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Effect of atorvastatin on tumor growth and metastasis in a breast cancer cell xenograft model and its

Liu LIU MD, PhD, Yaogui NING MM, Chen CHEN MD, Daowen WANG MD, PhD,

《医学前沿（英文）》 2009年 第3卷 第4期   页码 443-446 doi: 10.1007/s11684-009-0079-5

摘要： This paper aims to evaluate the effects and the possible mechanisms of atorvastatin on tumor growth and metastasis in a xenograft tumor model. Twenty-four female athymic BALB/C mice with MDA-MB-435 xenograft tumors were randomly assigned to three groups: a control group, a low-dose atorvastatin treatment group, and a high-dose atorvastatin treatment group. The mice in the treatment groups began to be administered with atorvastatin (10 or 20 mg/kg per day) when the xenograft tumors reached 1 cm in diameter. At the end of the experiment, the tumor volume and weight and the lung metastasis colonies of each mouse were measured. Western blotting was applied to detect phosphorylation of protein kinase B (PKB, Akt), extracellular signal regulated kinase (ERK), c-Jun N-terminal Kinase (JNK), and the expression of cytochrome P450 (CYP) subtype CYP2J2. Atorvastatin suppressed xenograft tumor growth and metastasis both in the low-dose and the high-dose treatment groups ( < 0.05). Atorvastatin also decreased the phosphorylated Akt (p-Akt) and p-ERK but increased p-JNK expression. However, atorvastatin did not alter the expression of CYP2J2 in tumor tissue. This suggests that atorvastatin has the efficacy of suppressing tumor growth and metastasis . These effects were not dependent on down-regulation of CYP2J2 expression.

关键词： atorvastatin     xenograft tumor     metastasis     CYP2J2    

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Patient-derived xenograft platform of OSCC: a renewable human bio-bank for preclinical cancer research

null

《医学前沿（英文）》 2016年 第10卷 第1期   页码 104-110 doi: 10.1007/s11684-016-0432-4

摘要：

Advances in next-generation sequencing and bioinformatics have begun to reveal the complex genetic landscape in human cancer genomes, including oral squamous cell carcinoma (OSCC). Sophisticated preclinical models that fully represent intra- and inter-tumoral heterogeneity are required to understand the molecular diversity of cancer and achieve the goal of personalized therapies. Patient-derived xenograft (PDX) models generated from human tumor samples that can retain the histological and genetic features of their donor tumors have been shown to be the preferred preclinical tool in translational cancer research compared with other conventional preclinical models. Specifically, genetically well-defined PDX models can be applied to accelerate targeted antitumor drug development and biomarker discovery. Recently, we have successfully established and characterized an OSCC PDX panel as part of our tumor bio-bank for translational cancer research. In this paper, we discuss the establishment, characterization, and preclinical applications of the PDX models. In particular, we focus on the classification and applications of the PDX models based on validated annotations, including clinicopathological features, genomic profiles, and pharmacological testing information. We also explore the translational value of this well-annotated PDX panel in the development of co-clinical trials for patient stratification and treatment optimization in the near future. Although various limitations still exist, this preclinical approach should be further tested and improved.

关键词： patient-derived xenograft models     personalized medicine     co-clinical trial     patient stratification     oral squamous cell carcinoma    

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Heterogeneity of the tumor immune microenvironment and clinical interventions

《医学前沿（英文）》 2023年 第17卷 第4期   页码 617-648 doi: 10.1007/s11684-023-1015-9

摘要： Heterogeneity of the tumor immune microenvironment and clinical interventions

关键词： Heterogeneity tumor immune    

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Proteins moonlighting in tumor metabolism and epigenetics

Lei Lv, Qunying Lei

《医学前沿（英文）》 2021年 第15卷 第3期   页码 383-403 doi: 10.1007/s11684-020-0818-1

摘要： Cancer development is a complicated process controlled by the interplay of multiple signaling pathways and restrained by oxygen and nutrient accessibility in the tumor microenvironment. High plasticity in using diverse nutrients to adapt to metabolic stress is one of the hallmarks of cancer cells. To respond to nutrient stress and to meet the requirements for rapid cell proliferation, cancer cells reprogram metabolic pathways to take up more glucose and coordinate the production of energy and intermediates for biosynthesis. Such actions involve gene expression and activity regulation by the moonlighting function of oncoproteins and metabolic enzymes. The signal−moonlighting protein−metabolism axis facilitates the adaptation of tumor cells under varying environment conditions and can be therapeutically targeted for cancer treatment.

