Abstract

Cancer vaccines based on tumor cell components have shown promising results in animal and clinical studies. The vaccine system contains abundant tumor antigen components, which can activate the immune system by antigens. However, their efficacy has been limited by the inability of antigens delivery, which are the core components of vaccines, further fail to be presented and activation of effective cells. Nanotechnology offers a novel platform to enhance the immunogenicity of tumor-associated antigens and deliver them to antigen-presenting cells (APCs) more efficiently. In addition, nanotreatment of tumor cells derivate active ingredients could also help improve the effectiveness of cancer vaccines. In this review, we summarize recent advances in the development of cancer vaccines by the combination of nanotechnology and tumor-based ingredients, including liposomes, polymeric nanoparticles, metallic nanoparticles, virus-like particles and tumor cells membrane, tumor lysate, and specific tumor antigens. These nanovaccines have been designed to increase antigen uptake, prolong antigen presentation, and modulate immune responses through codelivery of immunostimulatory agents. We also further discuss challenges and opportunities in the clinical translation of these nanovaccines.

Introduction

Cancer immunotherapy has revolutionized cancer treatment by harnessing the immune system to recognize and attack cancer cells [1–3]. Among various immunotherapeutic approaches, cancer vaccines have attracted significant attention due to their potential to induce long-lasting and specific immune responses against tumor cells [4–7]. By comparison with surgery, it hardly produce large wounds, nor does it cause higher toxicity in normal tissues and drug tolerance like chemotherapy in the treatment of tumor. However, the clinical efficacy of cancer vaccines based on tumor cell components, such as peptides and proteins, is limited by their poor immunogenicity and inefficient delivery to antigen presentation cells (APCs). Although, many cancer vaccines were applied with the immune-stimulatory agents, such as the programmed cell death protein 1 (PD-1), CpG oligonucleotide, etc. The clinical response rates remain low, especially in the hypoimmunogenic tumors. As we all know, pancreatic cancer is a more difficult type for immunotherapy as a low immunogenic tumor. Therefore, there are few effective cancer vaccines that can actively promote the pancreatic cancer treatment. Meanwhile, limited by the specific tumor antigens, the development of cancer vaccines was extremely difficult.

The field of cancer vaccines has seen significant advancements in recent years, with numerous studies focusing on different aspects of vaccine development and application [8–12]. These advances have been facilitated by the exploration of various types of cancer vaccines, including those targeting viral antigens, neoantigens, and other tumor-specific antigens [13–16]. One approach in cancer vaccine research involves targeting shared antigens from viral infections linked to certain cancer types, such as Epstein–Barr virus and HPV. Studies have shown promising results with vaccines targeting viral antigens like Epstein–Barr nuclear antigen 1 and latent membrane proteins, as well as HPV-related antigens, demonstrating favorable antitumor efficacy and the potential to establish durable T cell memory in rapidly progressing HPV-positive tumors [17]. Another significant area of research is neoantigen cancer vaccines. Neoantigens, derived from nonsynonymous cell variants, are only expressed in tumor cells and can bypass thymus-negative selection, leading to robust neoantigen-specific T cell responses [14]. Advances in genomic and transcriptional profiling have made identifying putative neoantigens possible, although challenges remain in predicting which neoantigens can effectively induce neoantigen-specific T cell responses [18–20]. Cancer vaccines are being developed to stimulate antitumor immunity with tumor antigens delivered in various forms, such as cells, peptides, viruses, and nucleic acids [21–24]. These vaccines aim to overcome tumor heterogeneity and reverse the immunosuppressive microenvironment. Challenges in the field include single antigen targeting, weak immunogenicity, off-target effects, and impaired immune response [25–27]. Current research and reviews provide insights into the principle of action, components, classification, delivery methods, and progress of cancer vaccines, offering a broader perspective for future vaccine design.

Recent studies have shown that tumor antigens can be used for the design of cancer vaccines without the necessity to identify, parse, and reconstruct certain antigens [28–31]. A novel concept has been proposed that the whole antigen vaccine systems derived from tumor cells could be designed to conquer cancer treatments [32–34]. The tumor cells themselves are a huge antigen pool with countless tumor antigen epitopes, which can be used to activate antitumor immune response. Among them, more studies have focused on the application of tumor cell membrane as tumor antigens to stimulate APCs and further activate the antitumor immune response of T cells. In addition, the activation of T cells in immune response requires the involvement of costimulatory molecules. Some studies are based on this theoretical foundation, using genetic engineering to modify tumor cell membranes. By retaining antigen on the cell membrane and inducing the expression of costimulatory molecule CD80, T cells can be directly activated, thereby achieving antitumor immune response [35] (Figure 1). Of course, many studies combine tumor cell membranes that retain tumor antigens with other functional molecules to directly activate dendritic cells (DCs) for antigen presentation, leading to the activation of T cell immune response. These are two different approaches aimed at achieving the same goal [36–38]. A series of nanovaccines developed on this basis have been widely used in the treatment of different tumor cells and preclinical experiments.

