腺相关病毒介导的pdx-1基因表达促进糖尿病大鼠肝脏细胞向胰岛素产生细胞转化的研究

目的：胰十二指肠同源盒基因-l（pancreatic duodenal homeobox-1，pdx-1）是胰岛发育和分化过程中重要的转录因子。本实验旨在研究腺相关病毒（adeno-associated virus，AAV）介导的pdx-1基因的表达是否可以诱导糖尿病大鼠肝脏细胞分化成产生胰岛素的细胞，以进一步为糖尿病的细胞替代疗法提供信息。方法：门静脉途径注射AAV．pdx-1或AAV对照载体到大鼠体内。6周后，用RT-PCR和免疫细胞化学法检测肝脏中胰岛素的基因表达及测定大鼠血糖、体重的变化。结果：AAV-pdx-1治疗组明显提高了糖尿病大鼠肝脏中胰岛素的基因表达和胰岛素阳性细胞数，改善了糖尿病大鼠的高血糖状态及增加了体重。结论：AAV-pdx-1可诱导糖尿病大鼠肝脏细胞分化成产生胰岛素的细胞，缓解了糖尿病状态。其分化的机制及分化的肝脏细胞亚群需进一步实验研究，以提高分化效率。     

The potential of Beclin 1 as a therapeutic target for the treatment of breast cancer

Introduction: Beclin 1 plays a crucial role in autophagy via the Beclin 1 interactome, and is involved in various biological processes such as protein sorting, chemokinesis, and cell death. Via these biologic functions, Beclin 1 contributes to both tumor suppression and tumor progression.

Areas covered: Beclin 1 plays a key biologic function on cell homeostasis and affects tumorigenesis. In this review, detailing up-to-date knowledge on the tumorigenic role of Beclin 1, its implication in breast cancer, and its utility as a breast cancer-specific drug target is discussed.

Expert opinion: Because Beclin 1 is expressed in breast cancer cells, Beclin 1 could be a unique, effective drug target for the prevention and treatment of breast cancer. However, the expression of Beclin 1 varies according to cancer molecular subtypes, and Beclin 1 is involved in both breast cancer suppression and tumor progression; therefore, the decision of using a Beclin 1 inducer or inhibitor should be made based on breast cancer stage and subtype.     

The role of adjuvant therapy for pancreatic cancer

Patients with pancreatic cancer have a very poor outlook. There have been major advances in the standard surgical treatment of this disease, resulting in decreased post-operative mortality and morbidity. The use of chemotherapy and radiotherapy has been developed to increase long-term patient survival following potentially curative resection. The standard chemotherapeutic agent is 5-fluorouracil (5-FU), although newer cytotoxic agents are in clinical trials for advanced cancer. Initial studies of adjuvant therapy have been based on small numbers of patients, but recently two large European randomised controlled trials of adjuvant therapy (EORTC and ESPAC-1) have been completed. These suggest that adjuvant chemotherapy has a significant survival advantage over resection alone but chemoradiotherapy does not. Promising new agents are being developed and tested mainly in clinical trials of advanced pancreatic cancer. The results of large-scale randomised controlled trials to assess adjuvant therapies for pancreatic cancer demonstrate the great surgical and oncological progress that has been made over the past decade.     

PAR-4 as a possible new target for pancreatic cancer therapy

Importance of the field: Pancreatic cancer (PC) is a deadly disease that is intractable to currently available treatment regimens. Although well described in different tumors types, the importance of apoptosis inducer prostate apoptosis response-4 (Par-4) in PC has not been appreciated. PC is an oncogenic kras driven disease, which is known to downregulate Par-4. Therefore, this review highlights its significance and builds a strong case supporting the role of Par-4 as a possible therapeutic target in PC.

Areas covered in this review: Literature-based evidence spanning the last 15 years on Par-4 and its significance in PC.

What the reader will gain: This review provides comprehensive knowledge of the significance of Par-4 and its association with kras status in PC, along with the crosstalk with crucial resistance and survival molecules NF-κB and Bcl-2 that ultimately are responsible for the overall poor outcome of different therapeutic approaches in this disease.

