Cancer metabolism: current perspectives and future directions

Cellular metabolism influences life and death decisions. An emerging theme in cancer biology is that metabolic regulation is intricately linked to cancer progression. In part, this is due to the fact that proliferation is tightly regulated by availability of nutrients. Mitogenic signals promote nutrient uptake and synthesis of DNA, RNA, proteins and lipids. Therefore, it seems straight-forward that oncogenes, that often promote proliferation, also promote metabolic changes. In this review we summarize our current understanding of how ‘metabolic transformation'' is linked to oncogenic transformation, and why inhibition of metabolism may prove a cancer′s ‘Achilles'' heel''. On one hand, mutation of metabolic enzymes and metabolic stress sensors confers synthetic lethality with inhibitors of metabolism. On the other hand, hyperactivation of oncogenic pathways makes tumors more susceptible to metabolic inhibition. Conversely, an adequate nutrient supply and active metabolism regulates Bcl-2 family proteins and inhibits susceptibility to apoptosis. Here, we provide an overview of the metabolic pathways that represent anti-cancer targets and the cell death pathways engaged by metabolic inhibitors. Additionally, we will detail the similarities between metabolism of cancer cells and metabolism of proliferating cells.     

Clinical proteomics-driven precision medicine for targeted cancer therapy: current overview and future perspectives

Cancer is a common disease that is a leading cause of death worldwide. Currently, early detection and novel therapeutic strategies are urgently needed for more effective management of cancer. Importantly, protein profiling using clinical proteomic strategies, with spectacular sensitivity and precision, offer excellent promise for the identification of potential biomarkers that would direct the development of targeted therapeutic anticancer drugs for precision medicine. In particular, clinical sample sources, including tumor tissues and body fluids (blood, feces, urine and saliva), have been widely investigated using modern high-throughput mass spectrometry-based proteomic approaches combined with bioinformatic analysis, to pursue the possibilities of precision medicine for targeted cancer therapy. Discussed in this review are the current advantages and limitations of clinical proteomics, the available strategies of clinical proteomics for the management of precision medicine, as well as the challenges and future perspectives of clinical proteomics-driven precision medicine for targeted cancer therapy.     

Kinase inhibitors with viral oncolysis: Unmasking pharmacoviral approaches for cancer therapy

There are more than 500 kinases in the human genome, many of which are oncogenic once constitutively activated. Fortunately, numerous hyperactive kinases are druggable, and several targeted small molecule kinase inhibitors have demonstrated impressive clinical benefits in cancer treatment. However, their often cytostatic rather than cytotoxic effect on cancer cells, and the development of resistance mechanisms, remain significant limitations to these targeted therapies. Oncolytic viruses are an emerging class of immunotherapeutic agents with a specific oncotropic nature and excellent safety profile, highlighting them as a promising alternative to conventional therapeutic modalities. Nonetheless, the clinical efficacy of oncolytic virotherapy is challenged by immunological and physical barriers that limit viral delivery, replication, and spread within tumours. Several of these barriers are often associated with oncogenic kinase activity and, in some cases, worsened by the action of oncolytic viruses on kinase signaling during infection. What if inhibiting these kinases could potentiate the cancer-lytic and anti-tumour immune stimulating properties of oncolytic virotherapies? This could represent a paradigm shift in the use of specific kinase inhibitors in the clinic and provide a novel therapeutic approach to the treatment of cancers. A phase III clinical trial combining the oncolytic Vaccinia virus Pexa-Vec with the kinase inhibitor Sorafenib was initiated. While this trial failed to show any benefits over Sorafenib monotherapy in patients with advanced liver cancer, several pre-clinical studies demonstrate that targeting kinases combined with oncolytic viruses have synergistic effects highlighting this strategy as a unique avenue to cancer therapy. Herein, we review the combinations of oncolytic viruses with kinase inhibitors reported in the literature and discuss the clinical opportunities that represent these pharmacoviral approaches.     