Introduction

Tumor microenvironment (TME) is a complex network of cancer cells and various other cellular and noncellular components. Microorganisms such as bacteria, viruses, fungi, phages, and protozoa naturally occur in the TME, modulating the metabolic composition and promoting or inhibiting tumorigenesis. In the last decades, a growing interest has emerged in microorganisms in the TME and their potential applications for cancer therapy 1, 2.

Bacterial and viral infections have been long associated with cancer development and have been used in cancer therapy decades ago. Bacteria have various effects on cancer cells through different modes of action, for instance, depending on the strain, tissue, and environment 1, 2. Viruses also naturally occur in the TME, and some strains promote cancer growth, such as the human papillomavirus (HPV) [3], while others have oncolytic activity, such as the influenza A virus (IAV) [4]. The different mechanisms through which bacteria and viruses affect tumor proliferation and metastasis include altering immune responses 5, 6, 7•, secreting cytotoxic molecules such as formate or colibactine 8••, 9, and alterations of metabolic and signaling pathways 8••, 10. The natural abilities of microorganisms to colonize and alter the TME can also be used for cancer detection and therapy with the help of engineered bacteria and viruses 2, 11, 12. However, the metabolic interactions among viruses, bacteria, cancer cells, and TME are not well understood. Metabolites function as signaling molecules, and we are just beginning to understand the functional role of small molecules within the TME 13, 14, 15. For instance, the immunometabolite itaconate has antimicrobial properties but may also affect tumor progression by altering cancer cell metabolism or the composition of the TME 16, 17•, 18, 19. Thus, further research is needed to identify the key players within the TME that affect immune responses and tumor progression.

Approaches in virotherapy

Virotherapy aims to transform the ‘cold’ immunosuppressive TME, characterized by high levels of TAMs, T-regulatory cells (Tregs), MDSCs, and activated M2-like macrophages, into a ‘hot’ immunoreactive TME (Figure 3). This transformation involves the recruitment of, for instance, NKs, DCs, and M1-like macrophages (Figure 3). OV administration targets different approaches in cancer therapies, such as making the virus dependent on specific genes within the cancer host cell to enable selective replication in malignant cells, followed by direct lysis. Furthermore, it is applied to deliver specific antibodies to inhibit tumor growth [45]. For instance, the recombinant human type-5 adenovirus (Ad5) selectively replicates in tumor cells with p53-defective influencing cancer cell growth [46]. OVs may also indirectly affect the TME and tumor growth by inducing the release of cytokines, such as interferon (IFN), damage-associated molecular patterns (DAMPs), high mobility group box 1 protein (HMGB1), or pathogen-associated molecular patterns (PAMPs) 41, 47, leading to further recruiting and activation of the innate and adaptive immune system, including DCs (Figure 3). DCs play an elementary role in connecting both immune systems and are infrequently present in the cold TME. These findings highlight various targets that can be used to modulate the immune response in the TME through OVs, aiming to constrain tumor growth and increase patient outcomes.

Conclusion

Bacterial and viral infections play a vital role in altering the composition of the TME, thus influencing its potential as pro- or anti-tumorigenic. Many bacteria and viruses influence TME, for instance, by secreting signal molecules, altering specific immune responses, causing DNA damage, or inducing metabolic rewiring. While promising approaches utilizing bacteria and viruses for cancer detection and therapy exist, how infections influence metabolism to promote either pro- or antitumor properties is still not well understood. Engineered bacteria and viruses could be optimized to work effectively against cancer with potentially less off-target effects compared with conventional therapies. For example, altering levels of cytokines or metabolites such as itaconate or arginine in the TME may promote an anticancer immune response, either alone or in combination with existing treatments. Expanding our current knowledge of the complex interaction of microorganisms and cancer cells will provide us with effective ways to develop new treatment strategies.

