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The role of the microenvironment in tumor immune surveillance  [cached]
Oluwadayo Oluwadara,Luca Giacomelli,Xenia Brant,Russell Christensen4
Bioinformation , 2011,
Abstract: The evidence appears compelling that the microenvironment, and associated biological cellular and molecular factors, may contribute to the progression of a variety of tumors. The effects of the microenvironment may directly influence the plasticity of T cell lineages, which was recently discussed (O’Shea & Paul, 2010 ). To review the putative role of the microenvironment in modulating the commitment of tumor immune surveillance, we use the model of oral premalignant lesions.
Dendritic Cells The Tumor Microenvironment and the Challenges for an Effective Antitumor Vaccination
Fabian Benencia,Leslee Sprague,John McGinty,Michelle Pate,Maria Muccioli
Journal of Biomedicine and Biotechnology , 2012, DOI: 10.1155/2012/425476
Abstract: Many clinical trials have been carried out or are in progress to assess the therapeutic potential of dendritic-cell- (DC-) based vaccines on cancer patients, and recently the first DC-based vaccine for human cancer was approved by the FDA. Herewith, we describe the general characteristics of DCs and different strategies to generate effective antitumor DC vaccines. In recent years, the relevance of the tumor microenvironment in the progression of cancer has been highlighted. It has been shown that the tumor microenvironment is capable of inactivating various components of the immune system responsible for tumor clearance. In particular, the effect of the tumor microenvironment on antigen-presenting cells, such as DCs, does not only render these immune cells unable to induce specific immune responses, but also turns them into promoters of tumor growth. We also describe strategies likely to increase the efficacy of DC vaccines by reprogramming the immunosuppressive nature of the tumor microenvironment.
Targeting Tumor Microenvironment: The Key Role of Immune System  [cached]
Jaleh Barar
BioImpacts , 2012,
Abstract: In recent years, huge investigations on cancer progression and invasion have led to understand the pivotal role of tumor microenvironment. The current era of cancer therapy is based on the concept of simply targeting precise mechanisms to kill or to suppress the growth and expansion of malignant cells. Clinical data clearly correlate with in vitro results, emphasizing the direct impact of cancer environment on disease progression. This provides the opportunity to advance cancer therapy by virtue of targeting cancerous cells and non-cancerous component of tumor in a combinatorial manner. This tailor-made strategy demands the profound knowledge of cross talk between the biofactors of tumor environment and corresponding pharmacology of drug candidates. The neighborhood of tumor is critical for how cancer cells grow and invade surrounding tissues. It appears that the tumor microenvironment as a “co-op” includes malignant cells, blood vessels, immune/inflammatory factors and extracellular matrix. As a longstanding dilemma, it is well-proved that immune system plays a direct role in the existence and progression of such coop. In some cases, immune cells e.g. tumor associated macrophages (TAMs) infiltrate into tumor and instead of fighting cancer cells, support them to grow. As an important fact, this tumor complexity should not be taken as granted where it can be advantageous in cancer therapy as well as early detection and prevention. The central aim of this editorial article is to highlight the importance of tumor microenvironment for successful cancer therapy.
