Antiangiogenic and radiotherapy for cancer treatment

Tumor growth and progression depends on tumor angiogenesis, the growth of tumor blood vessels, therefore, targeting tumor angiogenesis is a very promising approach for controlling tumor growth and/or causing regression. Tumor blood vessels have been recognized as a critical component of radiation response to the point of being independent of tumor oxygenation during radiation. An anti-angiogenic approach has been considered less likely to develop drug resistance. But recent findings suggest that anti-angiogenesis causes hypoxia that selects tumor cells (due to genetic instability) that are less dependent on blood supply and leads to drug resistance. The approach of combination of anti-angiogenesis with ionizing radiation by targeting both endothelial and tumor cells should minimize this possibility. The combination may produce a synergistic anti-tumor effect.     

Chemoimmunotherapy: reengineering tumor immunity

Cancer chemotherapy drugs have long been considered immune suppressive. However, more recent data indicate that some cytotoxic drugs effectively treat cancer in part by facilitating an immune response to the tumor when given at the standard dose and schedule. These drugs induce a form of tumor cell death that is immunologically active, thereby inducing an adaptive immune response specific for the tumor. In addition, cancer chemotherapy drugs can promote tumor immunity through ancillary and largely unappreciated immunologic effects on both the malignant and normal host cells present within the tumor microenvironment. These more subtle immunomodulatory effects are dependent on the drug itself, its dose, and its schedule in relation to an immune-based intervention. The recent approvals of two new immune-based therapies for prostate cancer and melanoma herald a new era in cancer treatment and have led to heightened interest in immunotherapy as a valid approach to cancer treatment. A detailed understanding of the cellular and molecular basis of interactions between chemotherapy drugs and the immune system is essential for devising the optimal strategy for integrating new immune-based therapies into the standard of care for various cancers, resulting in the greatest long-term clinical benefit for cancer patients.     

Cancer vaccine development: on the way to break immune tolerance to malignant cells

Exploiting a naturally occurring defense system, the immunotherapeutic approach embodies an ideal nontoxic treatment for cancer. Despite the evidence that immune effectors can play a significant role in controlling tumor growth either in natural conditions or in response to therapeutic manipulation, the cascade of molecular events leading to tumor rejection by the immune system remains to be fully elucidated. Nevertheless, some recent tumor immunology advancements might drastically change the way to design the next generation of cancer vaccines, hopefully improving the effectiveness of this therapeutic approach. In the present work, we will focus on three main areas of particular interest for the development of novel vaccination strategies: (a) cellular or molecular mechanisms of immune tolerance to malignant cells; (b) synergism between innate and adaptive immune response; (c) tumor-immune system interactions within the tumor microenvironment.     

Autoantibody biomarkers in the detection of cancer

By definition, tumor biomarkers are selective molecules that can distinguish between patients with cancer and controls. Serum tumor markers have been the most widely used approach for cancer detection. However, the limitations of these markers, which are based on the measurement of tumor antigens, preclude their general use in cancer screening and diagnosis. Here we give an overview of recent cancer biomarker developments based on the detection of autoantibodies produced against tumor antigens in patients' sera. This new detection method can measure the autoantibodies for a spectrum of tumor antigens in a single assay, with sensitivity and specificity exceeding those obtained using the conventional antigen determination method. Autoantibodies against serum cancer biomarkers offer a novel technology for cancer detection.     

Tumor-associated fibroblasts (part I): Active stromal participants in tumor development and progression?

Phenotypic and functional characteristics of tumor associated fibroblasts (TAF) in contrast to normal fibroblasts are reviewed in this first synopsis (part I). Terms as tumor stroma, desmo-plasia, TAF, myofibroblast, and fetal-type fibroblast are defined, and experimental systems to study heterologous cell interactions are presented. While we only start to gather information on the genotype of TAF, a broad range of data deals with the expression profile of these cells, covering e.g. ECM and ECM-modulating molecules, growth factors and cytokines. Summarizing the recent state of knowledge indicates that TAF provide sources for tumor diagnosis and therapy, that have to be further defined in an organ-specific approach in terms of the functional impact on the tumor cell and its environment (see part II).     