Targeting the metabolism and immune system in pancreatic ductal adenocarcinoma: Insights and future directions

Pancreatic cancer, specifically pancreatic ductal adenocarcinoma (PDAC), presents a challenging landscape due to its complex nature and the highly immunosuppressive tumor microenvironment (TME). This immunosuppression severely limits the effectiveness of immune-based therapies. Studies have revealed the critical role of immunometabolism in shaping the TME and influencing PDAC progression. Genetic alterations, lysosomal dysfunction, gut microbiome dysbiosis, and altered metabolic pathways have been shown to modulate immunometabolism in PDAC. These metabolic alterations can significantly impact immune cell functions, including T-cells, myeloid-derived suppressor cells (MDSCs), and macrophages, evading anti-tumor immunity. Advances in immunotherapy offer promising avenues for overcoming immunosuppressive TME and enhancing patient outcomes. This review highlights the challenges and opportunities for future research in this evolving field. By exploring the connections between immunometabolism, genetic alterations, and the microbiome in PDAC, it is possible to tailor novel approaches capable of improving immunotherapy outcomes and addressing the limitations posed by immunosuppressive TME. Ultimately, these insights may pave the way for improved treatment options and better outcomes for PDAC patients.     

A systematic assessment of statistics,risk factors,and underlying features involved in pancreatic cancer

Pancreatic cancer remains the fourth leading cause of cancer-related death in the world, and will continue to become the number two cause of cancer-related death unless a remarkable breakthrough is achieved. With a slim chance of early diagnosis, surgery can only provide a median survival of 17–23 months. The presence of a dense stroma makes this cancer resilient to chemotherapy, with very few potent inhibitors like nab paclitaxelin available that can work in combination with chemotherapeutic agents. Survival rates, on the one hand, lie at 8.5%. Variation in types of pancreatic cancer, on the other hand, makes it notoriously difficult to come up with a practical solution for the treatment of this disease. A deeper understanding of the root cause would be beneficial for diagnosis. Advancement in the field of genomics has made the identification of novel biomarkers relatively easier. By coupling this factor with the production of suitable inhibitors, testing in large numbers can be made possible with the help of cell lines. With the combined efforts of biological knowledge and modern technology, the cure for pancreatic cancer could be at hand.     

促凋亡基因Bax在胰腺癌中的研究进展

胰腺癌的恶性程度高、转移早、浸润性强,这与胰腺癌的细胞凋亡异常有密切的关系。Bax是目前研究最深入的促凋亡基因之一。多数研究认为,Bax在胰腺癌中存在高表达,其表达率从53%到100%不等。有研究认为Bax的表达预示着胰腺癌的良性预后,也有研究发现胰腺癌中Bax的表达与胰腺癌的分级分化等有关。Bax在胰腺癌中的表达受p53、PERIOD1、P13K/AKT等的调控。Bax表达异常及其突变可能与胰腺癌的发生有关。研究发现Bax表达可增强胰腺癌对吉西他滨和5-FU等化疗药物以及放射治疗的敏感性,而Bax/Bcl-2的比值可能与胰腺癌放化疗敏感性更相关。提高Bax基因表达、上调Bax活性等针对Bax的靶向治疗已显示出促进胰腺癌细胞凋亡、增强药物抗癌效应的作用。同时,作为最重要的促凋亡蛋白之一,Bax成为评价各种抗胰腺癌药物的疗效、探讨其作用机制的重要指标之一。对胰腺癌中Bax的深入研究,有利于了解其与胰腺癌的预后和耐药性的关系,为胰腺癌的靶向治疗提供新的方向。     

T-cell receptor-engineered T cells for cancer treatment: current status and future directions

T-cell receptor (TCR)-engineered T cells are a novel option for adoptive cell therapy used for the treatment of several advanced forms of cancer. Work using TCRengineered T cells began more than two decades ago, with numerous preclinical studies showing that such cells could mediate tumor lysis and eradication. The success of these trials provided the foundation for clinical trials, including recent clinical successes using TCRengineered T cells to target New York esophageal squamous cell carcinoma (NY-ESO-1). These successes demonstrate the potential of this approach to treat cancer. In this review, we provide a perspective on the current and future applications of TCR-engineered T cells for the treatment of cancer. Our summary focuses on TCR activation and both pre-clinical and clinical applications of TCR-engineered T cells. We also discuss how to enhance the function of TCR-engineered T cells and prolong their longevity in the tumor microenvironment.     