Abstract

Aim. This study investigated the effect of tumor size and other factors on the survival and prognosis of hepatocellular carcinoma (HCC). Methods. All HCC populations based on the National Cancer Institute’s SEER database to receive from 2010 to 2016 were employed in the study. Results. This study enrolled a total of 14,634 HCC. Among them, 1,686 patients had tumors ≤ 2 cm, 6,169 patients had tumors 2–5 cm, and 6,779 patients had tumors > 5 cm. The results using univariate analysis showed that all factors were significant prognostic factors for overall survival and specific survival. Patients with tumor size ≤ 2 cm were more likely to survive, while patients with tumor size > 5 cm had a lower survival rate. Patients who had surgery or surgery plus chemotherapy had a higher chance of survival in stages I-II, and the survival rate declined smoothly during the 80 months. The change rate of the mortality rate increased rapidly during the period of 1–12 cm; afterwards, the mortality rate’s HR was basically and smoothly maintained at a high level. Conclusions. Tumor size was positively correlated with the mortality rate of HCC. Survival rates were greater in patients with tumors ≤ 2 cm who underwent surgery or surgery plus chemotherapy. Patients with HCC in the early stage had a higher survival probability particularly when they had experienced surgery or surgery plus chemotherapy.

Introduction

Hepatocellular carcinoma (HCC) with an extremely high mortality rate is one of the most common malignant tumors. Previous study [1] showed the HCC has the poor of prognosis, and its survival rate of 5-year was under 20%. HCC has a special feature: growth with metastasis to distant organs, which accounts for poor survival. The HCC with distant metastasis is commonly found in the lungs, bones, and brain [2]. Moreover, the most common risk factor for HCC globally is the hepatitis B virus. In a previous study, the most common causative agent was the hepatitis C virus [3]. More than 90% of primary liver cancers are HCC [4]. In recent years, relevant research studies confirmed that specific therapeutic regimens, including surgical resection, chemotherapy, and radiotherapy, provided HCC patients favorable prognosis and long-term survival. The current meta-analysis from Francesca’s study [5] found that regorafenib was a safe and effective treatment option for patients with advanced HCC. In addition, the efficacy and safety of microwave ablation and radiofrequency ablation were similar, but microwave ablation reduced the long-term recurrence rate [6]. A review summarized the trajectory of various aspects of HCC management over the last 15 years, providing additional information for clinicians to aggregate [7]. Previous research studies [8] found that HCC patients were more likely to feel hopeless, depressed, and even have serious suicidal thoughts. HCC monitoring for national minority and individuals of lower socioeconomic status was poorly performed, further exacerbating the difference in HCC prognosis among these disadvantaged populations [9]. Current therapeutic regimens, including surgery of liver resection, transplantation, radiotherapy, percutaneous ethanol injection, transarterial chemoembolization, microwave ablation, radiofrequency ablation, cryoablation, irreversible electroporation, combination therapies (such as postoperative adjuvant chemoradiotherapy and nutrition supportive therapy) and palliative care, will create high costs for HCC [10].

Conclusions

This study revealed that the age of majority in HCC was over 50 years old, and the majority of HCC had solid tumor sizes of 2–5 cm and not otherwise specified histology. The incidence of HCC in males was much higher than that in females, and whites also proved to be more than half the population at risk for HCC. Based on different stages, the majority of patients were in the early stages of HCC. Furthermore, HCC patients were distributed in above 2 cm, and the distribution of basic information for different tumor sizes was consistent with the overall populations. Single patients had more challenges than married patients. Otherwise, survival rates were greater in patients with tumor size ≤2 cm who underwent surgery or surgery with chemotherapy. Patients with HCC in the early stage had a higher survival probability, particularly when they had undergone surgery or surgery plus chemotherapy. The most important thing was that we further determined that the larger the tumor, the greater the risk, and that surgical treatment was the major and critical of the three methods.

 Highlights

Abstract

Graphical abstract

Keywords

1. Introduction

2. Materials and methods

3. Results and discussion

4. Conclusions

CRediT authorship contribution statement

Declaration of Competing Interest

Acknowledgement

References

Abstract

Spectroscopic methods provide information on the spatial localization of biochemical components based on the analysis of vibrational spectra. Raman spectroscopy and Raman imaging can be used to analyze various types of human brain tumors and breast cancers. The objective of this study is to evaluate the Raman biomarkers to distinguish tumor types by Raman spectroscopy and Raman imaging. We have demonstrated that bands characteristic for carotenoids (1156 cm−1, 1520 cm−1), proteins (1004 cm−1), fatty acids (1444 cm−1, 1655 cm−1) and cytochrome (1585 cm−1) can be used as universal biomarkers to assess aggressiveness of human brain tumors. The sensitivity and specificity obtained from PLS-DA have been over 73%. Only for gliosarcoma WHO IV the specificity is lower and takes equal 50%. The presented results confirm clinical potential of Raman spectroscopy in oncological diagnostics.