Immune based therapies in cancer

Immunotherapy of cancer has become a more promising approach in the past decade. Developments in both basic immunology and tumor biology have increased our knowledge of the interactions between the tumor cells and the immune system. The molecular identification of tumor-associated antigens and understanding of immunological pathways have cleared the way for development of different strategies for anti-tumor vaccines. The success of any cancer vaccine relies on the induction of an effective tumor-specific immune response to break tolerance and to elicit a long lasting anti-tumor immunity. It is also increasingly clear that the interactions of host-tumor are quite complicated leading to tumor escape mechanisms, which add another level of difficulty to this interaction. This review will summarize the recent developments in tumor immunotherapy as well as the clinical trials addressing novel immunotherapeutic approaches to cancer.     

肿瘤生物治疗的新方法——减毒鼠伤寒沙门菌的应用

减毒鼠伤寒沙门菌由于具有肿瘤靶向性,能在肿瘤组织中复制并产生抗肿瘤效果的能力,使肿瘤治疗获得了新契机。减毒鼠伤寒沙门菌作为细菌载体使目的基因在肿瘤组织内特异表达,表现出良好治疗效果。近期研究发现,单独使用突变后的菌株A1-R在裸鼠模型上治疗乳腺癌和前列腺癌分别可达到40％和50％的治愈率;在小鼠肿瘤转移模型中也展现出良好的治疗效果。鼠伤寒沙门菌作为肿瘤治疗制剂有诱人的前景。本文就这些研究的最新进展做一综述。     

Potential adenovirus-mediated gene therapy of glioma cancer

Malignant gliomas are typically characterized by rapid cell proliferation and a marked propensity to invade and damage surrounding tissues. They are the main brain tumors notoriously resistant to currently available therapies, since they fail to undergo apoptosis upon anticancer treatments. With recent advances in neuroscience and improved understanding of the molecular mechanisms of invasive migration, gene therapy provides a new strategy for treating glioma cancer. Brain tumor gene therapy using viral vectors and stem cells has shown promise in animal model and human patient studies. Here, we review recent studies on engineering adenoviral vectors that can be used as therapy for brain tumors. The new findings presented in this study are essential for the further exploration of this cancer and they represent an approach for developing a newer and more effective therapeutic approach in the clinical treatment of human glioma cancer.     

Inflammation: A driving force speeds cancer metastasis

It has been increasingly recognized that tumor microenvironment plays an important role in carcinogenesis. Inflammatory component is present and contributes to tumor proliferation, angiogenesis, metastasis, and resistance to hormonal and chemotherapy. This review highlights the role of inflammation in the tumor metastasis. We focus on the function of proinflammatory factors, particularly cytokines during tumor metastasis. Understanding of the mechanisms by which inflammation contributes to metastasis will lead to innovative approach for treating cancer.

How tumor spreads remains an enigma and has received great attention in recent years, as metastasis is the major cause of cancer mortality. The complex and highly selective metastatic cascade not only depends on the intrinsic properties of tumor cells but also the microenvironment that they derive from. An inflammatory milieu consisting of infiltrated immune cells and their secretory cytokines, chemokines, and growth factors contribute significantly to the invasive and metastatic traits of cancer cells. Here, we review new insights into the molecular pathways that link inflammation in the tumor microenvironment to metastasis.     

Therapeutic Differentiation of Tumor-derived Insulin-producing Cells Selected for Resistance to Diabetogenic Drugs

Differentiation therapy has been proposed as a new approach to selectively engage the process of tumor cell differentiation during chemotherapy of cancer. Our recent in vitro study suggests that such an approach can be extended and utilized for the selection of tumor-derived insulin-producing cells for transplantation. Repeated treatment with streptozotocin selected toxin resistant subpopulation of insulin producing tumor RINmS cells, characterized increased level of insulin content and secretion. In the present study RINmS cells were found to have higher glucose sensitivity and insulin response compared with parental RINm cells. In addition, compounds known to induce elevated level of cAMP beta-cells, such as isobutyl methyl xanthine, and forskolin, potentiated glucose-induced insulin secretion of RINmS, but had no effect on the naive parental RINm cells. These experiments suggest that differentiation therapy can be utilized for engineering insulin producing cells with improved defense and secretory mechanisms.     

Mutation analysis of large tumor suppressor genes LATS1 and LATS2 supports a tumor suppressor role in human cancer

In recent years, human cancer genome projects provide unprecedented opportunities for the discovery of cancer genes and signaling pathways that contribute to tumor development. While numerous gene mutations can be identified from each cancer genome, what these mutations mean for cancer is a challenging question to address, especially for those from less understood putative new cancer genes. As a powerful approach, in silico bioinformatics analysis could efficiently sort out mutations that are predicted to damage gene function. Such an analysis of human large tumor suppressor genes, LATS1 and LATS2, has been carried out and the results support a role of hLATS1//2 as negative growth regulators and tumor suppressors.     

