Target For Anticancer Therapy Research Articles

A CRISPR/Cas9-Based Assay for High-Throughput Studies of Cancer-Induced Innervation

The aggressive nature of certain cancers and their adverse effects on patient outcomes have been linked to cancer innervation, where neurons infiltrate and differentiate within the cancer stroma. Recently we demonstrated how cancer plasticity and TGFβ signaling could promote breast cancer innervation that is associated with increased cancer aggressivity. Despite the promising potential of cancer innervation as a target for anti-cancer therapies, there is currently a significant lack of effective methods to study cancer-induced neuronal differentiation, hindering the development of high-throughput approaches for identifying new targets or pharmacological inhibitors against cancer innervation. To overcome this challenge, we used CRISPR-based endogenous labeling of the neuronal marker β3-tubulin in neuronal precursors to investigate cancer-induced neuronal differentiation in nerve-cancer cocultures and provide a tool that allows for better standardization and reproducibility of studies about cancer-induced innervation. Our approach demonstrated that β3-tubulin gene editing did not affect neuronal behavior and enabled accurate reporting of cancer-induced neuronal differentiation dynamics in high-throughput settings, which makes this approach suitable for screening large cohorts of cells or testing various biological contexts. In a more context-based approach, by combining this method with a cell model of breast cancer epithelial-mesenchymal transition, we revealed the role of cancer cell plasticity in promoting neuronal differentiation, suggesting that cancer innervation represents an underexplored path for epithelial-mesenchymal transition-mediated cancer aggressivity.

Oncogenic Viruses-Encoded microRNAs and Their Role in the Progression of Cancer: Emerging Targets for Antiviral and Anticancer Therapies.

Approximately 20% of all cases of human cancer are caused by viral infections. Although a great number of viruses are capable of causing a wide range of tumors in animals, only seven of these viruses have been linked to human malignancies and are presently classified as oncogenic viruses. These include the Epstein-Barr virus (EBV), human papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), Merkel cell polyomavirus (MCPyV), human herpesvirus 8 (HHV8), and human T-cell lymphotropic virus type 1 (HTLV-1). Some other viruses, such as the human immunodeficiency virus (HIV), are associated with highly oncogenic activities. It is possible that virally encoded microRNAs (miRNAs), which are ideal non-immunogenic tools for viruses, play a significant role in carcinogenic processes. Both virus-derived microRNAs (v-miRNAs) and host-derived microRNAs (host miRNAs) can influence the expression of various host-derived and virus-derived genes. The current literature review begins with an explanation of how viral infections might exert their oncogenic properties in human neoplasms, and then goes on to discuss the impact of diverse viral infections on the advancement of several types of malignancies via the expression of v-miRNAs. Finally, the role of new anti-oncoviral therapies that could target these neoplasms is discussed.

Differential CMS-Related Expression of Cell Surface Carbonic Anhydrases IX and XII in Colorectal Cancer Models-Implications for Therapy.

Tumor-associated carbonic anhydrases IX (CAIX) and XII (CAXII) have long been in the spotlight as potential new targets for anti-cancer therapy. Recently, CAIX/CAXII specific inhibitor SLC-0111 has passed clinical phase I study and showed differential response among patients with colorectal cancer (CRC). CRC can be classified into four different consensus molecular subgroups (CMS) showing unique expression patterns and molecular traits. We questioned whether there is a CMS-related CAIX/CAXII expression pattern in CRC predicting response. As such, we analyzed transcriptomic data of tumor samples for CA9/CA12 expression using Cancertool. Protein expression pattern was examined in preclinical models comprising cell lines, spheroids and xenograft tumors representing the CMS groups. Impact of CAIX/CAXII knockdown and SLC-0111 treatment was investigated in 2D and 3D cell culture. The transcriptomic data revealed a characteristic CMS-related CA9/CA12 expression pattern with pronounced co-expression of both CAs as a typical feature of CMS3 tumors. Protein expression in spheroid- and xenograft tumor tissue clearly differed, ranging from close to none (CMS1) to strong CAIX/CAXII co-expression in CMS3 models (HT29, LS174T). Accordingly, response to SLC-0111 analyzed in the spheroid model ranged from no (CMS1) to clear (CMS3), with moderate in CMS2 and mixed in CMS4. Furthermore, SLC-0111 positively affected impact of single and combined chemotherapeutic treatment of CMS3 spheroids. In addition, combined CAIX/CAXII knockdown and more effective treatment with SLC-0111 reduced clonogenic survival of CMS3 modelling single cells. In conclusion, the preclinical data support the clinical approach of targeted CAIX/CAXII inhibition by showing linkage of expression with response and suggest that patients with CMS3-classified tumors would most benefit from such treatment.