1. Introduction

The nervous system tumors are one of the most common types of cancer in the world. [1] In this paper we analyzed various types of human brain tumor such as: gliosarcoma [2], meningothelioma, anaplastic oligodendroglioma [3], pituitary adenoma [4], neurofibroma, testicular cancer metastasis to the brain and breast cancer. [5]

According to WHO meningotheliomas (Meningioma menigotheliale) account for some 15–18% of all intracranial tumors. Meningotheliomas are the most frequent brain tumors in adults and they occur more often in female than in male. [6] When meningotheliomas are benign tumor they carry a good prognosis. Standard treatment for meningotheliomas is surgical resection. It is estimated that 80% of meningotheliomas are grade I (mildly malignant). [7] The main symptoms in patient with meningotheliomas are sensory and motor deficits or gait disturbance.[8]

Malignant glioma is the most common type of primary brain tumor. There are known three subtypes of gliomas such as: anaplastic astrocytoma (AA), anaplastic oligoastrocytoma (AOA), anaplastic oligodendroglioma (AO), and anaplastic ependymoma. Anaplastic oligodendroglioma tumors are rare and uncommon; they constitute 2–7% of primary brain tumors. [9] The standard therapy for patients with anaplastic oligodendroglioma and the treatment include a lot of therapies such as: chemotherapy [10], stereotactic radiotherapies [11], targeted therapy [12], and reoperation. [13] Despite intensive study, the mortality among patients with malignant glioma is very high. It is estimated that 77% die within 1 year after diagnosis. [14]

1- Introduction

2- pH-responsive polymeric nanocarriers

3- Temperature-responsive polymeric nanocarriers

4- Redox potential-responsive polymeric nanocarriers

5- Enzyme-responsive polymeric nanocarriers

6- Light-responsive polymeric nanocarriers

7- Dual-responsive polymeric nanocarriers

8- Future perspectives

9- Conclusions

References

Abstract

In the last decade, considerable attention has been devoted to the use of biodegradable polymeric materials as potential drug delivery carriers. However, bioavailability and drug release at the disease site remain uncontrollable even with the use of polymeric nanocarriers. To address this issue, successful methodologies have been developed to synthesize polymeric nanocarriers incorporated with regions exhibiting a response to stimuli such as redox potential, temperature, pH, and light. The resultant stimuli-responsive polymeric nanocarriers have shown tremendous promise in drug delivery applications, owing to their ability to enhance the bioavailability of drugs at the disease site. In such systems, drug release is controlled in response to specific stimuli, either exogenous or endogenous. This review reports recent advances in the design of stimuli-responsive nanocarriers for drug delivery in cancer therapy. In particular, the synthetic methodologies investigated to date to introduce different types of stimuli-responsive elements within the biomaterials are described. The sufficient understanding of these stimuli-responsive nanocarriers will allow the development of a better drug delivery system that will allow us to solve the challenges encountered in targeted cancer therapy.

Conclusions

In this review, it was focused on the most recent advances in the development of stimuli-responsive nanocarriers for drug delivery in cancer therapy. These smart drug delivery systems respond to the distinct changes in cancer cells, such as changes in pH gradient and elevated secretion of certain enzymes, rather than the conditions in normal cells. Targeting tumors with stimuliresponsive nanocarriers could not only increase the therapeutic benefit and minimize associated toxicity, but could also enhance the curative effect by specifically releasing the anti-cancer drug in a powerful precise mode, both temporally and spatially. The different approaches adopted to incorporate stimuli responsive elements within the polymeric nanocarriers were discussed, with a particular focus on polymeric materials with stimuliresponsive mechanisms in response to pH, redox potential, enzymes, temperature, and light. Despite the tremendous progress that has been made regarding the engineering of new stimuli-responsive materials, several challenges still remain to be addressed with respect to nanomedicine applications. For example, their biodegradability and biocompatibility profiles should be critically investigated prior to utilization in human clinical trials. Many of these systems have only been reported as an in vitro proof-of-concept and follow-up work in vivo preclinical models has been described for only a few. However, the translation of these stimuli-responsive delivery systems from the bench to the bedside might be facilitated, to some extent, if the regulatory requirements for human clinical trials are considered in light of the key features that render a biopolymer suitable for biomedical application, such as biocompatibility, biodegradability, high drug loading capability, programmable release, excellent in vivo stability, non-cytotoxicity, and ability to support effective targeting. Given the ongoing developments in the field of bionanotechnology along with the wide knowledge accumulated over recent years, it is convinced that the collaborative efforts of chemists, biologists, and medicinal and pharmaceutical scientists will revolutionize the design of responsive polymeric materials for cancer therapy to significantly improve both the quality and duration of the lives of patients with cancer.

