基因组学在肺癌研究中从基础向临床应用的转化

随着人类基因组计划的完成,应用基因组计划的研究成果探讨肿瘤发生、发展、侵袭转移的分子机理,开发抗肿瘤分子靶向药物,已成为当今肿瘤学领域的前沿和重点课题。第十一届世界肺癌大会有关本领域的研究内容较多,除应用基因芯片研究肺癌癌变、发生、发展的分子机制,以及肺癌的分子病因学外,更多的研究关注应用基因芯片技术获得的肺癌基因表达谱(基于肺癌细胞中癌基因或抑癌基因的变化或新找到的基因)如何向临床应用转化的问题,包括肺癌的分子诊断、早期发现、特异性标志物的筛选、转移的早期诊断、化疗疗效和预后的判断,以及化疗耐药机制的研…     

The role of the IGF system in cancer: from basic to clinical studies and clinical applications

Insulin-like growth factors (IGFs) are important mediators of growth, development, and survival, are synthesized by almost any tissue in the body, and their action is modulated by a complex network of molecules, including binding proteins, proteases and receptors, which all comprise the IGF system. Evidence from in vitro and animal studies suggests that overexpression of IGFs by cancer cells and/or the nearby stroma as well as the type IGF-I receptor by the cancer cells may play a significant role in establishing a transformed phenotype in an increasing number of malignancies. More specifically, IGFs may promote cell cycle progression and inhibition of apoptosis either by directly associating with other growth factors or indirectly by interacting with other molecular systems which have an established role in carcinogenesis and cancer promotion, such as the steroid hormones and integrins. In addition, a growing number of epidemiologic studies suggest that increased serum levels of IGFs and/or altered levels of their binding proteins are associated with increased risk for developing several malignancies. These data indicate that IGF dysregulation should now be considered as an important independent factor for cancer risk, and a potential target for novel antineoplastic therapies and/or preventative strategies in high-risk groups.     

Interferon-beta gene therapy for cancer: basic research to clinical application

Interferon-beta gene therapy for cancer is the first such protocol developed in Japan. Here we describe the development process of our interferon-beta gene therapy from basic research to clinical application. Interestingly, the biological and biochemical characteristics of interferon-beta gene therapy through transfer of the interferon-beta gene into tumor cells by means of cationic liposomes differed from those of conventional interferon-beta protein therapy. Interferon-beta gene transfer could induce apoptosis in interferon-beta protein-resistant tumor cells, such as glioma, melanoma, and renal cell carcinoma. Induction of apoptosis was related to the level of intracellular mRNA of interferon-beta, prolongation of the phosphorylation time of molecules in the interferon-beta signal transduction pathway, such as JAK1, Trk2, and STAT1, and activation of DNase gamma. In our preclinical study we developed lyophilized cationic liposomes containing interferon-beta gene (gene drug) for clinical use and confirmed their safety. Thereafter, we performed a pilot clinical trial in patients with malignant glioma and confirmed the safety and effectiveness of this interferon-beta gene therapy. In this review we also comment on the status of gene therapy regulation in Japan. Interferon-beta gene therapy is expected to become widely available for clinical use in cancer patients, and this new strategy might be extended to molecular targeting therapy, or used in combination with cell therapy or other therapies.     

乳腺癌干细胞研究进展:从基础到临床

干细胞是一类具有自我更新和多向分化潜能的原始细胞,在一定条件下,可以分化成多种不同功能的细胞.基于干细胞的特性,在恶性肿瘤研究中提出了肿瘤干细胞理论,解释了肿瘤的发生、发展、复发和转移等生物学行为.乳腺癌干细胞是实体肿瘤干细胞研究进展较快的一个领域,但是乳腺癌干细胞理论及其如何应用于临床治疗尚存在较多问题.本文就这些问题及其展望进行综述.     

PI3K/Akt/mTOR signaling pathway in cancer stem cells: from basic research to clinical application

Cancer stem cells (CSCs) are a subpopulation of tumor cells that possess unique self-renewal activity and mediate tumor initiation and propagation. The PI3K/Akt/mTOR signaling pathway can be considered as a master regulator for cancer. More and more recent studies have shown the links between PI3K/Akt/mTOR signaling pathway and CSC biology. Herein, we provide a comprehensive review on the role of signaling components upstream and downstream of PI3K/Akt/mTOR signaling in CSC. In addition, we also summarize various classes of small molecule inhibitors of PI3K/Akt/mTOR signaling pathway and their clinical potential in CSC. Overall, the current available data suggest that the PI3K/Akt/mTOR signaling pathway could be a promising target for development of CSC-target drugs.     