关键词： moonlighting function     tumor metabolism     epigenetics    

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Complex interplay between tumor microenvironment and cancer therapy

null

《医学前沿（英文）》 2018年 第12卷 第4期   页码 426-439 doi: 10.1007/s11684-018-0663-7

摘要：

Tumor microenvironment (TME) is comprised of cellular and non-cellular components that exist within and around the tumor mass. The TME is highly dynamic and its importance in different stages of cancer progression has been well recognized. A growing body of evidence suggests that TME also plays pivotal roles in cancer treatment responses. TME is significantly remodeled upon cancer therapies, and such change either enhances the responses or induces drug resistance. Given the importance of TME in tumor progression and therapy resistance, strategies that remodel TME to improve therapeutic responses are under developing. In this review, we provide an overview of the essential components in TME and the remodeling of TME in response to anti-cancer treatments. We also summarize the strategies that aim to enhance therapeutic efficacy by modulating TME.

关键词： tumor microenvironment     therapy response     treatment resistance    

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Immunosuppressive tumor microenvironment contributes to tumor progression in diffuse large B-cell lymphoma

《医学前沿（英文）》 2023年 第17卷 第4期   页码 699-713 doi: 10.1007/s11684-022-0972-8

摘要： Anti-CD19 chimeric antigen receptor (CAR)-T cell therapy has achieved 40%–50% long-term complete response in relapsed or refractory diffuse large B-cell lymphoma (DLBCL) patients. However, the underlying mechanism of alterations in the tumor microenvironments resulting in CAR-T cell therapy failure needs further investigation. A multi-center phase I/II trial of anti-CD19 CD28z CAR-T (FKC876, ChiCTR1800019661) was conducted. Among 22 evaluable DLBCL patients, seven achieved complete remission, 10 experienced partial remissions, while four had stable disease by day 29. Single-cell RNA sequencing results were obtained from core needle biopsy tumor samples collected from long-term complete remission and early-progressed patients, and compared at different stages of treatment. M2-subtype macrophages were significantly involved in both in vivo and in vitro anti-tumor functions of CAR-T cells, leading to CAR-T cell therapy failure and disease progression in DLBCL. Immunosuppressive tumor microenvironments persisted before CAR-T cell therapy, during both cell expansion and disease progression, which could not be altered by infiltrating CAR-T cells. Aberrant metabolism profile of M2-subtype macrophages and those of dysfunctional T cells also contributed to the immunosuppressive tumor microenvironments. Thus, our findings provided a clinical rationale for targeting tumor microenvironments and reprogramming immune cell metabolism as effective therapeutic strategies to prevent lymphoma relapse in future designs of CAR-T cell therapy.

关键词： anti-CD19 chimeric antigen receptor T     immunotherapy     diffuse large B cell lymphoma     tumor microenvironment     tumor-associated macrophage     metabolism    

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Progress in tumor vascular normalization for anticancer therapy: challenges and perspectives

null

《医学前沿（英文）》 2012年 第6卷 第1期   页码 67-78 doi: 10.1007/s11684-012-0176-8

摘要：

Antitumor angiogenic therapy has been shown promising in the treatment of several advanced cancers since the approval of the first antiangiogenic drug Avastin in 2004. Although the current antiangiogenic drugs reduce the density of tumor blood vessels and result in tumor shrinkage at the early stage of treatment, recent studies have shown that antiangiogenic therapy has transient and insufficient efficacy, resulting in tumor recurrence in patients after several months of treatment. Blockage of blood and oxygen supplies creates a hypoxic and acidic microenvironment in the tumor tissues, which fosters tumor cells to become more aggressive and metastatic. In 2001, Jain proposed tumor vascular normalization as an alternative approach to treating cancers based on the pioneering work on tumor blood vessels by several other researchers. At present, normalizing the disorganized tumor vasculature, rather than disrupting or blocking them, has emerged as a new option for anticancer therapy. Preclinical and clinical data have shown that tumor vascular normalization using monoclonal antibodies, proteins, peptides, small molecules, and pericytes resulted in decreased tumor size and reduced metastasis. However, current tumor vascular normalizing drugs display moderate anticancer efficacy. Accumulated data have shown that a variety of vasculogenic/angiogenic tumor cells and genes play important roles in tumor neovascularization, growth, and metastasis. Therefore, multiple-targeting of vasculogenic tumor cells and genes may improve the efficacy of tumor vascular normalization. To this end, the combination of antiangiogenic drugs with tumor vascular normalizing therapeutics, as well as the integration of Western medicine with traditional Chinese medicine, may provide a good opportunity for discovering novel tumor vascular normalizing drugs for an effective anticancer therapy.