Introduction

Materials and methods

Results

Discussion

References

Abstract

Purpose: Questionnaire survey among the members of the German Spine Society (Deutsche Wirbels€ aulen-Gesellschaft, DWG) to objectify oncological infrastructure and current standard of care in spinal tumor treatment in Germany. Methods: All DWG-members were contacted via the society’s e-mail and asked to respond in anonymized form to a related questionnaire. Questions were asked regarding surgical specialty, type of institution involved, numbers of spinal procedures, as well as questions on treatment for primary tumors, whether the respondent belonged to a tumor center, decision-making procedures for surgery, and the type of procedure. Results: 84 centers providing surgical treatment for spinal tumors in their departments were identified. 52.6% were carrying out more than 500 spinal procedures per year. There was a significant association (P
0.05) between the numbers of spinal surgeries, the number of treated tumor patients per year, the organisation in a tumor center and the treatment of primary tumors. 76% are part of a local tumor center for interdisciplinary decision making (i.e.surgical treatment and adjuvant therapy). 74% of the institutions stated that conventional postoperative radiotherapy is standardly administered in the case of secondary lesions, with 24% of them referring patients to external services for radiotherapy. Conclusion: In spite of often large numbers of spinal operations, the centers perform relatively small numbers of tumor operations, particularly for primary tumors. A nearly three-quarter majority of the departments are integrated into interdisciplinary tumor care. However, there is a marked number that do not belong to an interdisciplinary organisation. Further advances in multidisciplinarity and oncology training are a continuous issue to increase treatment quality in spinal tumor patients.

Introduction

The diagnosis of a tumor on the spine is a severe and momentous event for those affected and represents an equally great challenge for the specialist disciplines treating these lesions. There is controversy regarding the value, necessity, options and extent of surgical interventions and on whether they are lastingly effective [1]. Oncological treatment is now primarily based on and guided by the biology of the underlying tumors, and currently a paradigm shift in surgical therapy is observed. Among the involved disciplines, the spinal surgeon is usually the first who is contacted either by the symptomatic patient or diagnostic radiologist. However, to provide the complete range of treatment, other disciplines as radiooncology, pathology, pain therapy, internal oncology etc. as well as the necessary infrastructure also have to be available locally to consecutively guarantee the patient a oncological treatment in accordance with the latest standards and guidelines. The treatments are mainly palliative in nature due to secondary lesions developing in 10e20% of all cancer patients [2]. Surgical procedures are aimed at relieving neurological complications, severe pain or restoring spinal integrity and vertebral stability in order to ensure an acceptable quality of life for the period remaining. With regard to primary tumors or so called „solitary“ metastases in definded constellations, the current data in the literature show that radical resection combined with adjuvant therapy is markedly superior to intralesional procedures [3e5].

Introduction

Theoretical background

Proposed method

Experimental results

Conclusion

References

Abstract

Super-resolution, which is one of the trend issues of recent times, increases the resolution of the images to higher levels. Increasing the resolution of a vital image in terms of the information it contains such as brain magnetic resonance image (MRI), makes the important information in the MRI image more visible and clearer. Thus, it is provided that the borders of the tumors in the related image are found more successfully. In this study, brain tumor detection based on fuzzy C-means with super-resolution and convolutional neural networks with extreme learning machine algorithms (SR-FCM-CNN) approach has been proposed. The aim of this study has been segmented the tumors in high performance by using Super Resolution Fuzzy-C-Means (SR-FCM) approach for tumor detection from brain MR images. Afterward, feature extraction and pretrained SqueezeNet architecture from convolutional neural network (CNN) architectures and classification process with extreme learning machine (ELM) were performed. In the experimental studies, it has been determined that brain tumors have been better segmented and removed using SR-FCM method. Using the SquezeeNet architecture, features were extracted from a smaller neural network model with fewer parameters. In the proposed method, 98.33% accuracy rate has been detected in the diagnosis of segmented brain tumors using SR-FCM. This rate is greater 10% than the rate of recognition of brain tumors segmented with fuzzy C-means (FCM) without SR.