Papillomaviruses and skin cancer in Africa

Although it was suggested long ago that certain epithelial cancers preceded by papillomas might be caused by viruses, the first proof that papillomaviruses were associated with cancer dates from the work on rabbits in 1934 by Shope and Rose. In the 1970s, the introduction of the blot hybridization technique enabled Orth and his co-workers at the Institut Pasteur, Paris, to demonstrate the presence in man of the DNA of human papillomavirus type 5 (HPV-5) in cancers following Lutz-Lewandovsky epidermodysplasia verruciformis. Some years later, it was possible to demonstrate the presence of the same HPV-5 DNA in the skin cancer of an immunosuppressed recipient of a renal transplant. The number of potentially oncogenic papillomaviruses has recently been increased by the demonstration at the Institut Pasteur of the presence of the DNAs of HPV-8 and HPV-14 in the skin cancers of patients with epidermodysplasia verruciformis. In recent years, an association has been demonstrated between HPV-6, -10, -11, -16, and -18 with verrucous cancers of the skin and mucous membranes, Bowenoid papules, Bowenoid skin diseases and cervical cancer. Such cancers of the skin and mucous membranes are usually treated by surgery, but it has been shown that oral administration of retinoids (synthetic derivatives of vitamin A) or the use of leucocyte interferon intralesionally are effective in cancers in situ following epidermodysplasia verruciformis.     

The role of angiogenesis in malignant pleural effusion: from basic research to clinical application

Malignant pleural effusion (MPE) is associated with advanced stages of various malignant diseases, especially lung cancer, and is a poor prognostic indicator in these patients. However, the management of MPE remains palliative. A better understanding of the pathogenesis of MPE may lead to the development of new and more effective therapeutic options. Here, we shed light on recent advances in the mechanisms of MPE formation and provide an overview of current targeted therapies for the vascular endothelial growth factor pathway. We also retrospectively enrolled 19 patients with lung adenocarcinoma from the West China Hospital to analyze the efficacy of bevacizumab for MPE using different routes of administration.     

Papillomaviruses in non-melanoma skin cancer: epidemiological aspects

Worldwide, non-melanoma skin cancers (NMSCs), which include squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), are the most commonly diagnosed cancers among Caucasians. It is well established that ultraviolet radiation (UVR) plays a central role in the development of these cancers, and more recently, a role for specific genetic mutations in the pathogenesis of BCC has been identified. The possibility that certain types of HPV, either alone or in conjunction with UVR, may play a role in the pathogenesis of these cancers is suggested by several lines of evidence reviewed below.*9 @2depidemiology / non-melanoma skin cancer / papillomavirus Copyright 2000 Academic Press.     

Telomerase and telomeres: from basic biology to cancer treatment

The limited capacity to divide is one of the major differences between normal somatic cells and cancerous cells. This 'finite life span' of somatic cells is closely linked to loss of telomeric DNA at telomeres, the 'chromosome caps' consisting of repeated (TTAGGG) sequences. In more than 85% of advanced cancers, this telomeric attrition is compensated by telomerase, 'the immortality enzyme', implying that telomerase inhibition may restore mortality in tumor cells.

This review discusses the progress in research on the structure and function of telomeres and the telomerase holoenzyme. In addition, new developments in telomere/telomerase targeting compounds such as antisense oligonucleotides and G-quadruplex stabilizing substances, but also new telomerase expression-related strategies such as telomerase promoter-driven suicide gene therapy and telomerase immunotherapy will be presented. It will be discussed how these data can be implemented in telomerase-directed therapies.     

Retinoids and breast cancer: From basic studies to the clinic and back again

All-trans retinoic acid (ATRA) is the most important active metabolite of vitamin A controlling segmentation in the developing organism and the homeostasis of various tissues in the adult. ATRA as well as natural and synthetic derivatives, collectively known as retinoids, are also promising agents in the treatment and chemoprevention of different types of neoplasia including breast cancer. The major aim of the present article is to review the basic knowledge acquired on the anti-tumor activity of classic retinoids, like ATRA, in mammary tumors, focusing on the underlying cellular and molecular mechanisms and the determinants of retinoid sensitivity/resistance. In the first part, an analysis of the large number of pre-clinical studies available is provided, stressing the point that this has resulted in a limited number of clinical trials. This is followed by an overview of the knowledge acquired on the role played by the retinoid nuclear receptors in the anti-tumor responses triggered by retinoids. The body of the article emphasizes the potential of ATRA and derivatives in modulating and in being influenced by some of the most relevant cellular pathways involved in the growth and progression of breast cancer. We review the studies centering on the cross-talk between retinoids and some of the growth-factor pathways which control the homeostasis of the mammary tumor cell. In addition, we consider the cross-talk with relevant intra-cellular second messenger pathways. The information provided lays the foundation for the development of rational and retinoid-based therapeutic strategies to be used for the management of breast cancer.     

Hyperthermia, cisplatin and radiation trimodality treatment: a promising cancer treatment? A review from preclinical studies to clinical application.

