Stages Of Cancer Development Research Articles

Long non-coding RNA (lncRNA) DSCAM-AS1 is upregulated in breast cancer.

Accumulating evidence highlights that long noncoding RNA (lncRNA) DSCAM-AS1 play a key regulatory role in different stages of cancer development and progression. This study aimed to investigate whether the expression of DSCAM-AS1 is deregulated in breast cancer. The relative expression of DSCAM-AS1 was measured in fifty breast cancerous and matched adjacent non-neoplastic tissue samples using quantitative real-time polymerase chain reaction (qPCR) technique. The association between DSCAM-AS1 expression and patients' clinicopathological features was evaluated. Sensitivity and specificity of the DSCAM-AS1 expression for diagnosing breast cancer was obtained by the receiver operating characteristic (ROC) curve analysis. Our results showed that the expression of DSCAM-AS1 was significantly up-regulated in breast cancerous tissues compared with the matched adjacent non-neoplastic tissues (P <0.05). Furthermore, we observed a significant association between the DSCAM-AS1 expression and lymph node metastasis (P =0.011) but no other clinicopathological characteristics (P >0.05). ROC curve analysis resulted in an area under the curve (AUC) of 0.67 and showed that the DSCAM-AS1 expression level may discriminate cancerous and non-cancerous tissues with 68% sensitivity and 76% specificity. This study provides further evidence that the expression of DSCAM-AS1 is deregulated in breast cancer and highlights its potential in breast cancer development.

PathFinder: Bayesian inference of clone migration histories in cancer.

Metastases cause a vast majority of cancer morbidity andmortality. Metastatic clones are formed by dispersal of cancer cells to secondary tissues, and are not medically detected or visible until later stages of cancer development. Clone phylogenies within patients provide a means of tracing the otherwise inaccessible dynamic history of migrations of cancer cells. Here, we present a new Bayesian approach, PathFinder, for reconstructing the routes of cancer cell migrations. PathFinder uses the clone phylogeny, the number of mutational differences among clones, and the information on the presence and absence of observed clones in primary and metastatic tumors. By analyzing simulated datasets, we found that PathFinder performes well in reconstructing clone migrations from the primary tumor to new metastases as well as between metastases. It was more challenging to trace migrations from metastases back to primary tumors. We found that a vast majority of errors can be corrected by sampling more clones per tumor, and by increasing the number of genetic variants assayed per clone. We also identified situations in which phylogenetic approaches alone are not sufficient to reconstruct migration routes.In conclusion, we anticipate that the use of PathFinder will enable a more reliable inference of migration histories and their posterior probabilities, which is required to assess the relative preponderance of seeding of new metastasis by clones from primary tumors and/or existing metastases. PathFinder is available on the web at https://github.com/SayakaMiura/PathFinder.

Transforming growth factor β in breast cancer: another new trick for the old dog.

Two recent papers from the laboratory of Professor Ming Li demonstrate that inhibition of transforming growth factor β specifically in CD4+ T cells can suppress tumor growth through an unanticipated mechanism.