Potential Therapeutic Targets in Ovarian Cancer: Autophagy and Metabolism.

Ovarian cancer (OC) is characterized by high mortality rates owing to late diagnosis and resistance to chemotherapy. Autophagy and metabolism play essential roles in the pathological process of cancer and have recently been proposed as potential targets for anticancer therapies. Autophagy is responsible for the catabolic clearance of functionally misfolded proteins and plays different roles depending on the stage and type of cancer. Thus, understanding and controlling autophagy is relevant for treating cancer. Autophagy intermediates can communicate with each other by providing substrates for glucose, amino acid, and lipid metabolism. Metabolites and metabolic regulatory genes modulate autophagy and influence the immune response. Therefore, autophagy and the functional manipulation of metabolism during starvation or overnutrition are being investigated as potential therapeutic targets. This review discusses the role of autophagy and metabolism in OC and highlights effective therapeutic strategies targeting these processes.

Involvement of protumor macrophages in breast cancer progression and characterization of macrophage phenotypes.

Tumor-associated macrophages (TAMs) are the most prominent immune cells in the breast cancer microenvironment, and the protumor functions of TAMs are thought to affect cancer progression and resistance to anticancer therapy. Numerous studies using human breast cancer samples, cell lines, and murine breast cancer models have revealed details of the mechanisms by which the protumor functions of TAMs are activated. Recent advances have highlighted the significant involvement of TAMs in the resistance of breast cancer cells to immunotherapy. Tumor-associated macrophages express a number of immunosuppressive genes, and single-cell sequence analyses of human and murine cancer samples have helped elucidate the mechanism of TAM-induced immunosuppression. As TAMs are considered suitable targets for anticancer therapies, we summarized the protumor functions of TAMs and the potential of anticancer therapies targeting TAMs, with a focus on breast cancer research.

Transcriptional Response to Hypoxia: The Role of HIF-1-Associated Co-Regulators.

The Hypoxia Inducible Factor 1 (HIF-1) plays a major role in the cellular response to hypoxia by regulating the expression of many genes involved in adaptive processes that allow cell survival under low oxygen conditions. Adaptation to the hypoxic tumor micro-environment is also critical for cancer cell proliferation and therefore HIF-1 is also considered a valid therapeutical target. Despite the huge progress in understanding regulation of HIF-1 expression and activity by oxygen levels or oncogenic pathways, the way HIF-1 interacts with chromatin and the transcriptional machinery in order to activate its target genes is still a matter of intense investigation. Recent studies have identified several different HIF-1- and chromatin-associated co-regulators that play important roles in the general transcriptional activity of HIF-1, independent of its expression levels, as well as in the selection of binding sites, promoters and target genes, which, however, often depends on cellular context. We review here these co-regulators and examine their effect on the expression of a compilation of well-characterized HIF-1 direct target genes in order to assess the range of their involvement in the transcriptional response to hypoxia. Delineating the mode and the significance of the interaction between HIF-1 and its associated co-regulators may offer new attractive and specific targets for anticancer therapy.