Take home message: Par-4 holds promise as a potential therapeutic target that can be induced by chemopreventive agents and small-molecule inhibitors either alone or in combination with standard chemotherapeutics leading to selective apoptosis in PC cells. It also acts as a chemosensitizer and therefore warrants further clinical investigations in this disease.     

Surface plasmon resonance-induced photoactivation of gold nanoparticles as mitochondria-targeted therapeutic agents for pancreatic cancer

Background: Noble metal nanoparticles such as gold nanoparticles can strongly absorb light in the visible region by inducing coherent collective oscillation of conduction band electrons in strong resonance with visible frequencies of light. This phenomenon is frequently termed as surface plasmon resonance (SPR).

Objectives: The main objective was to study the effects of laser photoactivated gold nanoparticles (by means of SPR) on human pancreatic cancer cells.

Results: Gold nanoparticles obtained using standard wet chemical methods (with sodium borohydride as a reducing agent) underwent photoexcitation using 2w 808 nm laser and further administered to 1.4E7 pancreatic cancer cell lines. Flow cytometry, transmission electron microscopy, phase contrast microscopy, quantitative proteomics and confocal microscopy combined with immunochemical staining were used to examine the interaction between photo excited gold nanoparticles and pancreatic cancer cells.

Conclusion: The study shows that phonon–phonon interactions following laser photoexcitation of gold nanoparticles exhibit increased intracellular uptake, as well as mitochondrial swelling, closely followed by mitochondrial inner membrane permeabilization and depolarization. This unique data may represent a major step in mitochondria-targeted anticancer therapies using laser-activated gold nanoparticles.     

The PD-1 pathway as a therapeutic target to overcome immune escape mechanisms in cancer

Introduction: Immunotherapy is emerging as a powerful approach in cancer treatment. Preclinical data predicted the antineoplastic effects seen in clinical trials of programmed death-1 (PD-1) pathway inhibitors, as well as their observed toxicities. The results of early clinical trials are extraordinarily promising in several cancer types and have shaped the direction of ongoing and future studies.

Areas covered: This review describes the biological rationale for targeting the PD-1 pathway with monoclonal antibodies for the treatment of cancer as a context for examining the results of early clinical trials. It also surveys the landscape of ongoing clinical trials and discusses their anticipated strengths and limitations.

Expert opinion: PD-1 pathway inhibition represents a new frontier in cancer immunotherapy, which shows clear evidence of activity in various tumor types including NSCLC and melanoma. Ongoing and upcoming trials will examine optimal combinations of these agents, which should further define their role across tumor types. Current limitations include the absence of a reliable companion diagnostic to predict likely responders, as well as lack of data in early-stage cancer when treatment has the potential to increase cure rates.     

Akt as a therapeutic target in cancer

Background: The phosphatidylinositol 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/v-akt murine thymoma viral oncogene homolog (Akt)/mammalian target of rapamycin (mTOR) pathway is central in the transmission of growth regulatory signals originating from cell surface receptors. Objective: This review discusses how mutations occur that result in elevated expression the PI3K/PTEN/Akt/mTOR pathway and lead to malignant transformation, and how effective targeting of this pathway may result in suppression of abnormal growth of cancer cells. Methods: We searched the literature for articles which dealt with altered expression of this pathway in various cancers including: hematopoietic, melanoma, non-small cell lung, pancreatic, endometrial and ovarian, breast, prostate and hepatocellular. Results/conclusions: The PI3K/PTEN/Akt/mTOR pathway is frequently aberrantly regulated in various cancers and targeting this pathway with small molecule inhibitors and may result in novel, more effective anticancer therapies.     

Non-histone nuclear factor HMGB1 as a therapeutic target in colorectal cancer

Introduction: High-motility group box (HMGB)-1 is the focus of recent cancer research. HMGB1 plays a critical role in cancer development, progression, and metastasis by activation of cancer cells, enhancement of tumor angiogenesis, and suppression of host anti-cancer immunity. HMGB1 is a relevant target for cancer treatment.