Introduction

The brain has a complex structure consisting of millions of cells. Brain tumors are caused by the rapid growth of cells. Uncontrolled growth of cells affects brain activity and may damage normal cells [1]. Imaging technologies have played a role in the analysis of brain anatomy and functions with the development of technology. The tumor region can be detected by using Magnetic Resonance Imaging (MRI). However, radiologists need to measure the size of the tumor site for treatment. Image processing methodologies play an important role in the monitoring of tumor sites between radiologists and computers in the diagnosis and treatment process with machine learning. Radiologists improve diagnostic accuracy from a different perspective in interpreting medical images with these hybrid techniques [2]. Using a higher resolution on medical images makes it easier for the doctor to diagnose diseases. Super-resolution (SR) is used to increase the resolution. In the literature, SR is used in medical images [3–5], MR images [6], brain MR images [6–9], cardiac MR images [10], and retinal fundus images [11]. Many methods were used in the detection and automatic classification of tumor regions using MR images in the literature. Saad et al. [12] established a hybrid system with Fuzzy C-Mean (FCM) region growing for tumor analysis. Sachdeva et al. [13,34] classified the brain tumor by using the support vector machine (SVM) and artificial neural network (ANN) machine learning model in a hybrid structure with Genetic Algorithm (GA) (GA-SVM and GA-ANN). Mallick et al. [14] used a hybrid method with image compression of wavelet transform and image compression using Deep Wavelet Autoencoder (DWA) for brain MR images. In addition, images were classified using Deep Neural Networks (DNN). Performance comparison of DWA-DNN model with other conventional classification techniques was performed. Zeng et al. [9] suggest a deep convolutional neural network model for single and multiple contrast super-resolution reconstructions for artificial and real brain MR images. Swati et al. [15] suggest a method based on learning to transfer brain MR images using a pretrained deep CNN model. The proposed method has a coverage accuracy of 94.82% under five-fold cross-validation since it does not use any handmade features and requires minimal pretreatment.

Nowadays, it is important for the detection of ultrasound images of breast tumors. In this paper, a new ultrasonic image feature extraction algorithm combining edge-based features and morphologic feature information is proposed, which has good effect on benign and malignant identification of breast tumors. This paper mainly studies three features (Sum of maximum curvature, Sum of maximum curvature and peak, Sum of maximum curvature and standard deviation) according to the shape histogram of ultrasound breast tumors from a local perspective. Based on the results of SVM classifier, it was found that the edgebased features have higher classification accuracy. The recognition system would perform better when morphologic features (Roughness, Regularity, Aspect ratio, Ellipticity, Roundness) were incorporated, compared with the control group whose input only with morphologic features. The results show that edge-based features can well describe breast tumors in ultrasound images, and have the potential to be used in breast ultrasound computer-aided design.

Introduction

The statistic report in 2017 shows that the average age of breast cancer patients in China is 48.7 [1]. Breast cancer has become a common disease among women in the current society [2]. Both the breast cancer’s morbidity and mortality are higher than that of other female malignant tumors. Clinical studies have shown that early detection and effective treatments can greatly improve the survival rate of female patients. However, there was no obvious symptoms in the initial when the patient got the cancer, which makes the detection difficult. Therefore, how to discover the lesion area of breast as early as possible so as to improve the cure rate of breast cancer has become a very important topic in the medical field. Ultrasound imaging is a convenient, low-cost, effective, realtime, non-radiation imaging tool, which has been widely used in clinical breast cancer detection [3,4]. In breast tumor diagnosis, the breast ultrasound computer-aided diagnosis (CAD) has been becoming more and more important. It performs better in image preprocessing, segmentation, feature extraction and selection, and tumor classification, including the objective evaluation ∗ Corresponding author. E-mail address: tongying@njit.edu.cn (Y. Tong). results, the classification accuracy, and the diagnostic sensitivity [5,6]. The extraction of different features is crucial in breast ultrasound CAD. Over the past years, research prevailingly concerned the morphologic feature extraction and texture feature extraction [7–9]. Texture features mainly reflect the surface properties of objects through pixels’ gray distribution and their surrounding spatial neighborhoods’ properties like the clarity, thickness and depth of the image texture.

1- Introduction

2- SOX2 in development

3- The role of SOX2 in embryonic and adult stem cells

4- The role of SOX2 in disease and cancer

5- Conclusions and future perspectives

References

Abstract

The transcription factor SOX2 is essential for embryonic development and plays a crucial role in maintaining the stemness of embryonic cells and various adult stem cell populations. On the other hand, dysregulation of SOX2 expression is associated with a multitude of cancer types and it has been shown that SOX2 positively affects cancer cell traits such as the capacity to proliferate, migrate, invade and metastasize. Moreover, there is growing evidence that SOX2 mediates resistance towards established cancer therapies and that it is expressed in cancer stem cells. These findings indicate that studying the role of SOX2 in the context of cancer progression could lead to the development of new therapeutic options. In this review, the current knowledge about the role of SOX2 in development, maintenance of stemness, cancer progression and the resistance towards cancer therapies is summarized.