Targeted drug delivery in pancreatic cancer

Effective drug delivery in pancreatic cancer treatment remains a major challenge. Because of the high resistance to chemo and radiation therapy, the overall survival rate for pancreatic cancer is extremely low. Recent advances in drug delivery systems hold great promise for improving cancer therapy. Using liposomes, nanoparticles, and carbon nanotubes to deliver cancer drugs and other therapeutic agents such as siRNA, suicide gene, oncolytic virus, small molecule inhibitor, and antibody has been a success in recent preclinical trials. However, how to improve the specificity and stability of the delivered drug using ligand or antibody directed delivery represent a major problem. Therefore, developing novel, specific, tumor-targeted drug delivery systems is urgently needed for this terrible disease. This review summarizes the current progress on targeted drug delivery in pancreatic cancer and provides important information on potential therapeutic targets for pancreatic cancer treatment.     

Opium consumption and pancreatic cancer: A meta-analysis

Pancreatic cancer represents a serious public health problem worldwide. Due to its high mortality, efforts on identifying risk factors are very important since only a few risk-related factors have been well established. The present study aimed to address this knowledge gap by estimating the risk of pancreatic cancer associated with opium use. We performed a thorough literature search of PubMed, Web of Science and Scopus, which yielded 3 case-control and 1 cohort study which were included in the analysis. A meta-analysis was conducted using the DerSimonian and Laird inverse-variance approach as the random effects method. The pooled risk ratio for pancreatic cancer in opium users was significantly increased (RR=1.98, 95 % CI 1.33–2.96, p = 0.0008) compared to never users. Subgroup analyses identified a significantly increased risk for pancreatic cancer in men (RR=1.74, 95 % CI 1.22–2.47, p = 0.002), in persons who consumed both raw teriak and refined shireh opium (RR=4.21, 95 % 1.27–13.93, p = 0.02) and in persons who smoked opium (RR=4.21, 95 % 1.27–13.93, p = 0.02). The findings of this study will help in efforts aimed at prevention of pancreatic cancer. Still, further epidemiological research is necessary.     

CCN1: a novel target for pancreatic cancer

CCN2 (formerly known as connective tissue growth factor) was identified by several different laboratories approximately 20 years ago. Almost since its identification as a factor induced in normal fibroblasts by transforming growth factor β and overexpressed in fibrotic disease, CCN2 has been hypothesized to be not only a marker but also a central mediator of fibrosis in vivo. Finally, in vivo data are emerging to validate this key hypothesis. For example, a neutralizing anti-CCN2 antibody was found to attenuate fibrogenesis in three separate animal models (Wang et al. in Fibrogenesis Tissue Repair 4:1–4, 2011). This commentary addresses recent data indicating that CCN2 appears to represent a key central mediator of fibrosis and a good target for anti-fibrotic drug intervention.     

胰腺疾病的肠道微生物群研究进展

肠道微生物群是指存在于人体消化道内的微生物组成的复杂群落。随着16S rRNA基因测序和宏基因组测序等高通量测序技术的发展,肠道微生物群已被证明与多种疾病息息相关。三大胰腺疾病与肠道微生物群密切相关,急性胰腺炎（acute pancreatitis,AP）、慢性胰腺炎（chronic pancreatitis,CP）和胰腺癌患者肠道微生物群的构成和丰度均与健康人群不同。反之,肠道微生物群的改变会减慢或加速胰腺疾病的发生发展。益生菌和抗菌药物的使用及粪菌移植等可减轻胰腺炎症反应,缓解胃肠道症状,影响胰腺癌化疗和免疫治疗的效果,因此可为胰腺疾病的诊疗提供新策略。本文总结了AP、CP和胰腺癌的肠道微生物群研究,阐述了疾病发生时肠道微生物群的变化、与胰腺相互作用的机制以及目前的主要研究技术,探讨了肠道微生物群在胰腺疾病诊疗中的研究进展。