Areas covered: This review aims to overview the biological feature and diverses role in cancer of HMGB1. HMGB1 is a non-histone chromosomal protein, a secretory protein binding to the receptor for advanced glycation end products in cancer cells and monocyte-lineage immune cells, and a DNA presenting chaperon for toll-like receptors. HMGB1 enhances proliferation, motility, invasion and survival of cancer cells. In contrast, HMGB1 induces apoptosis in monocyte-lineage immune cells and inhibits tumor-infiltrating macrophages and dendritic cells, lymph node sinus macrophages and liver Kupffer cells to attenuate anti-cancer immune responses and anti-metastatic organ defense. Then the novel techniques for inhibiting HMGB1 are reviewed.

Expert opinion: Various techniques targeting HMGB1 are subjected to trial. HMGB1 targeting is a potential therapeutic techniqueagainst cancer development, progression, and especially metastasis. Technical breakthroughs in application of HMGB1 targeting to human diseases are now urgently required.     

CIAPIN1 as a therapeutic target in cancer

Importance of the field: Cytokine-induced apoptosis inhibitor 1 (CIAPIN1) is a newly identified cytokine-induced apoptosis inhibitor, which has roles in cell division and angiogenesis. Owing to its prognostic value for human tumors and involvement in cancer progression and tumor cell resistance to anticancer agents, CIAPIN1 has been proposed as an attractive target for new anticancer interventions.

Areas covered in this review: We define CIAPIN1's potential function as a new therapeutic target for anticancer interventions and this review covers all related literature on CIAPIN1 in cancer from the past 5 years

What the reader will gain: Several preclinical studies have demonstrated that CIAPIN1 is associated with chemotherapy resistance, increased tumor recurrence and shorter patient survival in different human tumor models, making anti-CIAPIN1 therapy an attractive cancer treatment strategy. Recent studies also suggest that CIAPIN1 is expressed at low levels in some types of malignant tumors and that its overexpression may inhibit their proliferation or tumorigenesis.

Take home message: Considering that the exact expression and function of CIAPIN1 are still not well characterized and understood, better knowledge of CIAPIN1 in normal versus tumor tissues will be instrumental for the design of optimal strategies to selectively disrupt CIAPIN1 in cancer.     

TGF-beta in cancer and as a therapeutic target

Cancer develops through a series of genetic changes leading to malignant transformation. Numerous gene and pathways involved in stages of progression to frank malignancy have been elucidated. These genetic changes result in aberrations in fundamental cellular processes controlling proliferation, apoptosis, differentiation and genomic stability. Metastasis is the hallmark of malignancy. The process of metastasis is extremely complex and involves steps including dissemination of tumor cells from the primary tumor through the vascular and lymphatic system and growth selectively in distant tissues and organs. Transforming growth factor-beta which is a growth suppressive cytokine in many normal situations becomes an active and important participant in malignant disease including angiogenesis, extracellular matrix deposition, immuno-suppression and metastasis growth promotion. Transforming growth factor-beta and its receptors are targets for antibody therapeutics and small molecule kinase inhibitors.     

Emerging role of SETDB1 as a therapeutic target

Introduction: Epigenetic changes lead to aberrant gene expression in cancer. SETDB1, a histone lysine methyltransferase plays an important role in methylation and gene silencing. Aberrant histone methylation at H3K9 by SETDB1 promotes silencing of tumor suppressor genes and thus contributes to carcinogenesis. Recent studies indicate that SETDB1 is abnormally expressed in various human cancer conditions which contributed to enhanced tumor growth and metastasis. Hence, SETDB1 appears to be a promising epigenetic target for therapeutic intervention.

Areas covered: In this article, the structural features, localization and functions of SETDB1 are reviewed. Also, an overview of the role of SETDB1 in cancer and other disease mechanisms, the currently studied inhibitors for SETDB1 are mentioned.

