked correlation between increased angiogenesis, metastasization, and poorer prognosis. After a brief introduction on angiogenesis evidence and angiogenic factors role in different breast cancer subtypes, in this article, we have discerned the relationship between mast cell infiltration, angiogenesis, and tumor progression in human breast cancer with particular reference to the dual role of mast cells, in terms of both pro- or anti-tumoral activity and poor or good biomarker.

Glioma is a heterogeneous cellular environment in which immune cells play critical roles in tumor progression. Myeloid-derived suppressor cells (MDSCs) contribute to the formation of the immunosuppressive microenvironment of glioma; however, how glioma cells interact with MDSCs and how this interaction affects the function of other immune cells are unclear. Glioma cells can systemically communicate with immune cells via the secretion of exosomes, which contain microRNAs (miRNAs). Leveraging miRNA sequencing of exosomes, we identified enrichment of miR-1246 in glioma-derived exosomes and exosomes isolated from the cerebrospinal fluid (CSF) of glioma patients. We demonstrated that miR-1246 drives the differentiation and activation of MDSCs in a dual specificity phosphatase 3 (DUSP3)/extracellular signal‑regulated kinase (ERK)-dependent manner. In addition, postoperative CSF exosomal miR-1246 expression was found to be associated with the glioma recurrence rate. Hypoxia, a well-recognized feature of the glioblastoma microenvironment, increased miR-1246 levels in glioma-derived exosomes by enhancing miR-1246 transcription and selective packaging via upregulation of POU class 5 homeobox 1 (POU5F1) and heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1). Importantly, we identified a mechanism of 2-methoxyestradiol, a microtubule inhibitor currently undergoing clinical trials for glioblastoma. 2-Methoxyestradiol suppresses MDSC activation by inhibiting hypoxia-driven exosomal miR-1246 expression in glioma cells and PD-L1 expression in MDSCs.

RATIONALE AND OBJECTIVES: Glioblastoma image evaluation utilizes MRI contrast-enhanced, T1-weighted and non-contrast T2-weighted FLAIR acquisitions. Disease progression assessment relies on changes in tumor diameter, which correlate poorly with survival. To improve treatment monitoring in glioblastoma, we investigated serial voxel-wise comparison of anatomically-aligned FLAIR signal as an early predictor of GBM progression. MATERIALS AND METHODS: We analyzed longitudinal normalized FLAIR images (rFLAIR) from 52 subjects using voxel-wise Parametric Response Mapping (PRM) to monitor volume fractions of increased (PRM(rFLAIR+)), decreased (PRM(rFLAIR−)), or unchanged (PRM(rFLAIR0)) rFLAIR intensity. We determined response by rFLAIR between pre-treatment and 10 weeks post-treatment. Risk of disease progression in a subset of subjects (N=26) with stable disease or partial response as defined by Response Assessment in Neuro-Oncology (RANO) criteria was assessed by PRM(rFLAIR) between weeks 10 and 20 and continuously until the PRM(rFLAIR+) exceeded a defined threshold. RANO defined criteria were compared with PRM-derived outcomes for tumor progression detection. RESULTS: Patient stratification for progression-free survival (PFS) and overall survival (OS) was achieved at week 10 using RANO criteria (PFS: p

Purpose To evaluate the impact of reresection on the clinical outcome in patients with primary high-risk nonmuscle-invasive bladder cancer (NMIBC) who initially received en bloc transurethral resection. Methods A retrospective analysis of data on eligible high-risk NMIBC with en bloc resection from June 2015 to June 2019 was performed. Patients were divided into two groups based on the presence or absence of reresection after the initial en bloc resection. The primary study endpoint was recurrence-free survival. The secondary outcomes were the residual rate of the tumor after initial en bloc resection, tumor upstaging rate and progression-free survival. Results We identified 115 eligible patients, including 51 (44.3%) who underwent reresection within 6 weeks of the initial en bloc resection and 64 (55.7%) who did not undergo en bloc reresection after the initial en bloc resection. The clinicopathological features were similar in patients with or without reresection. On finding tumor residues after the first en bloc resection, there were 3 cases (5.9%) in the reresection group compared to 2 cases (3.1%) in the non-reresection group (P=0.473). Two patients (3.9%) in the reresection group had tumor progression to muscle-invasive bladder cancer, whereas one patient (1.6%) in the non-reresection group exhibited tumor progression (P=0.430). The 1-year recurrence-free survival rate was 94.1% in the reresection group and 90.6% in the non-reresection group (P=0.269). In multivariate analysis, multifocality and T1 staging were independent prognostic factors for recurrence in patients with high-risk NMIBC who underwent en bloc resection. Conclusion In patients with high-risk NMIBC not exceeding 4 cm in diameter with no more than 4 lesions and not in the anterior bladder wall, reresection after en bloc resection seems to have failed to improve the patient's prognosis. However, a randomized controlled clinical study is required to confirm this hypothesis.