The pharmacological basis for application of cannabidiol in cancer chemotherapy

Chemotherapy is one of the therapeutic approaches for cancer treatment and has demonstrated great success with the introduction of selectively acting molecules against specific biomarkers of some types of tumors. Despite this success there is a large unmet need for novel therapies that provide effective control on the progression of advanced or drug-resistant cancer diseases. In this review, we briefly summarized our knowledge of cannabinoids and the endocannabinoid system, as possible agents for cancer therapy. We analyzed the anticancer properties and mechanism of action of cannabidiol (CBD), the main non-psychoactive cannabinoid received from hemp of Cannabis plant. Despite of data for pleiotropic effects of CBD, we here present the results for the efficacy of CBD in the modulation of different stages of cancer development. The analysis of the anticancer properties of CBD is made in relation to the proposed or newly discovered molecular targets of action. Thereafter, we consider the specific effects of CBD on primary tumors, their invasiveness and metastases, whether the influence on identified tumor markers in different types of tumors reflect the therapeutic potential of CBD. The studies reviewed herein indicate that CBD elicit activity through the cannabinoid receptor dependent and independent pathways. The processes such as ceramide production, ER-stress, autophagy and apoptosis, angiogenesis and matrix remodeling also appear to regulate the anticancer activity of CBD. So, the pharmacological basis for therapeutic application of CBD is constructed on the scientific data for its antitumor activity, extensively provided studies in vitro and in vivo in animal tumor models, and available data on the safety profile of clinically approved CBD products. We also try to reduce the deficits of our understanding in relation of pharmacological synergistic interactions of CBD with cytostatic drugs, where data remains limited. It is recognized that more studies for defining the specific molecular and signaling mechanisms of anticancer action of cannabinoids, particularly CBD, requires further evaluation. We believe that the therapeutic advantages of CBD are associated not only with its non-psychoactive behavior, but also are related to its influence on the important biochemical pathways and signal molecules, defining the genome instability and specific changes of the malignant tumor cells.

Abstract B12: Potential neoantigen release and increased lymphocyte activity is facilitated by matrix metalloproteinase-dependent cleavage of mutant matrisome peptides in cutaneous melanoma

Abstract Introduction: Proteases in the cancer microenvironment have been studied for decades, with a general conclusion that such proteases facilitate the spread of cancer, although there is some controversy regrading that conclusion in later stages of cancer development. More recently, a very large collection of data regarding mutant amino acids in the potential substrates of the cancer microenvironment has become available. Methods: To better understand the potential impact of these mutant amino acids on protease function and cancer progression, we established a bioinformatics approach to assessing the impact of melanoma mutants, among a previously defined set of ECM structural proteins, on MMP2, a protease extensively associated with melanoma in terms of both protease sensitivity and MHC class I binding using original software. Additionally, T-cell receptor TRα and TRβ recombinations were bioinformatically obtained using whole-exome sequencing data from 479 melanoma tumor samples. Results: Tumor samples with mutant amino acids adjacent to ECM structural protein, MMP2-cleavage sites represented a better survival rate and a larger proportion of mutant peptides with high HLA class I binding affinities, particularly in comparison to melanoma samples lacking a T-cell infiltrate. Furthermore, even better MHC class I binders, as a group, were identified among the sample representing ECM structural proteins mutants not adjacent to MMP2 sensitive sites and evincing a relatively poor survival rate. Conclusion: Overall, this analysis suggested that MMP2 has the capacity of freeing mutant peptides that could facilitate an antitumor response and a better survival rate, and this analysis has the potential of resolving some of the controversy surrounding the role of cancer proteases in cancer progression. Citation Format: Saif Zaman, Boris I. Chobrutskiy, Jay S. Patel, Blake M. Callahan, Moody Mihyu, Andrea Diviney, Wei Lue Tong, George Blanck. Potential neoantigen release and increased lymphocyte activity is facilitated by matrix metalloproteinase-dependent cleavage of mutant matrisome peptides in cutaneous melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B12.

CRISPR-mediated modification of DNA methylation pattern in the new era of cancer therapy.