Expert opinion: Silencing of tumor suppressor genes due to excessive trimethylation at H3K9 by amplified SETDB1 levels is found in various cancerous conditions. Since epigenetic changes are reversible, SETDB1 holds promise as an important therapeutic target for cancer. Therefore, a better understanding of the role of SETDB1 and its interaction with various proteins in cancer-related mechanisms along with therapeutic interventions specific for SETDB1 may improve targeted cancer therapy.     

The potential of heparanase as a therapeutic target in cancer

Heparanase has generated substantial interest as therapeutic target for antitumor therapy, because its activity is implicated in malignant behavior of cancer cells and in tumor progression. Increased heparanase expression was found in numerous tumor types and correlates with poor prognosis. Heparanase, an endoglucuronidase responsible for heparan sulfate cleavage, regulates the structure and function of heparan sulfate proteoglycans, leading to disassembly of the extracellular matrix. The action of heparanase is involved in multiple regulatory events related, among other effects, to augmented bioavailability of growth factors and cytokines. Inhibitors of heparanase suppress tumor growth, angiogenesis and metastasis by modulating growth factor-mediated signaling, ECM barrier function and cell interactions in the tumor microenvironment. Therefore, targeting heparanase has potential implications for anti-tumor, anti-angiogenic and anti-inflammatory therapies. Current approaches for heparanase inhibition include development of chemically modified heparins, small molecule inhibitors and neutralizing antibodies. The available evidence supports the emerging utility of heparanase inhibition as a promising antitumor strategy, specifically in rational combination with other agents. The recent studies with compounds designed to block heparanase (e.g., modified heparins) provide a rational basis for their therapeutic application and optimization.     

Eag1 as a cancer target

Background: Ion channels are drug targets for many diseases but have only recently started to be regarded as potential primary cancer targets. Many types of ion channels have been identified that could be useful in cancer management. Objective: We focus on a voltage-gated potassium channel, ether à go-go 1 (Eag)1, which shows distinctive features such as a restricted expression pattern and peculiar electrophysiological properties. Methods: We review the literature on this channel and try to relate this knowledge to the context of other ion channels in cancer. Results/conclusion: Eag1 appears to be a promising cancer target, both as a tumor marker because of restricted expression, which could be useful in the context of therapeutic decisions, and as a therapeutic-agent-targeting molecule.     

Endothelin-1 as a target for therapeutic intervention in prostate cancer

The endothelins, a family of potentvasoconstricting peptides, have beenimplicated in the pathophysiology ofadvanced prostate cancer. Two endothelinreceptors, ET-A and ET-B are found innormal prostate tissue. Malignant prostatecells are notable for the loss of ET-Breceptors and increased levels ofendothelin-1 [ET-1]; this distortion of theendothelin system may be a significantfactor in the progression of prostatecancer. Proposed roles for endothelin inprostate cancer include growth promotion,apoptosis inhibition, bone formation, andstimulation of nociceptive receptors. ET-1can act alone as a mitogen, but its effectsare greatest as a comitogen with a varietyof growth factors, including basicfibroblast growth factor, insulin-likegrowth factors, and platelet derived growthfactor. Although their exact functions areunclear, ET-1, in conjunction with vascularendothelial growth factor, appears to playa major role in tumor angiogenesis. By avariety of methods, ET-1 alters the balanceof osteoblast and osteoclasts to the favornew bone formation that is characteristicof metastatic disease. Several studiesindicate that the refractory pain ofmetastatic cancer is related to the directnociceptive effects ET-1. These findingssuggest that ET receptors are promisingtherapeutic targets for pharmacologicintervention. Early clinical trialsindicate that the ET-A receptor antagonistused in prostate cancer is reasonably welltolerated with mild but pervasive symptomsrelated to ET-1's vasoconstrictive effects. Results of ongoing clinical trials areeagerly awaited in order to see if thehypothetical promise of ET antagonism willresult in clinical success.     