Gene expression profiling of the tumor microenvironment during breast cancer progression
Xiao-Jun Ma, Sonika Dahiya, Elizabeth Richardson, Mark Erlander, Dennis C Sgroi
Breast Cancer Research , 2009, DOI: 10.1186/bcr2222
Abstract: We combined laser capture microdissection and gene expression microarrays to analyze 14 patient-matched normal epithelium, normal stroma, tumor epithelium and tumor-associated stroma specimens. Differential gene expression and gene ontology analyses were performed.Tumor-associated stroma undergoes extensive gene expression changes during cancer progression, to a similar extent as that seen in the malignant epithelium. Highly upregulated genes in the tumor-associated stroma include constituents of the extracellular matrix and matrix metalloproteases, and cell-cycle-related genes. Decreased expression of cytoplasmic ribosomal proteins and increased expression of mitochondrial ribosomal proteins were observed in both the tumor epithelium and the stroma. The transition from preinvasive to invasive growth was accompanied by increased expression of several matrix metalloproteases (MMP2, MMP11 and MMP14). Furthermore, as observed in malignant epithelium, a gene expression signature of histological tumor grade also exists in the stroma, with high-grade tumors associated with increased expression of genes involved in immune response.Our results suggest that the tumor microenvironment participates in tumorigenesis even before tumor cells invade into stroma, and that it may play important roles in the transition from preinvasive to invasive growth. The immune cells in the tumor stroma may be exploited by the malignant epithelial cells in high-grade tumors for aggressive invasive growth.The tumor microenvironment or the stroma hosting the malignant breast epithelial cells is comprised of multiple cell types, including fibroblasts, myoepithelial cells, endothelial cells and various immune cells [1-4]. One prevailing view is that tumor-associated stroma is activated by the malignant epithelial cells to foster tumor growth – for example, by secreting growth factors, increasing angiogenesis, and facilitating cell migration, ultimately resulting in metastasis to remote organ sites [
Angiogenesis and immune supression: yin and yang of tumor progression?  [PDF]
Stanis?aw Szala
Post?py Higieny i Medycyny Do?wiadczalnej , 2009,
Abstract: Specialized variants of neoplastic cells that appear in tumors during cancer disease progression possess the ability to recruit certain kinds of hematopoietic and mesenchymal cells from the bone marrow or bloodstream. These tumor-recruited hematopoietic cells include monocytes, macrophages, granulocytes, mast and dendritic cells, as well as myeloblastic suppressor cells. Fibroblasts derived from undifferentiated mesenchymal cells are also recruited. Some of these cells (especially macrophages and fibroblasts) then undergo “education-like” phenotype reprogramming under the influence of the neoplastic cell population, resulting in the appearance of tumor-associated macrophages (TAM) and fibroblasts (CAF). Together with the extracellular matrix (ECM) as well with the remaining types of recruited cells, they contribute to the formation of a specific tumor microenvironment. Both the cells forming the tumor microenvironment and neoplastic cells engage in the two intimately linked processes of angiogenesis and immune suppression. The network of defective blood vessels formed during tumor angiogenesis and the resulting fluctuations in blood flow lead to under-oxygenation of the surrounding neoplastic cells and have substantial impact on their metabolic profile. A number of processes triggered in these under-oxygenated neoplastic cells appear to strongly favor further tumor progression. Such processes result in lower oxygen demand, enhanced angiogenesis, and epithelial-mesenchymal transition, owing to which the neoplastic cells acquire the ability to translocate. Under-oxygenation also leads to augmented genetic instability of the neoplastic cells. The tumor environment-forming cells also have their share in the establishment of an immunosuppressive environment which enables the neoplastic cells to escape immune surveillance. By providing a sophisticated milieu for the selection of increasingly malignant neoplastic cells (i.e. with proangiogenic and immunosuppressive phenotypes), the tumor microenvironment-forming cells substantially contribute to the progression of a neoplasm. Inhibited angiogenesis thus makes an immune response, both nonspecific and specific, possible. The remarks presented here may prove helpful in devising novel anticancer strategies involving antiangiogenic in combination with immunomodulatory drugs.