Abstract F2-3: Immunosuppressive macrophages and PARP inhibitor resistance

Abstract Despite objective responses to poly(ADP-ribose) polymerase (PARP) inhibition and improvements in progression-free survival (PFS) compared to standard chemotherapy in patients with BRCA-associated triple-negative breast cancer (TNBC), benefits are transitory. Using high-dimensional single-cell profiling of human TNBC, here we demonstrate that macrophages are the predominant infiltrating immune cell type in breast cancer susceptibility (BRCA)-associated TNBC. Macrophages are an innate immune cell that play a critical role in host defense and maintaining tissue homeostasis, however their infiltration into tumors has been associated with disease progression and resistance to therapy. Tumor associated macrophages (TAMs) represent a significant proportion of solid tumors, including breast cancer. TAMs play a major role in tumorigenesis as they can enhance tumor cell growth, angiogenesis and metastasis. In addition, TAMs can inhibit anti-tumor responses of T cells. Our recent work has shown that removal or conversion of TAMs to an anti-tumor phenotype enhances chemo- and immuno-therapy establishing TAMs as targets for anti-cancer therapy. Through multi-omics profiling, we show that PARP inhibitors enhance both anti- and pro-tumor features of macrophages through glucose and lipid metabolic reprogramming, driven by the sterol regulatory element-binding protein 1 (SREBF1, SREBP1) pathway. Combining PARP inhibitor therapy with colony-stimulating factor 1 receptor (CSF1R)-blocking antibodies significantly enhanced innate and adaptive antitumor immunity and extended survival in mice with BRCA-deficient tumors in vivo, and this was mediated by CD8+ T cells. Collectively, our results uncover macrophage-mediated immune suppression as a liability of PARP inhibitor treatment and demonstrate that combined PARP inhibition and macrophage-targeting therapy induces a durable reprogramming of the tumor microenvironment (TME), thus constituting a promising therapeutic strategy for TNBC. Therefore, targeting TAMs offers great potential to enhance both chemo- and immuno-therapy. Deep analysis of TAMs in solid tumors has revealed the complexity of TAMs and revealed major gaps in our knowledge of the functional and phenotypic characterization of TAM subsets associated with cancer, before and after treatment. Here we will discuss the complexity of TAMs in solid tumors including characterizing TAM subsets, location, and crosstalk with neighboring cells, as well as novel TAM-modulating strategies and combinations that are likely to enhance current therapies and overcome chemo- and immuno-therapy resistance. Citation Format: Jennifer Guerriero. Immunosuppressive macrophages and PARP inhibitor resistance [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr F2-3.

Molecular docking study of ethyl acetate fraction of Selaginella doederleinii Hieron extract as anti-Warburg effect in breast cancer

Context: Aerobic glycolysis is a breast cancer hallmark that has become a novel target for anticancer therapy. GLUT1, HK2, PKM2, and LDHA are oncogenic proteins in the pathway. The compounds of ethyl acetate fraction of Selaginella doederleinii Hieron extract can be developed as aerobic glycolysis inhibitors by impeding the proteins’ activity. Aims: To analyze the anticancer activity of compounds of the ethyl acetate fraction of S. doederleinii via inhibiting oncogenic proteins in the aerobic glycolysis pathway. Methods: The 3D protein structures were obtained from the RCSB database. Ligands were compounds of the ethyl acetate fraction predicted to have a good oral bioavailability based on our previous study. The ligand structures were downloaded from the PubChem database. Docking and analysis of chemical interactions were performed using Autodock Vina in Pyrx and Discovery Studio 2020, respectively. Results: Some compounds interacted with the specific binding site of proteins with low binding affinity. Diosgenin interacted with GLUT1 and LDHA with the binding affinity of -11.8 and -9.6 kcal/mol. Frutinone A was found to bind PKM2 and LDHA with the binding affinity of -10.0 and -8.4 kcal/mol. Vitexin interacted with GLUT1 and PKM2 with the binding affinity of -10.4 and -10.0 kcal/mol. Valerodine and 5-hydroxyferulic acid methyl ester could bind HK2 with a binding affinity of -6.1 and -6.8 kcal/mol. Conclusions: The compounds of ethyl acetate fraction of S. doederleinii extract were predicted to inhibit GLUT1, HK2, PKM2, and LDHA. Therefore, these compounds could be developed as anti-breast cancer agents targeting the aerobic glycolysis pathway.

Simultaneous activation of CXC chemokine receptor 4 and histamine receptor H1 enhances calcium signaling and cancer cell migration

C-X-C chemokine receptor 4 (CXCR4) is widely overexpressed in various types of cancer and is involved in several cancer phenotypes including tumor growth, survival, and metastasis. The roles of histamine and histamine receptor H1 (HRH1) in cancer pathogenesis remain controversial. Here, we show that HRH1 is widely expressed in various cancer cell lines and cancer tissues and that coexpression of CXCR4 and HRH1 is associated with poor prognosis in breast cancer. Using bimolecular fluorescence complementation and bioluminescence resonance energy transfer donor saturation assays, we demonstrate that CXCR4 and HRH1 can assemble into a heteromeric complex. Simultaneous activation of CXCR4 and HRH1 synergistically increases calcium flux in MDA-MB-231 cells that endogenously express CXCR4 and HRH1 but not in cells deficient in CXCR4 or HRH1. Costimulation of CXCR4 and HRH1 also significantly enhances CXCL12-induced MDA-MB-231 cell migration, while histamine alone does not induce cell migration. Synergistic effects on calcium flux and cell migration are inhibited by the Gαi inhibitor pertussis toxin and the Gαq inhibitor YM254890, suggesting that the Gαi and Gαq pathways are involved in the synergy. Enhanced calcium signaling and cell migration are also observed in NCI-H23 and HeLa cells, which coexpress CXCR4 and HRH1. Taken together, our findings demonstrate an interplay between CXCR4 and HRH1, and suggest the possibility of the CXCR4-HRH1 heteromer as a potential therapeutic target for anticancer therapy.