关键词： angiogenesis     vasculogenesis     neovascularization     tumor     vasculature     normalization     traditional Chinese medicine    

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Natural killer cell lines in tumor immunotherapy

null

《医学前沿（英文）》 2012年 第6卷 第1期   页码 56-66 doi: 10.1007/s11684-012-0177-7

摘要：

Natural killer (NK) cells are considered to be critical players in anticancer immunity. However, cancers are able to develop mechanisms to escape NK cell attack or to induce defective NK cells. Current NK cell-based cancer immunotherapy is aimed at overcoming NK cell paralysis through several potential approaches, including activating autologous NK cells, expanding allogeneic NK cells, usage of stable allogeneic NK cell lines and genetically modifying fresh NK cells or NK cell lines. The stable allogeneic NK cell line approach is more practical for quality-control and large-scale production. Additionally, genetically modifying NK cell lines by increasing their expression of cytokines and engineering chimeric tumor antigen receptors could improve their specificity and cytotoxicity. In this review, NK cells in tumor immunotherapy are discussed, and a list of therapeutic NK cell lines currently undergoing preclinical and clinical trials of several kinds of tumors are reviewed.

关键词： natural killer cell     natural killer cell line     tumor immunotherapy     genetic modification    

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Nanovaccines for remodeling the suppressive tumor microenvironment: New horizons in cancer immunotherapy

Kai Shi, Matthew Haynes, Leaf Huang

《化学科学与工程前沿（英文）》 2017年 第11卷 第4期   页码 676-684 doi: 10.1007/s11705-017-1640-4

摘要： Despite limited successes in clinical development, therapeutic cancer vaccines have experienced resurgence in recent years due to an enhanced emphasis upon co-mitigating factors underlying immune response. Specifically, reversing the immune-suppressive effects of the tumor microenvironment, mediated by a variety of cellular and molecular signaling mechanisms, has become fundamental toward enhancing therapeutic efficacy. Therein, our lab has implemented various nano-vaccines based on the lipid-coated calcium phosphate platform for combined immunotherapy, in which antigenic, epitope-associated peptides as well as immune-suppression inhibitors can be co-delivered, often functioning through the same formulation. In probing the mechanism of action of such systems and , an improved effect synergy can be elucidated, inspiring future preclinical efforts and hope for clinical success.

关键词： vaccine     nanoparticle     tumor     immunotherapy     microenvironment    

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carmustine loaded natural extracellular matrix hydrogel for inhibition of glioblastoma recurrence after tumor

《化学科学与工程前沿（英文）》 2022年 第16卷 第4期   页码 536-545 doi: 10.1007/s11705-021-2067-5

摘要： Many scientific efforts have been made to penetrate the blood-brain barrier and target glioblastoma cells, but the outcomes have been limited. More attention should be given to local inhibition of recurrence after glioblastoma resection to meet real medical needs. A biodegradable wafer containing the chemotherapeutics carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea, BCNU) was the only local drug delivery system approved for clinical glioblastoma treatment, but with a prolonged survival time of only two months and frequent side effects. In this study, to improve the sustained release and prolonged therapeutic effect of drugs for inhibiting tumor recurrence after tumor resection, both free BCNU and BCNU- poly (lactic-co-glycolic acid) (the ratio of lactic acid groups to glycolic acid groups is 75/25) nanoparticles were simultaneously loaded into natural extracellular matrix hydrogel from pigskin to prepare BCNU gels. The hydrogel was injected into the resection cavity of a glioblastoma tumor immediately after tumor removal in a fully characterized resection rat model. Free drugs were released instantly to kill the residual tumor cells, while drugs in nanoparticles were continuously released to achieve a continuous and effective inhibition of the residual tumor cells for 30 days. These combined actions effectively restricted tumor growth in rats. Thus, this strategy of local drug implantation and delivery may provide a reliable method to inhibit the recurrence of glioblastoma after tumor resection in vivo.