Host microenvironment in breast cancer development: Inflammatory cells, cytokines and chemokines in breast cancer progression - reciprocal tumor–microenvironment interactions
A Ben-Baruch
Breast Cancer Research , 2002, DOI: 10.1186/bcr554
Abstract: It has long been recognized that the interactions of tumor cells with their microenvironment may affect tumor growth and metastasis formation. The tumor microenvironment may differ between tumor types and disease stages, is complex, and consists of many cell types and factors. Of these, inflammatory cells and cytokines were recently suggested to play a key role in breast carcinoma. A large number of observations suggest that certain types of inflammatory cells are not innocent bystanders at breast tumor sites, and that they actively affect tumor development and progression. Inflammatory cells, primarily macrophages, may affect these processes via their ability to express a large variety of factors, including inflammatory cytokines. These cytokines may be secreted not only by inflammatory cells, but also by the tumor cells and stroma cells, together establishing a network of factors that significantly affects breast cancer.A short review is presented on the activities of inflammatory cells and inflammatory cytokines in breast carcinoma, illuminating the multifaceted abilities of these factors to affect the progression of this disease. In addition, the present review will provide an outline of the role of inflammatory chemokines in breast carcinoma. The ability of inflammatory cells, cytokines and chemokines to affect tumor cell–microenvironment interactions will be illustrated, providing evidence for the activities of these factors in breast cancer development and progression.Breast carcinomas are heavily infiltrated by different types of host leukocytes, including primarily T cells, and monocytes that differentiate into tumor-associated macrophages (TAM) at the tumor site [1-7]. The presence of the cellular infiltrate in breast tumors was initially regarded as evidence for the potential activity of immune mechanisms against the growing neoplasm. There are an increasing number of studies, however, suggesting that T-cell antitumor responses are impaired in advanced st
Keystone symposium: The role of microenvironment in tumor induction and progression, Banff, Canada, 5–10 February 2005
Jamie L Bascom, Paraic A Kenny
Breast Cancer Research , 2005, DOI: 10.1186/bcr1030
Abstract: It is now apparent that reciprocal interactions between tumor cells and their microenvironment – extracellular matrix (ECM), growth factors, fibroblasts, immune and endothelial cells – play an essential role in the earliest stages of transformation to malignant progression and metastasis. By better understanding the complex interactions between all of these factors, it is hoped that therapies might be effectively targeted against both epithelial and stromal determinants of tumor progression. In this regard, there were several encouraging presentations on novel clinical approaches that target these processes.Skiers and snowboarders among the delegates were blessed with 67 cm of fresh snow just prior to arrival, resulting in a stampede for the ski buses each day at 11 am. The quality of the meeting was perhaps best reflected by an equally urgent stampede back to the conference center in time for the evening sessions and posters.Zena Werb (University of California, San Francisco) set the scene for the meeting with a wide ranging plenary lecture detailing crucial interactions between epithelial and stromal cells during both normal mammary development and tumorigenesis. She described a series of wild-type/knockout tissue recombination experiments used to dissect the requirements for epithelially and stromally expressed growth factors and receptors in mammary gland development. In a lecture that was both visually and intellectually stimulating, she showed that intravital imaging technology is a valuable tool with which to interrogate the interactions between stromal and epithelial cells in tumorigenesis. Time-lapse fluorescent videos using mouse mammary tumor virus-polyoma middle T antigen (MMTV-PyMT) transgenic mice bearing various fluorescent markers demonstrated the dynamic interactions between the tumor and host cellular components.In the second keynote address, Joan Massagué (Memorial Sloan Kettering Cancer Center, New York), described a series of experiments that pr
Tumor Microenvironment and Immune Effects of Antineoplastic Therapy in Lymphoproliferative Syndromes
Tomás álvaro,Luis de la Cruz-Merino,Fernando Henao-Carrasco,José Luis Villar Rodríguez,David Vicente Baz,Manuel Codes Manuel de Villena,Mariano Provencio
Journal of Biomedicine and Biotechnology , 2010, DOI: 10.1155/2010/846872
Abstract: Lymphomas represent a wide group of heterogenic diseases with different biological and clinical behavior. The underlying microenvironment-specific composition seems to play an essential role in this scenario, harboring the ability to develop successful immune responses or, on the contrary, leading to immune evasion and even promotion of tumor growth. Depending on surrounding lymphoid infiltrates, lymphomas may have different prognosis. Moreover, recent evidences have emerged that confer a significant impact of main lymphoma's treatment over microenvironment, with clinical consequences. In this review, we summarize these concepts from a pathological and clinical perspective. Also, the state of the art of lymphoma's anti-idiotype vaccine development is revised, highlighting the situations where this strategy has proven to be successful and eventual clues to obtain better results in the future.