Metabolic Phenotype Intricacies on Altered Glucose Metabolism of Breast Cancer Cells upon Glut-1 Inhibition and Mimic Hypoxia In Vitro.

Breast cancer is the frequently diagnosed cancer and the leading cancer death among women. The growing tumour of the breast is composed of both normoxic and hypoxic cells, and the heterogeneity of tumour affects the targeted treatment strategies against breast cancer. The functional and therapeutic status of the Warburg effect is mostly recognized, and the genes involved in glycolysis have become a target for anticancer therapeutic strategies. Glut-1 is essential for basal glucose uptake among the glucose transporters and could act as a potential target for anticancer therapy. In the present study, we explored the alteration in the metabolic phenotype of SKBR-3 cells, representing HER-2 overexpressed breast cancer cell line, with Glut-1 inhibition by a synthetic small molecule inhibitor WZB117 in the presence or absence of cobalt chloride (CoCl2) induced biochemical hypoxia in vitro. We found that WZB117 and CoCl2 in combination could inhibit metabolic phenotype characteristics such as glucose uptake, cell migration, lactate and ATP production in SKBR-3 cells. Also, Glut-1 inhibition induced apoptosis and cell cycle arrest at the G0-G1 phase even under CoCl2-induced mimic hypoxia. Our findings suggest that Glut-1 inhibition by WZB117 could overcome the protective effect of CoCl2 mimic hypoxia by regulating glycolysis and altering the metabolic phenotype of breast cancer cells. The considering excellent efficacy and minimal toxicity suggest that WZB117 may be a promising anticancer drug to the current therapies.

Lysosomes as a Target of Anticancer Therapy.

Lysosomes are organelles containing acidic hydrolases that are responsible for lysosomal degradation and the maintenance of cellular homeostasis. They play an important role in autophagy, as well as in various cell death pathways, such as lysosomal and apoptotic death. Various agents, including drugs, can induce lysosomal membrane permeability, resulting in the translocation of acidic hydrolases into the cytoplasm, which promotes lysosomal-mediated death. This type of death may be of great importance in anti-cancer therapy, as both cancer cells with disturbed pathways leading to apoptosis and drug-resistant cells can undergo it. Important compounds that damage the lysosomal membrane include lysosomotropic compounds, antihistamines, immunosuppressants, DNA-damaging drugs, chemotherapeutics, photosensitizers and various plant compounds. An interesting approach in the treatment of cancer and the search for ways to overcome the chemoresistance of cancer cells may also be combining lysosomotropic compounds with targeted modulators of autophagy to induce cell death. These compounds may be an alternative in oncological treatment, and lysosomes may become a promising therapeutic target for many diseases, including cancer. Understanding the functional relationships between autophagy and apoptosis and the possibilities of their regulation, both in relation to normal and cancer cells, can be used to develop new and more effective anticancer therapies.

Design of novel anti-cancer drugs targeting TRKs inhibitors based 3D QSAR, molecular docking and molecular dynamics simulation