Distant metastasis is a major cause of death in patients with colorectal cancer (CRC) but the management of advanced and metastatic CRC still remains problematic due to the distinct molecular alterations during tumor progression. Tumor angiogenesis is a key step in tumor growth, invasion and metastasis. However, the signaling pathways involved in angiogenesis are poorly understood. The results of the present study showed that secretogranin II (SCG2) was significantly downregulated in malignant CRC tissues, and higher expression of SCG2 was correlated with longer disease‐free survival and overall survival of CRC patients. The results of an animal study showed that ectopic expression of SCG2 significantly inhibited CRC tumor growth by disrupting angiogenesis. Furthermore, the inhibition of expression of vascular endothelial growth factor (VEGF) by SCG2 and rescue of VEGF effectively blocked SCG2‐induced inhibition of angiogenesis. Investigations into the underlying mechanism suggested that SCG2 promoted degradation of hypoxia‐inducible factor (HIF)‐1α by interacting with the von Hippel–Lindau tumor suppressor in CRC cells. Blocking of degradation of HIF‐1α effectively attenuated the SCG2‐mediated decrease in expression of VEGF in CRC cells. Collectively, these results demonstrated that treatment with SCG2 effectively inhibited CRC tumor growth by disrupting the activities of HIF‐1α/VEGF, thereby clarifying the anti‐tumor and anti‐angiogenesis roles of SCG2 in CRC, while providing a novel therapeutic target and a potential prognostic marker of disease progression., Tumor angiogenesis is a key step in tumor growth, invasion and metastasis. However, the signaling pathways involved in colorectal cancer (CRC) angiogenesis are poorly understood. Here we show that secretogranin II (SCG2) was significantly downregulated in malignant CRC tissues and higher expression of SCG2 correlated with longer disease‐free survival and overall survival of patients with CRC. SCG2 impaired tumor growth and angiogenesis by inhibiting vascular endothelial growth factor expression and promoting hypoxia‐inducible factor‐1α degradation. Therefore, SCG2 may serve as a novel therapeutic target and a potential prognostic marker of disease progression in patients with CRC.

Despite improvements in outcome, 15-25% of newly diagnosed multiple myeloma (MM) patients have treatment resistant high-risk (HR) disease with a poor survival. The lack of a genetic basis for HR has focused attention on the role played by epigenetic changes. Aberrant expression and somatic mutations affecting genes involved in the regulation of tri-methylation of the lysine (K) 27 on histone 3 H3 (H3K27me3) are common in cancer. H3K27me3 is catalyzed by EZH2, the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2). The deregulation of H3K27me3 has been shown to be involved in oncogenic transformation and tumor progression in a variety of hematological malignancies including MM. Recently we have shown that aberrant overexpression of the PRC2 subunit PHD Finger Protein 19 (PHF19) is the most significant overall contributor to HR status further focusing attention on the role played by epigenetic change in MM. By modulating both the PRC2/EZH2 catalytic activity and recruitment, PHF19 regulates the expression of key genes involved in cell growth and differentiation. Here we review the expression, regulation and function of PHF19 both in normal and the pathological contexts of solid cancers and MM. We present evidence that strongly implicates PHF19 in the regulation of genes important in cell cycle and the genetic stability of MM cells making it highly relevant to HR MM behavior. A detailed understanding of the normal and pathological functions of PHF19 will allow us to design therapeutic strategies able to target aggressive subsets of MM. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-02185-1.