Potential biochemical therapy of glioma cancer

Glioma is a highly invasive, rapidly spreading form of brain cancer that is resistant to surgical and medical treatment. The recent progresses made in intracellular and ion channels of glioma cells provide a potential new approach for biochemical therapy of brain tumor. In this paper, we reviewed clinical data on chemotherapy by temozolomide and results from new studies on voltage-gated potassium channels, large-conductance Ca(2+)-activated K(+) channels, volume-activated chloride channels, glioma-specific chloride channel and their modulators. These new findings may represent future directions for brain tumor studies and treatment.     

Immunoelectron microscope localization of bromodeoxyuridine incorporated into DNA of Ehrlich tumor cell nucleoli

The distribution of DNA within the nucleolus of Ehrlich tumor cells has been investigated by means of a recent immunocytochemical approach involving an electron microscopic detection of incorporated 5-bromodeoxyuridine (BUdR) into DNA by an anti-BUdR monoclonal antibody. An immunogold method has been performed on ultrathin sections of cells embedded in Lowicryl K4M. In the nucleolus, gold particles are essentially found over the perinucleolar chromatin adn over its intranucleolar invaginations which are connected with the fibrillar centers. In addition, a few gold particles are also observed in the fibrillar centers, preferentially toward their peripheral regions. In contrast, the dense fibrillar component is completely devoid of labeling. The results are discussed in the context of other recent findings concerning the functional organization of the nucleolus.     

Spinal metastases: From conventional fractionated radiotherapy to single-dose SBRT

AimTo review the recent evolution of spine SBRT with emphasis on single dose treatments.BackgroundRadiation treatment of spine metastases represents a challenging problem in clinical oncology, because of the high risk of inflicting damage to the spinal cord. While conventional fractionated radiation therapy still constitutes the most commonly used modality for palliative treatment, notwithstanding its efficacy in terms of palliation of pain, local tumor control has been approximately 60%. This limited effectiveness is due to previous lack of technology to precisely target the tumor while avoiding the radiosensitive spinal cord, which constitutes a dose-limiting barrier to tumor cure.Materials and methodsA thorough review of the available literature on spine SBRT has been carried out and critically assessed.ResultsStereotactic body radiotherapy (SBRT) emerges as an alternative, non-invasive high-precision approach, which allows escalation of tumor dose, while effectively sparing adjacent uninvolved organs at risk. Engaging technological advances, such as on-line Cone Beam Computed Tomography (CBCT), coupled with Dynamic Multi-Leaf Collimation (DMLC) and rapid intensity-modulated (IMRT) beam delivery, have promoted an interactive image-guided (IGRT) approach that precisely conforms treatment onto a defined target volume with a rapid dose fall-off to collateral non-target tissues, such as the spinal cord. Recent technological developments allow the use of the high-dose per fraction mode of hypofractionated SBRT for spinal oligometastatic cancer, even if only a few millimeters away from the tumor.ConclusionSingle-dose spine SBRT, now increasingly implemented, yields unprecedented outcomes of local tumor ablation and safety, provided that advanced technology is employed.     

Lymphokine activated killer cells

Various subpopulations of human leukocytes may be induced by lymphokines to exert cytotoxic activity. In man major histocompatibility complex non-restricted tumor cell lysis by interleukin-2 (IL-2) induced peripheral blood lymphocytes is attributed mainly to natural killer cells. These T cell receptor negative large granular lymphocytes are called lymphokine activated killer (LAK) cells. In order to explore the potential of LAK cells in tumor therapy, several clinical studies have been conducted, using IL-2 alone or in combination with ex vivo IL-2-activated peripheral blood lymphocytes. Objective responses have reproducibly been achieved only in renal cell carcinoma and malignant melanoma and were associated with considerable toxicity. In view of restricted efficacy and increasing doubts as to whether LAK cells indeed account for the in vivo observed responses, more recent strategies focus on tumor antigen specific cytotoxic T cells or tumor infiltrating lymphocytes. Successful translation of this approach into clinical practice, however, may be dependent on some basic problems of tumor immunology to be solved which were thought to be by-passed by the LAK cell approach.     