Tropomyosin receptor kinase (TRK) enzymes are responsible for different types of tumors caused by neurotrophic tyrosine receptor kinase gene fusion and have been identified as an effective target for anticancer therapy. The study of the mechanism between polo-like kinase (PLKs) and pyrazol inhibitors was performed using 3D-QSAR modeling, molecular docking, and MD simulations in order to design high-activity inhibitors. The HQSAR (Q 2 = 0.793, R 2 = 0.917, R 2 ext = 0.961), CoMFA (Q 2 = 0.582, R 2 = 0.722, R 2 ext = 0.951), CoMSIA/SE (Q 2 = 0.603, R 2 = 0.801, R 2 ext = 0.849), and Topomer CoMFA (Q 2 = 0.726, R 2 = 0.992, R 2 ext = 0.717) showed good reliability and predictability. All models have been successfully tested by external validation, so all five established models are reliable. The analysis of the different contour maps of different models gives structural information to improve the inhibitory function. Molecular docking results show that the amino acids Met 592, GLU 590, LEU 657, VAL 524, and PHE 589 are the active sites of the tropomyosin receptor TRKs. The results obtained by MD showed that compound 19i could form a more stable complex protein (PDB id: 5KVT). Based on these results, we developed new compounds and their expected inhibitory activities. The results of physicochemical and ADME-Tox properties showed that the four proposed molecules are orally bioavailable, and they are not toxic in the Ames test. Thus, these results would provide modeling information that could help experimental researchers find TRK type I inhibitors more efficiently. Communicated by Ramaswamy H. Sarma

Synergistic Effect of Co-Culturing Breast Cancer Cells and Fibroblasts in the Formation of Tumoroid Clusters and Design of In Vitro 3D Models for the Testing of Anticancer Agents.

Breast cancer is still the leading cause of women's death due to relapse and metastasis. In vitro tumor models are considered reliable tools for drug screening and understanding cancer-driving mechanisms due to the possibility of mimicking tumor heterogeneity. Herein, a 3D breast cancer model (3D-BCM) is developed based on enzymatically-crosslinked silk fibroin (eSF) hydrogels. Human MCF7 breast cancer cells are encapsulated into eSF hydrogels, with and without human mammary fibroblasts. The spontaneously occurring conformational change from random coil to β-sheet is correlated with increased eSF hydrogels' stiffness over time. Moreover, mechanical properties analysis confirms that the cells can modify the stiffness of the hydrogels, mimicking the microenvironment stiffening occurring in vivo. Fibroblasts support cancer cells growth and assembly in the eSF hydrogels up to 14 days of culture. Co-cultured 3D-BCM exhibits an upregulated expression of genes related to extracellular matrix remodeling and fibroblast activation. The 3D-BCM is subjected to doxorubicin and paclitaxel treatments, showing differential drug response. Overall, these results suggest that the co-culture of breast cancer cells and fibroblasts in eSF hydrogels allow the development of a mimetic in vitro platform to study cancer progression. This opens up new research avenues to investigate novel molecular targets for anti-cancer therapy.

Carbonic anhydrases III and IX are new players in the crosstalk between adrenocortical carcinoma and its altered adipose microenvironment

PurposeAdrenocortical carcinoma (ACC), a rare malignancy of the adrenocortex, is characterized by a crosstalk between the adipose microenvironment and tumor. Here, we assessed the involvement of carbonic anhydrase (CA) enzymes III and IX (CAIII and CAIX), in the metabolic alterations of the adipose tissue characterizing obesity and in the local crosstalk between the tumor adipose microenvironment and ACC.Results/methodsCAIII and CAIX expression is altered in visceral adipose tissue (VAT) in obesity and in ACC. A significant CAIX upregulation was present in ACC at advanced stages (n = 14) (fold increase FI = 7.4 ± 0.1, P < 0.05) associated with lower CAIII levels (FI = 0.25 ± 0.06, P < 0.001), compared with lower stages (n = 9). In vitro coculture between visceral adipose stem cells (ASCs) and ACC cell lines, H295R and MUC-1, mimicking the interaction occurring between VAT and advanced ACC, showed a significant CAIX upregulation in H295R but not in MUC-1 cells, and a decreased expression of CAIII. The effect on adipose cells was different when cocultured with H295R or MUC-1 cells. Coculture did not modulate CAIII expression in ASCs, which, however, was significantly downregulated with H295R (FI = 0.34 ± 0.11, P < 0.05) and upregulated by MUC-1 when cocultured ASCs were induced to differentiate toward adipocytes, with an expression profile similar to what found in VAT of obese subjects. CAIX expression was markedly increased in ASCs cocultured with H295R and to a less extent following adipogenesis induction (FI = 150.9 ± 46.5 and FI = 4.6 ± 1.1, P < 0.01, respectively).ConclusionOur findings highlight a modulation of CAIII and CAIX in the metabolic crosstalk between ACC and its local adipose microenvironment, suggesting that CAs might represent a potential target for novel anticancer therapies.