In the last 2decades, a wide variety of studies have been conducted on epigenetics and its role in various cancers. A major mechanism of epigenetic regulation is DNA methylation, including aberrant DNA methylation variations such as hypermethylation and hypomethylation in the promoters of critical genes, which are commonly detected in tumors and markthe early stages of cancer development. Therefore, epigenetic therapy has been of special importance in the last decade for cancer treatment. In epigenetic therapy, all efforts are made to modulate gene expression to the normal status. Importantly, recent studies have shownthat epigenetic therapy is focusing on the new gene editing technology, CRISPR-Cas9. This tool was found to be able to effectively modulate gene expression and alter almost any sequencein the genome of cells, resulting in events such as a change in acetylation, methylation, or histone modifications. Of note, the CRISPR-Cas9 system can be used for the treatment of cancers caused by epigenetic alterations. The CRISPR-Cas9 system has greateradvantages than other available methods, including potent activity, easy design andhigh velocity as well as the ability to target any DNA or RNA site. In this review, we described epigenetic modulators, which can be used in the CRISPR-Cas9 system, as well as their functions in gene expression alterations that lead to cancer initiation and progression. In addition, we surveyed various species of CRISPR-dead Cas9 (dCas9) systems, a mutant version of Cas9 with no endonuclease activity. Such systems are applicable in epigenetic therapy for gene expression modulation through chemical group editing on nucleosomes and chromatin remodeling, which finally return the cell to the normal status and prevent cancer progression.

Brief review on the roles of neutrophils in cancer development.

Neutrophils, which are traditionally regarded as a hallmark of inflammation, are also a member of the intratumoral immune cells. The roles of neutrophils in cancer development are diverse and undefined. So far, they are known to be involved in tumor initiation and tumor cell proliferation and metastasis. They show heterogeneity in both phenotypes and functions during early versus late stage of cancer development. Because they are also associated with the clinical outcomes of various types of solid tumors, cancer treatments that target neutrophils might be highly effective. In this review, we briefly cover the latest findings on the multiple roles of neutrophils in cancer development and point out the future directions as well.

Anti-Breast Cancer Activities of Ketoprofen-RGD Conjugate by Targeting Breast Cancer Stem-Like Cells and Parental Cells.

Cancer Stem Cells (CSCs) play an important role in various stages of cancer development, advancement, and therapy resistance. Ketoprofen-RGD has been revealed to act as an anti-cancer agent against some tumors. We aimed to explore the effects of a novel Ketoprofen-RGD compound on the suppression of Breast Cancer Stem-like Cells (BCSCs) and their parental cells. Mammospheres were developed from MCF-7 cells and assessed by CSC surface markers through flowcytometry. The anti-proliferative and pro-apoptotic activities of Ketoprofen-RGD were measured by MTS assay and flowcytometry. The expression levels of stemness markers and JAK2/STAT proteins were measured by quantitative Real Time-PCR (qRT-PCR) and western blotting, respectively. Intracellular Reactive Oxygen Species (ROS) was measured using a cell permeable, oxidant-sensitive fluorescence probe (carboxy-H2DCFDA). Ketoprofen-RGD significantly reduced the mammosphere formation rate and the expression of three out of six stemness markers and remarkably decreased viability and induced apoptosis of spheroidal and parental cells compared to controls. Further experiments using CD95L, as a death ligand, and ZB4 antibody, as an extrinsic apoptotic pathway blocker, showed that Ketoprofen-RGD induced intrinsic pathway, suggesting a mechanism by which Ketoprofen-RGD triggers apoptosis. ROS production was also another way to induce apoptosis. Results of western blot analysis also revealed a marked diminish in the phosphorylation of JAK2 and STAT proteins. Our study, for the first time, elucidated an anti-BCSC activity for Ketoprofen-RGD via declining stemness markers, inducing toxicity, and apoptosis in these cells and parental cells. These findings may suggest this compound as a promising anti-breast cancer.

Abstract LB-077: Dendritic cell dysfunction precedes tumor formation during pancreatic oncogenesis