     

Bio-ontologies: current trends and future directions

In recent years, as a knowledge-based discipline, bioinformatics has been made more computationally amenable. After its beginnings as a technology advocated by computer scientists to overcome problems of heterogeneity, ontology has been taken up by biologists themselves as a means to consistently annotate features from genotype to phenotype. In medical informatics, artifacts called ontologies have been used for a longer period of time to produce controlled lexicons for coding schemes. In this article, we review the current position in ontologies and how they have become institutionalized within biomedicine. As the field has matured, the much older philosophical aspects of ontology have come into play. With this and the institutionalization of ontology has come greater formality. We review this trend and what benefits it might bring to ontologies and their use within biomedicine.     

Immunoassay-based proteome profiling of 24 pancreatic cancer cell lines

Pancreatic ductal adenocarcinoma is one of the most deadly forms of cancers, with a mortality that is almost identical to incidence. The inability to predict, detect or diagnose the disease early and its resistance to all current treatment modalities but surgery are the prime challenges to changing the devastating prognosis. Also, relatively little is known about pancreatic carcinogenesis. In order to better understand relevant aspects of pathophysiology, differentiation, and transformation, we analysed the cellular proteomes of 24 pancreatic cancer cell lines and two controls using an antibody microarray that targets 741 cancer-related proteins. In this analysis, 72 distinct disease marker proteins were identified that had not been described before. Additionally, categorizing cancer cells in accordance to their original location (primary tumour, liver metastases, or ascites) was made possible. A comparison of the cells' degree of differentiation (well, moderately, or poorly differentiated) resulted in unique marker sets of high relevance. Last, 187 proteins were differentially expressed in primary versus metastatic cancer cells, of which the majority is functionally related to cellular movement.     

Stereotactic radiotherapy for early lung cancer: Evidence-based approach and future directions

AimTo review key studies evaluating stereotactic radiotherapy in the setting of early-stage non-small cell lung cancer (NSCLC) for inoperable or high-risk patients, and discuss areas of ongoing research and clinical trials.BackgroundThe use of stereotactic radiotherapy for the treatment of early stage non-small cell lung cancer (NSCLC) has increased rapidly over the past decade. Numerous studies have reported outcomes for patients treated with SBRT who are unfit for surgical resection, or at high risk of surgical complications.Materials and methodsA narrative review.ResultsThe preponderance of evidence suggests that SBRT is associated with excellent local control (∼90% at 3 years) and a favorable toxicity profile. In patients with higher operative risks, such as the elderly and patients with severe COPD, SBRT may provide a less-toxic treatment than surgery with similar oncologic outcomes. Ongoing studies are evaluating the use of SBRT for locally advanced or oligometastatic NSCLC.ConclusionsA large body of evidence now exists to support the use of SBRT for early-stage NSCLC. Decisions regarding the optimal choice of treatment should be individualized, and made in the context of a multidisciplinary team.     

Amphibian teeth: current knowledge, unanswered questions, and some directions for future research

Elucidation of the mechanisms controlling early development and organogenesis is currently progressing in several model species and a new field of research, evolutionary developmental biology, which integrates developmental and comparative approaches, has emerged. Although the expression pattern of many genes during tooth development in mammals is known, data on other lineages are virtually non-existent. Comparison of tooth development, and particularly of gene expression (and function) during tooth morphogenesis and differentiation, in representative species of various vertebrate lineages is a prerequisite to understand what makes one tooth different from another. Amphibians appear to be good candidates for such research for several reasons: tooth structure is similar to that in mammals, teeth are renewed continuously during life (=polyphyodonty), some species are easy to breed in the laboratory, and a large amount of morphological data are already available on diverse aspects of tooth biology in various species. The aim of this review is to evaluate current knowledge on amphibian teeth, principally concerning tooth development and replacement (including resorption), and changes in morphology and structure during ontogeny and metamorphosis. Throughout this review we highlight important questions which remain to be answered and that could be addressed using comparative morphological studies and molecular techniques. We illustrate several aspects of amphibian tooth biology using data obtained for the caudate Pleurodeles waltl. This salamander has been used extensively in experimental embryology research during the past century and appears to be one of the most favourable amphibian species to use as a model in studies of tooth development.     