Background: It is substantiated that LncRNAs are associated with carcinoma progression. OIP5- AS1 is a tumor-related carcinoma suppressor lncRNA, previously discovered in zebrafish, which is involved in the progression of a variety of cancers, has a regulatory effect on carcinoma, and interacts with miRNA and other biomolecules to affect the physiological and pathological processes of carcinoma cells. This article will discuss the effect of OIP5-AS1 in various cancers and its regulatory mechanism. Methods: This paper summarized and analyzed OIP5-AS1, which functions on the germination and progression of carcinoma and its regulatory mechanism. Meanwhile, the related research was retrieved and collected by the PubMed system. Results: OIP5-AS1 is overexpressed in various tumors, which regulates and controls tumor growth and participates in tumor progression, including breast carcinoma, ovarian carcinoma, cervical carcinoma, lung carcinoma, laryngeal squamous cell gastric carcinoma and hepatocellular carcinoma. The research evidence proves that OIP5-AS1 takes part in carcinoma proliferation, growth, migration, invasion, and apoptosis. Conclusion: OIP5-AS1 probably can be an effective biomarker or a potential therapeutic target in multiple tumors.

Purpose A chordoma is a slow-growing, invasive neoplasm in the neuraxis, thought to arise from notochordal cells. At 10-year follow-up, the average survival rate is 50%, though the interindividual prognosis varies substantially. Here, we aim to provide a comprehensive overview of the genes and proteins expressed in these tumors and their prognostic value, as to facilitate prognostication for chordoma patients. Methods A systematic search of clinical studies that investigated expressed factors related to chordoma survival was performed in PubMed. Data extraction included RNA and protein expression data and prognostic value (in terms of overall survival, progression free survival, disease free survival and recurrence free survival), both by univariate and multivariate analysis. Results Seventy-eight original studies, collectively evaluating 134 expressed factors, were included in this review. By univariate analysis 96, and by multivariate analysis 32 of these molecular factors had a predictive value for patient survival. Of those studied in multivariate analyses, 26 factors had a negative effect while six had a positive effect on patient survival. Conclusions Identification of molecular factors that are associated with survival contributes towards better prognostication of chordoma patients. Given chordoma’s rarity, oftentimes only univariate analyses can be performed. Robust multivariate analyses are scarcer but provide independently significant prognostic factors. The data presented in this review aids in prognostication for the individual patient and facilitates the development of targeted therapies.

Purpose The identification of optimal drug administration schedules to overcome the emergence of resistance that causes treatment failure is a major challenge in cancer research. We report the outcomes of a computational strategy to assess the dynamics of tumor progression as a function of time under different treatment regimens. Methods We developed an evolutionary game theory model that combined Lotka-Volterra equations and pharmacokinetic properties with 2 competing cancer species: nivolumab-response cells and Janus kinase (JAK1/2) mutation cells. We selected 3 therapeutic schemes that have been tested in the clinical trials: 3 mg/kg Q2w, 10 mg/kg Q2w, and 480 mg Q4w. The simulation was performed under the intervals of 75, 125, and 175 days, respectively, for each regimen. The data sources of the pharmacokinetic parameters used in this study were collected from previous published clinical trials. Other parameters in the evolutionary model come from the existing references. Findings Predictions under various dose schedules indicated a strong selection for nivolumab-independent cells. Under the 3 mg/kg dose strategy, the reproduction rate of JAK mutation cells was highest, with strongest tumor elimination ability at a 75-day interval between treatments. Prolonged drug intervals to 125 or 175 days delayed tumor evolution but accelerated tumor recurrence. Although 10 mg/kg Q2w had an obvious clinical effect in a short time, it further promotes the progress of resistant population compared with the 3 mg/kg dose. Our model suggests that 480 mg Q4w would be more valuable in terms of clinical efficacy, but complete resistant occurs earlier regardless the interval. Implications The results of this study emphasize that increasing the dose or shortening the interval between doses accelerates the evolution of heterogeneous populations, although the short-term effect is significant. In practice, the therapeutic regimen should be balanced according to the evolutionary principle.