Abstract Dysfunction of type 1 conventional dendritic cells (cDC1s) - the dendritic cell subtype crucial for spontaneous anti-tumor T cell immunity - has long been hypothesized to develop secondarily to invasive cancer. Here, we reveal that cDC1 dysfunction instead develops in the earliest stages of cancer development upon formation of preinvasive pancreatic intraepithelial neoplasias (PanINs) in the KrasG12D Trp53R172H Pdx1-Cre-driven (KPC) mouse model of pancreatic ductal adenocarcinoma. This results in systemically increased cDC1 apoptosis and insufficient upregulation of T cell-polarizing cytokines during cDC1 maturation. CD8+ T cell activation following vaccination is subsequently impaired in PanIN- and tumor-bearing mice. Yet, combination therapy with CD40 agonist and Flt3 ligand in tumor-bearing mice returns cDC1 abundance to normal levels and induces an IFNg response signature, repairing cDC1 maturation and restoring full CD8+ T cell activation. This study therefore reveals the unexpectedly early and systemic onset of cDC1 dysregulation while elaborating therapeutically tractable strategies towards cDC1 repair. Citation Format: Jeffrey H. Lin, Robert H. Vonderheide. Dendritic cell dysfunction precedes tumor formation during pancreatic oncogenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-077.

Asparagine: An Achilles Heel of Virus Replication?

Asparagine biosynthesis and breakdown are tightly regulated in mammalian cells. Recent studies indicate that asparagine supply could be a limiting factor for the replication of some viruses such as vaccinia virus and human cytomegalovirus. In this Viewpoint, we highlight the importance of asparagine metabolism during virus replication and rationalize that asparagine metabolism could be a viable target for broad-spectrum antiviral development. To achieve this goal, more studies into asparagine metabolism during viral infections are demanded. These efforts would benefit beyond viral diseases, as asparagine supply is also a limiting factor in various stages of cancer development.

Targeting Endoglin-Expressing Regulatory T Cells in the Tumor Microenvironment Enhances the Effect of PD1 Checkpoint Inhibitor Immunotherapy.

Endoglin is a coreceptor for TGFβ ligands that is highly expressed on proliferating endothelial cells and other cells in the tumor microenvironment. Clinical studies have noted increased programmed cell death (PD)-1 expression on cytotoxic T cells in the peripheral blood of patients with cancer treated with TRC105, an endoglin-targeting antibody. In this study, we investigated the combination of endoglin antibodies (TRC105 and M1043) with an anti-PD1 antibody. The combination anti-endoglin/anti-PD1 antibodies was tested in four preclinical mouse models representing different stages of cancer development. To investigate the underlying mechanism, Fc-receptor-knockout mice were used complemented with depletion of multiple immune subsets in mice. Tumor growth and the composition of immune infiltrate were analyzed by flow cytometry. Finally, human colorectal cancer specimens were analyzed for presence of endoglin-expressing regulatory T cells (Treg). In all models, the combination of endoglin antibody and PD1 inhibition produced durable tumor responses, leading to complete regressions in 30% to 40% of the mice. These effects were dependent on the presence of Fcγ receptors, indicating the involvement of antibody-dependent cytotoxic responses and the presence of CD8+ cytotoxic T cells and CD4+ Th cells. Interestingly, treatment with the endoglin antibody, TRC105, significantly decreased the number of intratumoral Tregs. Endoglin-expressing Tregs were also detected in human colorectal cancer specimens. Taken together, these data provide a rationale for combining TRC105 and anti-PD1 therapy and provide additional evidence of endoglin's immunomodulatory role.