Introduction

In 1990, a new transcription factor with a distinctive DNA-binding domain was described to be involved in testis determination. The gene encoding for this protein was found to be located on the sex-determining region of the Y chromosome and was therefore termed sexdetermining region Y (SRY) gene [1,2]. The Sry protein binds to specific DNA sequences with its high-mobility-group (HMG) domain. Since its discovery a new gene family has been established on the basis of sequence similarities to this HMG domain (Fig. 1). The so-called Sry-related HMG box (SOX) proteins contain an HMG domain with at least 50% sequence similarity to the HMG domain of Sry. Up to the present day, 20 different SOX genes have been found in the murine and human genome which in turn have been divided into eight subgroups based on sequence identity and similar functions [3,4]. In this review, we will focus on SOX2, a member of the SOXB1 subgroup. Among all SOX genes, SOX2 is probably the most recognized due to its role in reprogramming somatic cells into induced pluripotent stem cells (iPSCs) [5]. The human SOX2 gene is situated on chromosome 3 at the position q26.3–27 and encodes for a protein of 317 amino acids [6]. The structural centerpiece of SOX2 is its HMG domain that is highly conserved among species. Apart from binding to specific DNA consensus sequences, this domain also contains a nuclear localization and a nuclear export signal. The function of the C-terminal transactivation domain is to recognize and bind the promoters of target genes and by doing so activating or repressing gene expression [7].

2- Tumour-Associated Macrophage (TAM)

3- Phenotypical Distinction of Macrophage Subtypes

4- TAM in Colon Tumour

5- Potential Candidates to Reeducate TAM

6- Conclusion

References

Introduction

Colorectal cancer (CRC), also known as bowel cancer or colon cancer, is a type of cancer that begins its abnormal cell growth in the colon or rectum part of the large intestine. In men, CRC has been reported to be the third most common case to occur. On the other hand, it is the second most commonly occurring cancer incidence among women in the world [1, 2]. According to Ferlay et al. [3], approximately 1.36 million people around the world have been affected with cancer. As shown in Table 1, in the United States of America (USA) alone, it is estimated that about 71,420 and 64,010 new CRC cases will be reported among males and females, respectively [4]. Meanwhile, in Asian countries, the disease has become one of the major health concerns in which the number of CRC cases being reported is increasing in an alarming state [5]. Among Asian countries, Japan has been recorded to have the highest incidence of CRC, followed by Hong Kong [6, 7]. Malaysia, in particular, has categorised CRC to be its second most common cancer reported. Table 2 shows that ethnic Chinese holds the highest incidence rate per 100,000 (27.35), followed by Malay (18.95), and Indian (17.55) [8]. Several risk factors have been identified to be associated with the development of CRC. Obesity, lack of physical activity, tobacco use, moderate-to-heavy alcohol consumption, hypertension, abnormal blood lipids, and colonisation of Streptococcus gallolyticus (S. gallolyticus) are said to be the exogenous risk factors. Conversely, personal or familial history of colorectal polyps, inherited CRC syndromes (e.g., hereditary nonpolyposis colon cancer (HNPCC) and Cowden’s disease), inflammatory bowel disease, and type 2 diabetes are said to be the endogenous risk factors [9–11]. As shown in Figure 1, in the presence of exogenous and/or endogenous risk factors, cancer development might occur if the risk factors managed to interact synergistically [12].

1- Introduction

2- Materials and methods

3- Results

4- Discussion

References

Abstract

Diosmetin is a natural flavonoid obtained from citrus fruits and some medicinal herbs. Previous studies have reported the anti-cancer activity of diosmetin in some types of tumors. However, it is still unclear whether diosmetin exerts anti-cancer effects, particularly anti-angiogenic effects, in skin cancer. In this study, we used B16F10 melanoma cells and human umbilical vein endothelial cells to investigate the inhibitory effect of diosmetin on cell proliferation, migration and tube formation in vitro. Rat aorta ring assays were performed to determine the effect of diosmetin on ECs sprouting ex vivo. Furthermore, a B16F10 mouse melanoma model was used to observe the effect of diosmetin on tumor growth, angiogenesis, and metastasis in vivo. Our results showed that diosmetin not only suppressed tumor cell proliferation and migration but also induced cell apoptosis via the caspase pathway in B16F10 cells, and potently inhibited tube formation and cell migration in HUVECs. Rat aorta ring assays showed that diosmetin attenuated the ECs sprouting. Moreover, the mouse melanoma model showed that diosmetin significantly delayed tumor growth by inhibiting tumor vessels sprouting and expansion during tumor progression. Notably, diosmetin induced the normalization of tumor vasculature through the downregulation of angiopoietin-2 and the improvement of pericyte coverage, leading to suppression of metastasis formation in lungs and lymph nodes. In conclusion, our results demonstrate that diosmetin suppresses tumor progression and metastasis by inducing tumor cell death and inhibiting tumor angiogenesis as well as normalizing the defective tumor vasculature, suggesting that diosmetin is a potential adjuvant chemotherapy agent.