This review discusses available clinical and experimental data and the underlying mechanisms involved in trimodality treatment consisting of hyperthermia, cisplatin and radiotherapy. The results of phase I/II clinical trials show that trimodality treatment is effective and feasible in various cancer types and sites with tolerable toxicity. Based on these results, phase III trials have been launched to investigate whether significant differences in treatment outcome exist between trimodality and standard treatment. In view of the clinical interest, it is surprising to find so few preclinical studies on trimodality treatment. Although little information is available on the doses of the modalities and the treatment sequence resulting in the largest degree of synergistic interaction, the results from in vivo and in vitro preclinical studies support the use of trimodality treatment for cancer patients. Animal studies show an improvement in treatment outcome after trimodality treatment compared with mono- and bimodality treatment. Studies in different human tumour cell lines show that a synergistic interaction can be obtained between hyperthermia, cisplatin and radiation and that this interaction is more likely to occur in cell lines which are more sensitive to cisplatin.     

Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis

During the past 20 years, several types of human papillomaviruses (HPVs) have been identified that cause specific types of cancers. The etiology of cancer of the cervix has been linked to several types of HPV, with a high preponderance of HPV16. The role of these virus infections has been established 1) by the regular presence of HPV DNA in the respective tumor biopsy specimens, 2) by the demonstration of viral oncogene expression (E6 and E7) in tumor material, 3) by the identification of transforming properties of these genes, 4) by the requirement for E6 and E7 expression for maintaining the malignant phenotype of cervical carcinoma cell lines, 5) by the interaction of viral oncoproteins with growth-regulating host-cell proteins, and 6) by epidemiologic studies pointing to these HPV infections as the major risk factor for cervical cancer development. In addition to cancer of the cervix, a major proportion of anal, perianal, vulvar, and penile cancers appears to be linked to the same HPV infections. In addition, close to 20% of oropharyngeal cancers contain DNA from the same types of HPV. Recent evidence also points to a possible role of other HPV infections in squamous cell carcinomas of the skin. This review covers recent developments in understanding molecular mechanisms of HPV carcinogenesis, mainly discussing functions of viral oncoproteins and the regulation of viral oncogenes by host-cell factors. Modifications in host-cell genes, most likely engaged in the control of HPV gene expression in proliferating cells, emerge as important events in HPV-mediated carcinogenesis.     

Anti-PD-L1/PD-1 immune therapies in ovarian cancer: basic mechanism and future clinical application

Tumor immune therapy, especially anti-programmed cell death ligand-1/programmed cell death-1 (PD-L1/PD-1) treatment, is currently the focus of substantial attention. Ovarian cancer is the leading cause of mortality from gynecological malignancies, and novel treatment modalities, including immune therapy, are needed. However, a basic understanding of tumor immunity associated with the PD-L1/PD-1 signal has only recently emerged. In this review, we first discuss the importance of local tumor immunity, which affects the clinical outcome of ovarian cancer. We subsequently provide an overview of the basic findings regarding how the PD-L1/PD-1 signal influences local tumor immunity in ovarian cancer. Finally, we discuss what is needed to apply immune therapy in future clinical medicine.     

Melatonin: from basic research to cancer treatment clinics.

Melatonin, the chief secretory product of the pineal gland, is a direct free radical scavenger, an indirect antioxidant, as well as an important immunomodulatory agent. In both in vitro and in vivo investigations, melatonin protected healthy cells from radiation-induced and chemotherapeutic drug-induced toxicity. Furthermore, several clinical studies have demonstrated the potential of melatonin, either alone or in combination with traditional therapy, to yield a favorable efficacy to toxicity ratio in the treatment of human cancers. This study reviews the literature from laboratory investigations that document the antioxidant and oncostatic actions of melatonin and summarizes the evidence regarding the potential use of melatonin in cancer treatment. This study also provides rationale for the design of larger translational research-based clinical trials.     

PCA3: from basic molecular science to the clinical lab

Prostate cancer is the second leading cause of cancer deaths in men in the United States. Use of the serum prostate specific antigen (PSA) test to screen men for prostate cancer since the late 1980s has improved the early detection of prostate cancer, however low specificity of the test translates to numerous false positive results and many unnecessary biopsies. New biomarkers to aid in prostate cancer diagnosis are emerging and prostate cancer gene 3 (PCA3) is one such marker. PCA3 is a noncoding RNA that is highly over-expressed in prostate cancer tissue compared to benign tissue. A non-invasive test for PCA3 was developed using whole urine collected after a digital rectal exam (DRE). Numerous clinical studies have demonstrated the utility of PCA3 for the diagnosis of prostate cancer and some studies suggest that PCA3 may also have prognostic value. The use of PCA3 in combination with serum PSA and other clinical information enhances the diagnostic accuracy of prostate cancer detection and will enable physicians to make more informed decisions with patients at risk for prostate cancer.