Application of magnetic iron oxide nanomaterials in tumor imaging

The incidence of malignant tumor increases year by year, becoming one of the major diseases affecting the health globally. Early diagnosis is the key to reduce the burden of cancer morbidity and mortality. However, due to inconspicuous characteristics in the early stage of cancer development, and the lack of efficient and accurate diagnostic methods, the early cancer diagnosis is far from satisfied. Iron oxide nanomaterials have shown great potential in cancer diagnosis because of their unique size-dependent properties, surface functionalization feasibility and good biocompatibility. As the only inorganic nanomaterials approved by FDA for clinical use, great progress has been achieved recently for iron oxide nanomaterials in materials design and biomedical applications, especially, being used as novel contrast agents for magnetic resonance imaging (MRI). This review will discuss the application of magnetic iron oxide nanomaterials in cancer diagnosis in recent years. At first, magnetic iron oxide nanomaterials are ideal MRI contrast agents, for the imaging modal (T1, T2 or T1-T2) can be adjusted by the magnetic iron oxide nanomaterials diameters and morphologies. Superparamagnetic iron oxide nanoparticles (diameter >5 nm) are typical MRI T2 contrast agents, while exceedingly small magnetic iron oxide nanoparticles (ES-MIONs, are an efficient and reliable T1 contrast agent. Even T1-T2 dual-modal contrast agents can be obtained by separating T1 contrast agent (paramagnetic shell) and T2 contrast agent (superparamagnetic nanoparticle core) with a non-magnetic silica layer, called artifact filtering nanoparticle imaging agent, AFIA. This dual-mode nanoparticle imaging agent (AFIA) can perform the “AND” logic gate algorithm in the post data processing, displaying areas that only show high MRI contrast differences in both T1 and T2 images, thereby eliminating the pseudo-errors (artifacts) in the original image. That strategy can help clinicians diagnose and evaluate diseases such as early tumors, vascular systems disease and central nervous system disease that are greatly disturbed by artifacts with more efficiency. Secondly, different imaging technologies (MRI, PET, SPECT, X-ray, optical imaging, etc.) have their pros and cons in terms of spatial resolution, sensitivity, penetration ability, and so on and so forth. If multi-modal imaging can be achieved, it will be possible to diagnose tumor more accurately and sensitively. For example, the optical imaging probes are connected to the magnetic iron oxide nanomaterials to obtain MRI-optical dual-mode imaging agents for highly sensitive imaging of sub-millimeter cell clusters. The dual-modality imaging system combining MRI and PET/SPECT can provide high-sensitivity, high-resolution tomographic images, and at the same time obtain biological anatomical structure and biological metabolism information as well. With the quick development in nanomedicine, magnetic nanoparticles-based diagnostics are believed to play vital roles in cancer early diagnosis in the future. Active targeting technology is also an important research field of tumor diagnosis. The combination of bio-active molecules with magnetic iron oxide nanomaterials can increase the active targeting function on the basis of passive target aggregation via EPR effect. It is believed that in the near future, there will be more efficient targeted imaging materials emerging to evaluate and diagnose the basic situation of malignant tumors from multiple layers, making early diagnosis and treatment of cancer possible.

Generation of Anisotropic Strain Dysregulates Wild-Type Cell Division at the Interface between Host and Oncogenic Tissue

Epithelial tissues are highly sensitive to anisotropies in mechanical force, with cells altering fundamental behaviours such as cell adhesion, migration and cell division. It is well known that in the later stages of carcinoma (epithelial cancer), the presence of tumours alters the mechanical properties of a host tissue and that these changes contribute to disease progression. However, in the earliest stages of carcinoma, when a clonal cluster of oncogene-expressing cells first establishes in the epithelium, the extent to which mechanical changes alter cell behaviour in the tissue as a whole remains unclear. This is despite knowledge that many common oncogenes, such as oncogenic Ras, alter cell stiffness and contractility. Here, we investigate how mechanical changes at the cellular level of an oncogenic cluster can translate into the generation of anisotropic strain across an epithelium, altering cell behaviour in neighbouring host tissue. We generated clusters of oncogene-expressing cells within otherwise normal in vivo epithelium, using Xenopus laevis embryos. We find that cells in kRasV12, but not cMYC, clusters have increased contractility, which introduces radial stress in the tissue and deforms surrounding host cells. The strain imposed by kRasV12 clusters leads to increased cell division and altered division orientation in the neighbouring host tissue, effects that can be rescued by reducing actomyosin contractility specifically in the kRasV12 cells. Our findings indicate that some oncogenes can alter the mechanical and proliferative properties of host tissue from the very earliest stages of cancer development, changes which have the potential to contribute to tumorigenesis.