Analysis of a three-way race between tumor growth,a replication-competent virus and an immune response

Replication-competent viruses have the potential to overcome the delivery barrier in tumors that has plagued traditional gene-therapy approaches to cancer treatment. However, recent clinical data suggests that a cytokine-based immune response against the virus-infected tumor cells may severely limit the efficacy of the replication-competent approach. This paper generalizes our earlier spatial model to incorporate an immune response against the infected tumor cells. An approximate but accurate condition is derived for the virus—if uniformly injected throughout the tumor—to eradicate the tumor in the presence of the immune response. To validate the model using clinical data describing the temporal interaction of tumor necrosis factor and free virus in the plasma, we needed the immune response to be time-delayed and experience either saturated stimulation or second-order clearance. The resulting estimates of some unknown parameters provide some implications for the delivery of treatment.     

Cancer therapy

In recent years a growing recognition that molecularly-targeted therapies face formidable obstacles has revived interest in more generic tumor cell phenotypes that could be exploited for therapy. Two recent reports demonstrate that cancer cell survival is critically dependent on the activity of MTH1, a nucleotide pyrophosphatase that converts the oxidized nucleotides 8-oxo-dGTP and 2-OH-dATP to the corresponding monophosphates, thus preventing their incorporation into genomic DNA. Tumor cells frequently overexpress MTH1, probably because malignant transformation creates oxidative stress that renders the nucleotide pool highly vulnerable to oxidation. As a result, MTH1 inhibition in cancer cells results in accumulation and incorporation of 8-oxo-dGTP and 2-OH-dATP into DNA, leading to DNA damage and cell death. This toxic effect is highly cancer cell-specific, as MTH1 is generally dispensable for the survival of normal, untransformed cells. Importantly, MTH1 proves to be a “druggable” enzyme that can be inhibited both by an existing protein kinase inhibitor drug, crizotinib, and by novel compounds identified through screening. Inhibition of MTH1 leading to toxic accumulation of oxidized nucleotides specifically in tumor cells therefore represents an example of a “non-personalised” approach to cancer therapy.     

非肌层侵润性膀胱癌的治疗

膀胱癌是一种全球性疾病。在我国泌尿外科肿瘤中的发病率和死亡率均占首位,非肌层侵润性膀胱癌占初发膀胱肿瘤的70%。对膀胱癌的研究已成为目前学术界的热点话题。目前学界对于非肌层侵润性膀胱癌主要采用以外科手术为主的综合治疗方案。为探讨该类肿瘤的治疗方法,本文就近年来对非肌层侵润性膀胱癌的各种治疗措施进行了比较系统的阐述。我们希望能尽可能的找到高效低风险并且经济的方法,为膀胱癌的诊断和治疗提供新途径。     

非肌层侵润性膀胱癌的治疗

膀胱癌是一种全球性疾病。在我国泌尿外科肿瘤中的发病率和死亡率均占首位,非肌层侵润性膀胱癌占初发膀胱肿瘤的70%。对膀胱癌的研究已成为目前学术界的热点话题。目前学界对于非肌层侵润性膀胱癌主要采用以外科手术为主的综合治疗方案。为探讨该类肿瘤的治疗方法,本文就近年来对非肌层侵润性膀胱癌的各种治疗措施进行了比较系统的阐述。我们希望能尽可能的找到高效低风险并且经济的方法,为膀胱癌的诊断和治疗提供新途径。     

The role of microRNAs in 5-FU resistance of colorectal cancer: Possible mechanisms

Colorectal cancer (CRC) is one of the most common cancers globally. Despite recent advances in therapeutic approaches, this cancer continues to have a poor prognosis, particularly when diagnosed late. 5-Fluorouracil (5-FU) has been commonly prescribed for patients with CRC, but resistance to 5-FU is one of the main reasons for failure in the treatment of this condition. Recently, microRNAs (miRNAs) have been established as a means of modifying the signaling pathways involved in initiation and progression of CRC and their role as oncogene or tumor suppressor have been investigated in various studies. Moreover, miRNAs through various mechanisms play an important role in inducing tumor resistance or sensitivity to anticancer drugs. Detecting and targeting these mechanisms may be a new therapeutic approach. This review summarizes the current knowledge about the potential roles of miRNAs in 5-FU resistance, with particular emphasis on molecular mechanism involved.