关键词： BCNU     glioblastoma recurrence     tumor resection     nanoparticles     hydrogel    

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Bacteria-mediated tumor-targeted delivery of tumstatin (54-132) significantly suppresses tumor growth

《医学前沿（英文）》 2022年 第16卷 第6期   页码 873-882 doi: 10.1007/s11684-022-0925-2

摘要： Tumor growth is an angiogenesis-dependent process and accompanied by the formation of hypoxic areas. Tumstatin is a tumor-specific angiogenesis inhibitor that suppresses the proliferation and induces the apoptosis of tumorous vascular endothelial cells. VNP20009, an attenuated Salmonella typhimurium strain, preferentially accumulates in the hypoxic areas of solid tumors. In this study, a novel Salmonella-mediated targeted expression system of tumstatin (VNP-Tum5) was developed under the control of the hypoxia-induced J23100 promoter to obtain anti-tumor efficacy in mice. Treatment with VNP-Tum5 effectively suppressed tumor growth and prolonged survival in the mouse model of B16F10 melanoma. VNP-Tum5 exhibited a higher efficacy in inhibiting the proliferation and inducing the necrosis and apoptosis of B16F10 cells in vitro and in vivo compared with VNP (control). VNP-Tum5 significantly inhibited the proliferation and migration of mouse umbilical vascular endothelial cells to impede angiogenesis. VNP-Tum5 downregulated the expression of anti-vascular endothelial growth factor A, platelet endothelial cell adhesion molecule-1, phosphorylated phosphoinositide 3 kinase, and phosphorylated protein kinase B and upregulated the expression of cleaved-caspase 3 in tumor tissues. This study is the first to use tumstatin-transformed VNP20009 as a tumor-targeted system for treatment of melanoma by combining anti-tumor and anti-angiogenic effects.

关键词： Salmonella VNP20009     tumstatin     B16F10     melanoma     apoptosis     angiogenesis    

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Endostatin specifically targets both tumor blood vessels and lymphatic vessels

Wei Zhuo, Yang Chen, Xiaomin Song, Yongzhang Luo

《医学前沿（英文）》 2011年 第5卷 第4期   页码 336-340 doi: 10.1007/s11684-011-0163-5

摘要： Endostatin, a 20 kDa C-terminal fragment of collagen XVIII, was first identified as a potent angiogenic inhibitor. The anti-angiogenic function of endostatin has been well documented during the past decade. Recently, several studies demonstrated that endostatin also inhibits tumor lymphangiogenesis and lymphatic metastasis. However, the exact mechanism that endostatin executes its anti-angiogenic and anti-lymphangiogenic functions remains elusive. In the current mini-review, we briefly summarize recent novel findings, including the functions of endostatin targeting not only angiogenesis but also lymphangiogenesis, and the underlying mechanism by which endostatin internalization regulates its biological functions.

关键词： endostatin     angiogenesis     lymphangiogenesis     nystatin     internalization     tumor    

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Gene expression disparity in giant cell tumor of bone

Xiaohua PAN, Shuhua YANG, Deming XIAO, Yong DAI, Lili REN

《医学前沿（英文）》 2009年 第3卷 第1期   页码 49-56 doi: 10.1007/s11684-009-0012-y

摘要： The aim of this paper was to study the differential gene expression of giant cell tumor of bone (GCTB) by gene chip technology. Total RNA of 8 fresh GCTB specimens (Jaffe I∶6 cases, II∶1 case, III∶1 case; Campanacci I∶6 cases, II∶1 case, III∶1 case; Enneking Staging G T M : 5 cases, G T M : 2 cases, G T M : 1 case) and 4 normal bony callus specimens (the control group) were extracted and purified to get mRNA and then reverse transcribed to complementary DNA, respectively. Microarray screening with a set of 8064 human cDNA genes was conducted to analyze the difference among the samples and the control. The hybridization signals were scanned. The gene expression disparity between the GCTB samples and normal bony callus was significantly different ( <0.01), and the disparity of over 5-fold was found in 47 genes in the GCTB specimens, with 25 genes up-regulated and 22 down-regulated including the extracellular matrix and transforming-related genes, oncogene and its homolog genes, cytokine and its receptor genes. Specific gene spectrum associated with GCTB can be identified by cDNA microarray, which will be the foundation of progressive etiology elucidation, diagnosis and treatment of GCTB.