ZEB1/miR-200c/AGR2: A New Regulatory Loop Modulating the Epithelial-Mesenchymal Transition in Lung Adenocarcinomas.

Epithelial-mesenchymal transition (EMT) is a process involved not only in morphogenesis and embryonic development, but also in cancer progression, whereby tumor cells obtain a more aggressive metastatic phenotype. Anterior gradient protein 2 (AGR2) maintains the epithelial phenotype and blocks the induction of EMT, thus playing an undeniable role in tumor progression. However, the mechanism through which AGR2 expression is regulated, not only during EMT, but also in the early stages of cancer development, remains to be elucidated. In the present study, we show an inverse correlation of AGR2 with ZEB1 (zinc finger enhancer binding protein, δEF1) that was verified by analysis of several independent clinical data sets of lung adenocarcinomas. We also identified the ZEB1 binding site within the AGR2 promoter region and confirmed AGR2 as a novel molecular target of ZEB1. The overexpression of ZEB1 decreased the promoter activity of the AGR2 gene, which resulted in reduced AGR2 protein level and the acquisition of a more invasive phenotype of these lung cancer cells. Conversely, silencing of ZEB1 led not only to increased levels of AGR2 protein, but also attenuated the invasiveness of tumor cells. The AGR2 knockout, vice versa, increased ZEB1 expression, indicating that the ZEB1/AGR2 regulatory axis may function in a double negative feedback loop. In conclusion, we revealed for the first time that ZEB1 regulates AGR2 at the transcriptional level, while AGR2 presence contributes to ZEB1 mRNA degradation. Thus, our data identify a new regulatory mechanism between AGR2 and ZEB1, two rivals in the EMT process, tightly associated with the development of metastasis.

Numerical study of microwave induced thermoacoustic imaging for initial detection of cancer of breast on anatomically realistic breast phantom

Background and objectiveMicrowave-induced thermoacoustic imaging (MITAI) represents an innovative imaging approach for detection of breast cancer at initial phases by integrating the benefits provided by procedures of microwave and ultrasound imaging. The present investigation examines an innovative three-dimensional numerical modeling of MITAI as a problem with multi-physics nature. MethodsSimulations are performed by the use of COMSOL software. An anatomically realistic breast phantom representing various parts of a real breast, such as three different types of tissue, fibro-connective/glandular, transitional; and fatty, is taken into consideration along with a tumor. This breast phantom with a tumor is irradiated by a 2.45 GHz pulsed rectangular waveguide. The temperature increase and its consequent pressure caused by electromagnetic absorption are analyzed. ResultsMore temperature increase occurs in the tumor area than in the other parts of the breast, the fact which results in further increase in the pressure in the tumor area than other parts. This makes the tumor distinguishable. The ability of the MITAI process regarding the tumor size, shape (both geometrical shape and spatial orientation), location, the irradiation power level, and the pulse width is also investigated. It is demonstrated that tumor size does not have a significant impact on the efficiency of detection. In fact, very small tumors in the early stages of cancer development (with a radius of 0.25 cm) are also detectable by employing the MITAI technique. The geometrical shape of the tumor does not considerably affect the detecting performance just by itself. The spatial orientation of the tumor actually has a great impact on it. The location of the tumor is an essential factor involved in detection efficiency of MITAI. Tumors located in the fatty tissues would be much easier to be detected than those in the glandular tissues. Moreover, results denote that with augmentation of the irradiation power level or increasing the pulse width, stronger acoustic waves would be produced to make tumor detection easier. ConclusionThese modeling and techniques may be applied aiming for determination of the amount of the generated pressure differences and acoustic pressure magnitude, and can be utilized as an effective prognosticator in practical tests.

The Clinical Diagnostic and Prognostic Value of Dickkopf-1 in Cancer.