Introduction

Malignant melanoma is the most lethal form of skin cancer, accounting for approximately 90% of the deaths caused by this disease [1,2]. In recent decades, the incidence of melanoma has steadily risen. Worldwide, there were about 55,000 deaths in 2012 [3] and according to the International Agency for Research on Cancer, in 2030, an estimated 351,396 new cases and 87,725 deaths are expected to occur [4]. The aggressiveness of melanoma is associated with its high metastatic potential [5]. If recognized during the early stages, melanoma can be removed by surgical excision. However, once it metastasizes, it is difficult to treat and has poor prognosis. Chemotherapy is the most commonly chosen treatment option for the management of melanoma that has disseminated. In general, however, the current chemotherapies to treat melanoma have low efficacy and cause severe adverse effects [6]. Therefore, the development of anti-cancer drug that are both effective and safe is urgently required. Diosmetin, the aglycone part of the flavonoid glycosides diosmin, is abundant in citrus fruits, oregano and is also obtained from some medicinal herbs such as Rosa agrestis Savi (Rosaceae) and Anastatica hierochuntica L. (Brassicaceae) [7–10]. Several therapeutic activities of diosmetin, such as antibacterial, anti-inflammatory, and antioxidant properties, have been reported [11–13]. It has been also demonstrated that diosmetin has a potent anti-proliferative effect in some tumor cells, including MDA-MB 468 breast cancer cells [14], uterine cervical carcinoma cells injected in mice [15], and HepG2 hepatocellular carcinoma cells [16,17]. However, the therapeutic activity of diosmetin in malignant melanoma is still unknown. Angiogenesis, the formation of new vasculature through the sprouting and extension from pre-existing vessels, occurs in several pathological conditions including various malignant solid tumors [18,19]. In tumor progression, tumor-induced angiogenesis supplies nutrients and oxygen and removes metabolites, resulting in further tumor growth [20]. Moreover, tumor vasculature is one of the routes to the spreading of tumor cells to distant organs [21]. Therefore, inhibition of tumor-induced angiogenesis has become a promising strategy for cancer therapy. On the other hand, tumor blood vessels have impaired structure and functionality [21–24].

2- Materials and Methods

3- Results and Discussion

4- Conclusions

References

Introduction

Galangin (Gal) is an active flavonoid extracted and isolated from the roots of Alpinia officinarum Hance, an annual plant, and has a long history of use as a medicine and edible herb in China to warm the stomach, prevent vomiting, and remove cold and pain. It is also listed in the Chinese Pharmacopoeia [1]. Many studies have reported that galangin possesses a broad range of pharmacological activity such as being anti-inflammatory, antibacterial, and antifungal and suppressing vitiligo, Alzheimer’s disease, and cancer [2]. Recent studies have found that galangin can induce apoptosis and promote autophagy [3]. However, it does not easily dissolve in aqueous solution which could limit its potential for clinical use. In the past decades, researchers have developed many nanotechnological solutions to solubilize poorly soluble drugs. Compared with other nanoformulations, liposomes have many advantages, such as excellent biocompatibility, the capability to enhance absorption of drugs, and the capability to reduce their toxicity; thus, liposomes are a good potential drug delivery system which can improve the solubility of liposoluble drugs [4]. However, a major problem exists with intravenously administered liposomes as they suffer rapid clearance from the blood, possibly due to the adsorption of plasma proteins on their phospholipid membranes allowing more rapid recognition by mononuclear macrophages which phagocytose and clear them from plasma [5]. Therefore, in this study, measures that improve the stability of common liposomes for intravenous delivery were proposed, including the modification of the liposomal surface with polyethylene glycol to avoid macrophage phagocytosis [6]. Research on galangin has, until now, largely focused on pharmacological activity, with no studies on pharmacokinetics having been reported. We hypothesize that polyethylene glycol (PEG) modification of liposomes could prolong the half-life of circulating liposomes and improve the aqueous solubility and pharmacokinetic properties of galangin loaded within. In this study, we prepared galangin-loaded PEG-modified liposomes and evaluated their targeting to liver cancer cells in vitro and the pharmacokinetic parameters in vivo in rats.