Death of a tumor: targeting CCN in pancreatic cancer

The matricellular protein CCN2 (connective tissue growth factor, CTGF) has been previously implicated in tumorigenesis. In pancreatic cancer cells, CCN2 expression occurs downstream of ras/MEK/ERK. Direct evidence that CCN2 mediates tumor progression in pancreatic cancer has been lacking. An exciting recent report by Bennewith et al. (Cancer Res 69:775–784, 2009) has used shRNA knockdown of CCN2 to illustrate that CCN2 contributes to growth of pancreatic tumor cells, both in vitro and in vivo. This report briefly summarizes these findings.     

Therapeutic advances targeting tumor angiogenesis in pancreatic cancer: Current dilemmas and future directions

Pancreatic cancer (PC) is one of the most lethal malignancies, which is generally resistant to various treatments. Tumor angiogenesis is deemed to be a pivotal rate-determining step for tumor growth and metastasis. Therefore, anti-angiogenetic therapy is a rational strategy to treat various cancers. However, numerous clinical trials on anti-angiogenetic therapies for PC are overwhelmingly disappointing. The unique characteristics of tumor blood vessels in PC, which are desperately lacking and highly compressed by the dense desmoplastic stroma, are reconsidered to explore some optimized strategies. In this review, we mainly focus on its specific characteristics of tumor blood vessels, discuss the current dilemmas of anti-angiogenic therapy in PC and their underlying mechanisms. Furthermore, we point out the future directions, including remodeling the abnormal vasculature or even reshaping the whole tumor microenvironment in which they are embedded to improve tumor microcirculation, and then create therapeutic vulnerabilities to the current available therapeutic strategies.     

Immunotherapy in colorectal cancer: current achievements and future perspective

Following dramatic success in many types of advanced solid tumors, interest in immunotherapy for the treatment of colorectal cancer (CRC) is increasingly growing. Given the compelling long-term durable remission, two programmed cell death 1 (PD-1)-blocking antibodies, pembrolizumab and nivolumab (with or without Ipilimumab), have been approved for the treatment of patients with metastatic colorectal cancer (mCRC) that is mismatch-repair-deficient and microsatellite instability-high (dMMR-MSI-H). Practice-changing results of several randomized controlled trials to move immunotherapy into the first-line treatment for MSI-H metastasis cancer and earlier stage were reported successively in the past 2 years. Besides, new intriguing advances to expand the efficacy of immunotherapy to mCRC that is mismatch-repair-proficient and low microsatellite instability (pMMR-MSI-L) demonstrated the potential benefits for the vast majority of mCRC cases. Great attention is also paid to the advances in cancer vaccines and adoptive cell therapy (ACT). In this review, we summarize the above progresses, and also highlight the current predictive biomarkers of responsiveness in immunotherapy with broad clinical utility.     

Delivery of dsRNA for RNAi in insects: an overview and future directions

Abstract RNA interference (RNAi) refers to the process of exogenous double‐stranded RNA (dsRNA) silencing the complementary endogenous messenger RNA. RNAi has been widely used in entomological research for functional genomics in a variety of insects and its potential for RNAi‐based pest control has been increasingly emphasized mainly because of its high specificity. This review focuses on the approaches of introducing dsRNA into insect cells or insect bodies to induce effective RNAi. The three most common delivery methods, namely, microinjection, ingestion, and soaking, are illustrated in details and their advantages and limitations are summarized for purpose of feasible RNAi research. In this review, we also briefly introduce the two possible dsRNA uptake machineries, other dsRNA delivery methods and the history of RNAi in entomology. Factors that influence the specificity and efficiency of RNAi such as transfection reagents, selection of dsRNA region, length, and stability of dsRNA in RNAi research are discussed for further studies.