Discovering Gummadiol and Isoarboreol as potential inhibitors of sphingosine kinase 1: virtual screening and MD simulation studies

Sphingosine kinase 1 (SphK1) dysfunction is well-known to be linked to various severe diseases, including breast, lung, prostate, and hematological cancers. Due to its crucial function in the onset of cancer and its progression, it is considered a notable drug target for anticancer therapy. Small molecule inhibitors with high specificity and efficacy towards SphK1 are needed for their therapeutic use. In order to find possible SphK1 inhibitors, we conducted a stepwise structure-based virtual screening of plant-based molecules available from the IMPPAT library. A multi-step virtual screening, including physicochemical and ADMET evaluation, PAINS, molecular docking, PASS analysis followed by molecular dynamics (MD) simulation and principal component analysis, identifies two compounds, Gummadiol and Isoarboreol, against SphK1. All-atom MD simulations were performed for 100 ns which examined the structural changes and stability of the docked complexes in the aqueous environment. The time evolution data of structural deviations and compactness, PCA and free energy landscapes suggested that the binding of Gummadiol and Isoarboreol with SphK1 is considerably stable throughout the trajectory. The study highlighted the use of phytochemicals in anticancer therapeutics and presented Gummadiol and Isoarboreol as promising inhibitors of SphK1. Communicated by Ramaswamy H. Sarma

Inflammation in Urological Malignancies: The Silent Killer

Several studies have investigated the role of inflammation in promoting tumorigenesis and cancer progression. Neoplastic as well as surrounding stromal and inflammatory cells engage in well-orchestrated reciprocal interactions to establish an inflammatory tumor microenvironment. The tumor-associated inflammatory tissue is highly plastic, capable of continuously modifying its phenotypic and functional characteristics. Accumulating evidence suggests that chronic inflammation plays a critical role in the development of urological cancers. Here, we review the origins of inflammation in urothelial, prostatic, renal, testicular, and penile cancers, focusing on the mechanisms that drive tumor initiation, growth, progression, and metastasis. We also discuss how tumor-associated inflammatory tissue may be a diagnostic marker of clinically significant tumor progression risk and the target for future anti-cancer therapies.

Glycodelin is a potential biomarker for malignant tumors

Objective of the study to analyze and summarize the available data on the role of glycodelin in carcinogenesis and its expression in various cancers.Material and Methods. A literature search was conducted in Medline, PubMed Central, NCBI databases in the time interval from January 1983 to October 2019 using the key words glycodelin and cancer. Of the 104 publications found, 21 were used to write the review.Results. This paper presents the overview of the findings in current research focusing on the properties of glycodelin, the major lipocalin protein of the human reproductive system. Some lipocalins are known to play a key role in cancer development as well as influence signaling pathways in the regulation of cell motility, differentiation and neovascularization. Most likely they can be used as cancer markers. Glycodelin A is determined in serum and, due to its special immunoregulatory properties, can serve as a useful prognostic marker and a promising target for future anti-cancer therapies. The presence of glycodelin A in breast cancer tissue is known to be mostly linked to a better prognosis than is attributed to glycodelin-negative tissue, as glycodelin is a protein typical of differentiated tissue. On the other hand, glycodelin might play a role in neovascularisation, thereby promoting tumor growth. Glycodelin is a biomarker of aggressive malignant pleural mesothelioma and a prognostic biomarker of metastatic non-small cell lung cancer at late stages. Glycodelin hyperexpression is associated with brain metastasis in lung adenocarcinoma, and its determination can be used as an additional prognostic factor.Conclusion. The review refects basic scientifc data and results of clinical trials, as well as identifes future prospects that allow the development of new methods for cancer detection and treatment. It should be noted that glycodelin plays an important role in tumor development, progression, angiogenesis, and the formation of distant metastases, and therefore can serve as a useful diagnostic and prognostic marker. Further studies of the functional properties of glycodelin are needed to develop promising strategies in cancer therapy.