The Wnt signaling pathway extensively participates in diverse processes such as embryonic development, maintenance of homeostasis and tumor pathogenesis. Dickkopf-1 (DKK1), a Wnt inhibitor, plays a vital role for over the past decades regarding its role in the regulation of several types of cancers. However, studies have shown that DKK1 is expressed differently in cancer and plays a role as a cancer-promoting factor or a tumor suppressor, which is worthy of further exploration. We herein study whether DKK1 is highly expressed in all cancers and plays a crucial role in promoting cancer. Furthermore, we discussed as to which stages of cancer development it plays in. Finally, the present detection methods were introduced and indicated the clinical application of DKK1 in tumor development.

Beta Human Papillomavirus 8E6 Attenuates LATS Phosphorylation after Failed Cytokinesis.

Beta genus human papillomaviruses (β-HPVs) cause cutaneous squamous cell carcinomas (cSCCs) in a subset of immunocompromised patients. However, β-HPVs are not necessary for tumor maintenance in the general population. Instead, they may destabilize the genome in the early stages of cancer development. Supporting this idea, β-HPV's 8E6 protein attenuates p53 accumulation after failed cytokinesis. This paper offers mechanistic insight into how β-HPV E6 causes this change in cell signaling. An in silico screen and characterization of HCT 116 cells lacking p300 suggested that the histone acetyltransferase is a negative regulator of Hippo pathway (HP) gene expression. HP activation restricts growth in response to stimuli, including failed cytokinesis. Loss of p300 resulted in increased HP gene expression, including proproliferative genes associated with HP inactivation. β-HPV 8E6 expression recapitulates some of these phenotypes. We used a chemical inhibitor of cytokinesis (dihydrocytochalasin B [H2CB]) to induce failed cytokinesis. This system allowed us to show that β-HPV 8E6 reduced activation of large tumor suppressor kinase (LATS), an HP kinase. LATS is required for p53 accumulation following failed cytokinesis. These phenotypes were dependent on β-HPV 8E6 destabilizing p300 and did not completely attenuate the HP. It did not alter H2CB-induced nuclear exclusion of the transcription factor YAP. β-HPV 8E6 also did not decrease HP activation in cells grown to a high density. Although our group and others have previously described inhibition of DNA repair, to the best of our knowledge, this marks the first time that a β-HPV E6 protein has been shown to hinder HP signaling.IMPORTANCE β-HPVs contribute to cSCC development in immunocompromised populations. However, it is unclear if these common cutaneous viruses are tumorigenic in the general population. Thus, a more thorough investigation of β-HPV biology is warranted. If β-HPV infections do promote cSCCs, they are hypothesized to destabilize the cellular genome. In vitro data support this idea by demonstrating the ability of the β-HPV E6 protein to disrupt DNA repair signaling events following UV exposure. We show that β-HPV E6 more broadly impairs cellular signaling, indicating that the viral protein dysregulates the HP. The HP protects genome fidelity by regulating cell growth and apoptosis in response to a myriad of deleterious stimuli, including failed cytokinesis. After failed cytokinesis, β-HPV 8E6 attenuates phosphorylation of the HP kinase (LATS). This decreases some, but not all, HP signaling events. Notably, β-HPV 8E6 does not limit senescence associated with failed cytokinesis.

The Promise for Histone Methyltransferase Inhibitors for Epigenetic Therapy in Clinical Oncology: A Narrative Review.