Tp53 and its potential therapeutic role as a target in bladder cancer

Introduction: Despite more than 30 years of research on p53 resulting in >50,000 publications, we are now beginning to figure out the complexity of the p53 pathway, gene ontology and conformational structure of the molecule. Recent years brought great advances in p53 related drugs and the potencial ways in which p53 is inactivated in cancer.

Areas covered: We searched for related publications on Pubmed and ClinicalTrial.gov using the following keywords ‘p53, Tp53, p53 and bladder cancer, p53 and therapeutic target’. Relevant articles improved the understanding on p53 pathways and their potential as candidate to targeted therapy in bladder cancer.

Expert opinion: Novel strategies developed to restore the function of mutants with chemical chaperones or by using compounds to improved pharmacokinetic properties are in development with potential to be applied in the oncology clinic. Other strategies targeting aberrantly overexpressed p53 regulators with wild-type p53 are also an active area of research. In particular, studies inhibiting the interaction of p53 with its negative regulators MDMX and MDM2 are an important field in drug discovery. Small molecules for inhibition of MDM2 are now in clinical trials process. However, personalized anticancer therapy might eventually advance through analyses of p53 status in cancer patients.     

Characterization of B cell-mediated PD-1/PD-L1 interaction in pancreatic cancer patients

Pancreatic ductal adenocarcinoma (PDAC) is a common type of pancreatic cancer with one of the worst survival rate of all malignancies. Recent studies have identified that immunosuppressive B cells could employ the PD-1/PD-L1 pathway to suppress antitumour T cell responses; hence, we examined the expression and function of PD-L1 in B cells. We found that the PD-L1 expression was significantly enriched in tumour-infiltrating (TI) B cells than in peripheral blood (PB) B cells from the same patients. Additionally, the PB B cells from stage III and stage IV PDAC patients presented significantly higher PD-L1 than the PB B cells from healthy controls. High PD-L1 expression in PB B cells could be achieved by stimulation via CpG and less effectively via anti-BCR plus CD40L, but not by coculture with pancreatic cancer cell lines in vitro. Also, STAT1 and STAT3 inhibition significantly suppressed PD-L1 upregulation in stimulated B cells. CpG-stimulated PB B cells could inhibit the IFN-γ expression and proliferation of CD8 T cells in a PD-L1-dependent manner. Also, TI CD8 T cells incubated with whole TI B cells presented significantly lower IFN-γ expression and lower proliferation, than TI CD8 T cells incubated with PD-L1⁺ cell-depleted TI B cells, suggesting that PD-L1⁺ B cells could also suppress CD8 T cells in the tumour. Overall, this study identified that B cells could suppress CD8 T cells via PD-L1 expression, indicating a novel pathway of immuno-regulation in pancreatic cancer.     

MUC4 mucin- a therapeutic target for pancreatic ductal adenocarcinoma

Introduction: Pancreatic cancer (PC) is characterized by mucin overexpression. MUC4 is the most differentially overexpressed membrane-bound mucin that plays a functional role in disease progression and therapy resistance.

Area covered: We describe the clinicopathological significance of MUC4, summarize mechanisms contributing to its deregulated expression, review preclinical studies aimed at inhibiting MUC4, and discuss how MUC4 overexpression provides opportunities for developing targeted therapies. Finally, we discuss the challenges for developing MUC4-based therapeutics, and identify areas where efforts should be directed to effectively exploit MUC4 as a therapeutic target for PC.

Expert opinion: Studies demonstrating that abrogation of MUC4 expression reduces proliferation and metastasis of PC cells and enhances sensitivity to therapeutic agents affirm its utility as a therapeutic target. Emerging evidence also supports the suitability of MUC4 as a potential immunotherapy target. However, these studies have been limited to in vitro, ex vivo or in vivo approaches using xenograft tumors in immunodeficient murine models. For translational relevance, MUC4-targeted therapies should be evaluated in murine models with intact immune system and accurate tumor microenvironment. Additionally, future studies evaluating MUC4 as a target for immunotherapy must entail characterization of immune response in PC patients and investigate its association with immunosuppression and survival.