关键词： giant cell tumor of bone     gene     microarray     cDNA    

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Identification of cancer stem cells provides novel tumor models for drug discovery

null

《医学前沿（英文）》 2012年 第6卷 第2期   页码 112-121 doi: 10.1007/s11684-012-0199-1

摘要：

Cancer stem cells (CSCs) have received considerable attention from the research community since they were first reported in human acute myeloid leukemia 15 years ago. Accumulating evidence suggests that CSCs are responsible for tumor initiation and progression, drug resistance, and metastasis in both liquid and solid tumors. These findings lead to the development of novel compounds targeting CSC populations that is becoming increasingly important for eradicating CSCs in heterogeneous tumor masses and to cure the cancer. Since 2003, we have participated in CSC studies and encountered crucial early events in the field. This article reviews the history of CSC biology, clarifies the term and its definition, and further addresses the issue of how to utilize CSCs in therapeutic target discovery and drug development based on our substantial experience.

关键词： cancer stem cell     tumor model     drug discovery    

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-1BBL expressed by eukaryotic cells activates immune cells and suppresses the progression of murine tumor

Hui QIU, Hui ZHANG, Zuohua FENG

《医学前沿（英文）》 2009年 第3卷 第1期   页码 20-25 doi: 10.1007/s11684-009-0006-9

摘要： The interaction by co-stimulatory molecules 4-1BB and 4-1BB ligand (4-1BBL) plays an important role in the activation, proliferation and differentiation of T lymphocytes. The function of 4-1BB/4-1BBL expressed by the immune cells has been the focus for many tumor immunotherapy efforts. In this study, 4-1BBL was expressed in non-immune cells and non-tumor cells, and the role of 4-1BBL in lymphocyte activation and tumor suppression was investigated. The plasmid p4-1BBL containing the full length of mouse 4-1BBL cDNA sequence was constructed, and the plasmid was transfected into baby hamster kidney (BHK) cells and murine muscle cells by means of lipofectin-mediated or naked plasmid DNA injection into the muscle directly. The study demonstrated that the molecule 4-1BBL expressed by BHK cells could enhance the proliferation and cytotoxicity of lymphocytes, and it could increase the expression level of IL-2 and IFN-γ. The treatment with plasmid p4-1BBL revealed that the number of CD8 T cells in the peri-tumoral tissue increased markedly, and the growth rate of the tumor was significantly lower than that of control group. These findings suggest that expression of 4-1BBL by normal cells in the tumor microenvironment can enhance the proliferation and other functions of T lymphocytes. This therapeutic method may provide a promising approach for tumor immunotherapy.

关键词： 4-1BB ligand     tumor immunotherapy     tumor microenvironment    

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标题 作者 时间 类型 操作

Effect of atorvastatin on tumor growth and metastasis in a breast cancer cell xenograft model and its

Liu LIU MD, PhD, Yaogui NING MM, Chen CHEN MD, Daowen WANG MD, PhD,

期刊论文

Patient-derived xenograft platform of OSCC: a renewable human bio-bank for preclinical cancer research

null

期刊论文

Heterogeneity of the tumor immune microenvironment and clinical interventions

期刊论文

Proteins moonlighting in tumor metabolism and epigenetics

Lei Lv, Qunying Lei

期刊论文

Complex interplay between tumor microenvironment and cancer therapy

null

期刊论文

Immunosuppressive tumor microenvironment contributes to tumor progression in diffuse large B-cell lymphoma

期刊论文

Progress in tumor vascular normalization for anticancer therapy: challenges and perspectives

null

期刊论文

Natural killer cell lines in tumor immunotherapy

null

期刊论文

Nanovaccines for remodeling the suppressive tumor microenvironment: New horizons in cancer immunotherapy

Kai Shi, Matthew Haynes, Leaf Huang

期刊论文

carmustine loaded natural extracellular matrix hydrogel for inhibition of glioblastoma recurrence after tumor

期刊论文

Bacteria-mediated tumor-targeted delivery of tumstatin (54-132) significantly suppresses tumor growth

期刊论文

Endostatin specifically targets both tumor blood vessels and lymphatic vessels

Wei Zhuo, Yang Chen, Xiaomin Song, Yongzhang Luo

期刊论文

Gene expression disparity in giant cell tumor of bone

Xiaohua PAN, Shuhua YANG, Deming XIAO, Yong DAI, Lili REN

期刊论文

Identification of cancer stem cells provides novel tumor models for drug discovery

null

期刊论文

-1BBL expressed by eukaryotic cells activates immune cells and suppresses the progression of murine tumor

Hui QIU, Hui ZHANG, Zuohua FENG

期刊论文