Tumor and Microenvironment Modification during Progression of Murine Orthotopic Bladder Cancer  [PDF]
Sin Mun Tham,Kee Hui Ng,Sim Hwee Pook,Kesavan Esuvaranathan,Ratha Mahendran
Journal of Immunology Research , 2011, DOI: 10.1155/2011/865684
Abstract: The aim of this study was to monitor changes in the expression of immune-related genes in the bladder after tumor implantation. Mice were orthotopically implanted with MB49-PSA cells (C57BL/6 mice) on day 1 and terminated on days 7, 14, 21, and 28. Another mouse model (MBT-2/C3H mice) was examined at day 7. Gene expression analysis was performed using a TaqMan Low Density Mouse Immune Panel (Applied Biosystems, USA) on RNA extracted from the bladders. Selected genes were reconfirmed by real-time PCR analysis and RT-PCR on the mRNA from other animals. Immune suppressive (IL13, IL1β, PTGS2, NOS2, IL10, CTLA4, and CCL22) and immune stimulatory genes (CSF2, GZMB, IFNγ, CXCL10, TNFα, CD80, IL12a, and IL6) and AGTR2 were increased by day 7. By day 28, IL10, CCL2, CCL5, CXCL11, CTLA4, GZMB, IFNγ, CSF2, and IL6 were significantly increased. Therapeutic strategies involving TH1 induction and TH2 dampening may improve responses to immunotherapy. 1. Introduction Bladder cancer is the 7th most common cancer worldwide. Though bladder cancer is not usually life threatening, it is prone to recurrences which may progress to invasive cancer. Transurethral resection of the bladder tumor (TURBT) followed by Mycobacterium bovis, Bacillus Calmette Guerin (BCG) immunotherapy reduces the incidence of recurrence, but some 30–50% of patients do not respond to therapy [1, 2]. Recurrences are attributed to remnant tumor cells missed during surgery as a second surgical procedure prior to BCG therapy improves the response to therapy [1]. The immune response induced by BCG immunotherapy may inadvertently ensure the survival of less immunogenic remnant tumor cells which could give rise to recurrence and progression. The increased incidence of progression in patients who fail BCG immunotherapy gives some credence to this latter possibility [1]. Tumor immune editing is a dynamic process that has 2 important participants the tumor cells and the immune cells. Their interaction determines whether tumor regression or growth occurs. Orthotopic murine models of bladder cancer generated by implanting syngenic cell lines have been used to evaluate response to gene therapy. One such model, MB49 cells implanted in C57BL/6 mice, has been shown to be fairly similar to human bladder cancers [3]. Several cytokine genes have been evaluated for their ability to induce tumor regression in this model. Intravesical delivery of IL2 cured 40% of mice [4], IFNγ cured 50–80% of mice based on the amount of IFNγ secreting retrovirus delivered [5], TNFα cured 67% of mice [6], IFNα singly and/or with GMCSF cured
IFN-γ, IL-17 and TGF-β involvement in shaping the tumor microenvironment: The significance of modulating such cytokines in treating malignant solid tumors
Heba A Alshaker, Khalid Z Matalka
Cancer Cell International , 2011, DOI: 10.1186/1475-2867-11-33
Abstract: The failure of the immune system to recognize and eradicate cancer cells may partly be a result of insufficient immunological activation. It is now increasingly recognized that the microenvironment plays a critical role in the progression of tumors where immune-resistant tumor variants are selected initiating the process of cancer immunoediting. Tumor-derived soluble factors can impel various mechanisms for escape from immune attack in the tumor microenvironment [1,2]. The tumor microenvironment is a pivotal factor in the course of carcinogenesis and is largely dependent on its interactions with microenvironmental components in a bidirectional way and consequently tumor progression or regression [3,4].The tumor microenvironment was lately recognized as the product of a developing crosstalk between different cells types. In addition to tumor cells, the tumor microenvironment is comprised of immune cells, fibroblasts, stromal cells and the extracellular matrix [3]. Normal cellular microenvironment can inhibit tumor cell proliferation and cancer formation [4]. Contrariwise, as tissue becomes cancerous pathological interactions between cancer cells and host immune cells in the tumor microenvironment and lymphoid organs create an immunosuppressive network that protects the tumor from immune attack leading to tumor growth, progression as well as invasion and metastasis which is basically due to a deranged relationship between tumor and stromal cells [3-5]. In this review, we are stressing on the interface between infiltrated immune cells and tumor cells with the emphasis on the bidirectional activities of cytokines mainly IFN-γ, TGF-β and IL-17 within the tumor microenvironment and their role in shaping it. The aim, however, is to stress on the beneficial role of modulating such cytokines that favor anti-tumor activity and ultimately leads to eradicating solid tumors.As surveillance cells in the tumor microenvironment, dendritic cells (DCs), natural killer (NK), and natur
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