Diversity of MLE Helicase Functions in the Regulation of Gene Expression in Higher Eukaryotes

The Drosophila melanogaster Maleless (MLE) protein is a conserved helicase involved in a wide range of gene expression regulation processes. A MLE ortholog, named DHX9, was found in many higher eukaryotes, including humans. DHX9 is involved in diverse processes, such as genome stability maintenance, replication, transcription, splicing, editing and transport of cellular and viral RNAs, and translation regulation. Some of these functions are understood in detail today, while most of them remain uncharacterized. Study of the functions of the MLE ortholog in mammals in vivo is limited by the fact that the loss of function of this protein is lethal at the embryonic stage. In D. melanogaster, helicase MLE was originally discovered and studied for a long time as a participant in dosage compensation. Recent evidence indicates that helicase MLE is involved in the same cell processes in D. melanogaster and mammals and that many of its functions are evolutionarily conserved. Experiments in D. melanogaster revealed new important MLE functions, such as a role in hormone-dependent regulation of transcription and interactions with the SAGA transcription complex, other transcriptional cofactors, and chromatin remodeling complexes. Unlike in mammals, MLE mutations do not cause embryonic lethality in D. melanogaster, and the MLE functions are possible to study in vivo throughout ontogenesis in females and up to the pupal stage in males. The human MLE ortholog is a potential target for anticancer and antiviral therapies. Further investigation of the MLE functions in D. melanogaster is therefore of both basic and applied importance. The review discusses the systematic position, domain structure, and conserved and specific functions of MLE helicase in D. melanogaster.

Heparan sulfate proteoglycans in cancer: Pathogenesis and therapeutic potential.

The heparan sulfate proteoglycans (HSPGs) are glycoproteins that consist of a proteoglycan "core" protein and covalently attached heparan sulfate (HS) chain. HSPGs are ubiquitously expressed in mammalian cells on the cell surface and in the extracellular matrix (ECM) and secretory vesicles. Within HSPGs, the protein cores determine when and where HSPG expression takes place, and the HS chains mediate most of HSPG's biological roles through binding various protein ligands, including cytokines, chemokines, growth factors and receptors, morphogens, proteases, protease inhibitors, and ECM proteins. Through these interactions, HSPGs modulate cell proliferation, adhesion, migration, invasion, and angiogenesis to display essential functions in physiology and pathology. Under physiological conditions, the expression and localization of HSPGs are finely regulated to orchestrate their physiological functions, and this is disrupted in cancer. The HSPG dysregulation elicits multiple oncogenic signaling, including growth factor signaling, ECM and Integrin signaling, chemokine and immune signaling, cancer stem cell, cell differentiation, apoptosis, and senescence, to prompt cell transformation, proliferation, tumor invasion and metastasis, tumor angiogenesis and inflammation, and immunotolerance. These oncogenic roles make HSPGs an attractive pharmacological target for anti-cancer therapy. Several therapeutic strategies have been under development, including anti-HSPG antibodies, peptides and HS mimetics, synthetic xylosides, and heparinase inhibitors, and shown promising anti-cancer efficacy. Therefore, much progress has been made in this line of study. However, it needs to bear in mind that the roles of HSPGs in cancer can be either oncogenic or tumor-suppressive, depending on the HSPG and the cancer cell type with the underlying mechanisms that remain obscure. Further studies need to address these to fill the knowledge gap and rationalize more efficient therapeutic targeting.

Prognostic significance ofPD-L1 expression in pancreatic cancer: evidence from anupdated meta-analysis.

Recent studies revealed that programmed cell death ligand 1 (PD-L1) expression was associated with unfavorable prognosis in various solid tumors, but its clinical relevance for pancreatic cancer has not yet been well established. This meta-analysis summarizes thepotential prognostic value ofPD-L1 in pancreatic cancer. Aquantitative meta-analysis was performed by asystematic search ofdatabases including PubMed, EMBASE, Web ofScience, Cochrane library, Scopus and Ovid for eligible studies on theprognostic significance ofPD-L1 in pancreatic cancer patients. Pooled hazard ratios (HRs) and their 95% confidence intervals (CIs) were calculated to evaluate thestrength ofthelink between PD-L1 expression and clinical prognosis ofpatients. Seventeen eligible studies with 2669 patients were included in our study. Asignificant association was observed between PD-L1 abundance and poor overall survival (OS) ofpatients with pancreatic cancers, with apooled hazard ratio (HR) of1.902, 95% CI: 1.657-2.184. Sensitivity analysis confirmed thereliability ofour results. Subgroup analysis shows that differences in regions and detection methods ofPD-L1 did not change theoverall predictive value ofPD-L1 for poor prognosis in pancreatic cancer patients. This meta-analysis indicated that theexpression ofPD-L1 is associated with aworse OS in pancreatic cancer patients. Additionally, PD-L1 may act as a potential parameter for predicting poor prognosis and thus providing apromising target for anticancer therapy in pancreatic cancer.