Epigenetic processes are essential for normal development and the maintenance of tissue-specific gene expression in mammals. Changes in gene expression and malignant cellular transformation can result from disruption of epigenetic mechanisms, and global disruption in the epigenetic landscape is a key feature of cancer. The study of epigenetics in cancer has revealed that human cancer cells harbor both genetic alterations and epigenetic abnormalities that interplay at all stages of cancer development. Unlike genetic mutations, epigenetic aberrations are potentially reversible through epigenetic therapy, providing a therapeutically relevant treatment option. Histone methyltransferase inhibitors are emerging as an epigenetic therapy approach with great promise in the field of clinical oncology. The recent accelerated approval of the enhancer of zeste homolog 2 (EZH2; also known as histone-lysine N-methyltransferase EZH2) inhibitor tazemetostat for metastatic or locally advanced epithelioid sarcoma marks the first approval of such a compound for the treatment of cancer. Many other histone methyltransferase inhibitors are currently in development, some of which are being tested in clinical studies. This review focuses on histone methyltransferase inhibitors, highlighting their potential in the treatment of cancer. We also discuss the role for such epigenetic drugs in overcoming epigenetically driven drug resistance mechanisms, and their value in combination with other therapeutic approaches such as immunotherapy.

Dendritic cell dysfunction precedes tumor formation during pancreatic oncogenesis

Abstract Dysfunction of type 1 conventional dendritic cells (cDC1s) – the dendritic cell subtype crucial for spontaneous anti-tumor T cell immunity – has long been hypothesized to develop secondarily to invasive cancer. Here, we reveal that cDC1 dysfunction instead develops in the earliest stages of cancer development upon formation of preinvasive pancreatic intraepithelial neoplasias (PanINs) in the KrasG12D Trp53 R172H Pdx1-Cre-driven (KPC) mouse model of pancreatic ductal adenocarcinoma. This results in systemically increased cDC1 apoptosis and insufficient upregulation of T cell-polarizing cytokines during cDC1 maturation. CD8+ T cell activation following vaccination is subsequently impaired in PanIN- and tumor-bearing mice. Yet, combination therapy with CD40 agonist and Flt3 ligand in tumor-bearing mice returns cDC1 abundance to normal levels and induces an IFNg response signature, repairing cDC1 maturation and restoring full CD8+ T cell activation. This study therefore reveals the unexpectedly early and systemic onset of cDC1 dysregulation while elaborating therapeutically tractable strategies towards cDC1 repair.

Characterising the prognostic potential of HLA-DR during colorectal cancer development

HLA-DR, an MHC class II molecule that mediates antigen presentation, is a favourable prognostic indicator in colorectal cancer (CRC). However, the dynamics and location of HLA-DR expression during CRC development are unclear. We aimed to define HLA-DR expression by immunohistochemistry in colorectal epithelium and stromal tissue at different stages of cancer development, assessing non-neoplastic colorectal adenocarcinoma–adjacent tissue, adenomas and carcinoma tissues, and to associate HLA-DR levels with clinical outcomes. Patients with higher than median HLA-DR expression survived at least twice as long as patients with lower expression. This association was significant for HLA-DR staining in the colorectal carcinoma epithelium (n = 152, p = 0.011, HR 1.9, 95% CI 1.15–3.15) and adjacent non-neoplastic epithelium (n = 152, p < 0.001, HR 2.7, 95% CI 1.59–4.66), but not stroma. In stage II cases, however, the prognostic value of HLA-DR expression was significant only in adjacent non-neoplastic tissues, for both epithelium (n = 63, p = 0.015, HR 3.6, 95% CI 1.279–10.25) and stroma (n = 63, p = 0.018, HR 5.07, 95% CI 1.32–19.49). HLA-DR was lower in carcinoma tissue compared to matched adenomas (n = 35), in epithelium (p < 0.01) and stroma (p < 0.001). HLA-DR was further reduced in late-stage carcinoma (n = 101) compared to early stage (n = 105), in epithelium (p < 0.001) and stroma (p < 0.01). HLA-DR expression was lower (p < 0.05) in the adjacent non-neoplastic epithelium of patients with cancer recurrence. We demonstrate a progressive loss of HLA-DR in epithelial and stromal tissue compartments during CRC development and show prognostic ability in carcinoma–adjacent non-neoplastic tissues, highlighting the importance of this molecule in the anti-cancer immune response. These findings may have wider implications for immunotherapeutic interventions.