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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.
Immune Microenvironment in Tumor Progression: Characteristics and Challenges for Therapy  [PDF]
Valerie Chew,Han Chong Toh,Jean-Pierre Abastado
Journal of Oncology , 2012, DOI: 10.1155/2012/608406
Abstract: The tumor microenvironment plays a critical role in cancer development, progression, and control. The molecular and cellular nature of the tumor immune microenvironment influences disease outcome by altering the balance of suppressive versus cytotoxic responses in the vicinity of the tumor. Recent developments in systems biology have improved our understanding of the complex interactions between tumors and their immunological microenvironment in various human cancers. Effective tumor surveillance by the host immune system protects against disease, but chronic inflammation and tumor “immunoediting” have also been implicated in disease development and progression. Accordingly, reactivation and maintenance of appropriate antitumor responses within the tumor microenvironment correlate with a good prognosis in cancer patients. Improved understanding of the factors that shape the tumor microenvironment will be critical for the development of effective future strategies for disease management. The manipulation of these microenvironmental factors is already emerging as a promising tool for novel cancer treatments. In this paper, we summarize the various roles of the tumor microenvironment in cancer, focusing on immunological mediators of tumor progression and control, as well as the significant challenges for future therapies. 1. Introduction The tumor microenvironment consists of cancer cells, stromal tissue, and extracellular matrix. The immune system is an important determinant of the tumor microenvironment. Indeed, the complex interplay between cancer cells and the host immune response has been extensively investigated in the past few decades. Several immunological deficiencies have been linked with enhanced tumor development in mouse models as well as in humans [1, 2]. The higher incidence of cancers in transplant patients receiving long-term immunosuppressive treatment is well documented [3–5]. Similarly, mice with compromised immune functions due to genetic modifications develop more tumors [6–9]. It is now well recognized that effective tumor surveillance by the immune system is critical to maintain homeostasis in the host. Despite exerting a key role in host protection, tumor surveillance by the immune system may eventually fail. As described in the three “Es” of cancer immunoediting, tumor cells are initially eliminated by the immune system before becoming clinically detectable. This is then followed by an equilibrium phase, where a selection process for less immunogenic tumor variants take place until the tumors finally “escape” the immune
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
Immune Microenvironment in Colorectal Cancer: A New Hallmark to Change Old Paradigms  [PDF]
Luis de la Cruz-Merino,Fernando Henao Carrasco,David Vicente Baz,Esteban Nogales Fernández,Juan José Reina Zoilo,Manuel Codes Manuel de Villena,Enrique Grande Pulido
Journal of Immunology Research , 2011, DOI: 10.1155/2011/174149
Abstract: Impact of immune microenvironment in prognosis of solid tumors has been extensively studied in the last few years. Specifically in colorectal carcinoma, increased knowledge of the immune events around these tumors and their relation with clinical outcomes have led to consider immune microenvironment as one of the most important prognostic factors in this disease. In this review we will summarize and update the current knowledge with respect to this intriguing and complex new hallmark of cancer, paying special attention to infiltration by T-infiltrating lymphocytes and their subtypes in colorectal cancer, as well as its eventual clinical translation in terms of long-term prognosis. Finally, we suggest some possible investigational approaches based on combinatorial strategies to trigger and boost immune reaction against tumor cells. 1. Introduction The term immunity derives from the Latin word “immunitas”, referred to the exemption of Roman senators in legal procedures while holding their public office. In time, this term has won many other meanings; in the Medical field it is employed to describe the reaction of an organism towards the aggression caused by external pathogens, initially infectious agents. More recently, antigens derived from neoplastic processes have been reported as responsible for triggering immune responses. Most solid tumors induce an immune response in the host, confirmed by histopathological studies. In this sense, tissue affected by colorectal cancer is invaded by immune cells from the host, suggesting that the amount of lymphocytes may play a prognostic role with a potential impact upon patient’s survival [1]. In Europe, 376.000 new cases of colorectal cancer are diagnosed each year, with mortality close to 203.700 patients. It is one of the most frequent cancers worldwide, in both genders [2, 3], and in most developed countries; as a result of screening and diagnostic techniques and advances in the field of surgery and radio-chemotherapy, survival has significantly increased in the last decades. Most tumors affecting the colorectal area are adenocarcinoma-like which in most cases are well or moderately differentiated. If colorectal neoplasias invade through the muscularis mucosa into the submucosa, local host reactions take place in cancer tissue and proinflammatory cells accumulate along the margins of the tumor, creating an immune microenvironment and triggering an immune response targeted towards the tumor [4]. 2. Tumor Immune Microenvironment: Immune-Surveillance and Tumor-Infiltrating Lymphocytes (TILs) In normal conditions,
Hypoxia Promotes Tumor Growth in Linking Angiogenesis to Immune Escape  [PDF]
Salem Chouaib,Bernard Escudier
Frontiers in Immunology , 2012, DOI: 10.3389/fimmu.2012.00021
Abstract: Despite the impressive progress over the past decade, in the field of tumor immunology, such as the identification of tumor antigens and antigenic peptides, there are still many obstacles in eliciting an effective immune response to eradicate cancer. It has become increasingly clear that tumor microenvironment plays a crucial role in the control of immune protection. Tumors have evolved to utilize hypoxic stress to their own advantage by activating key biochemical and cellular pathways that are important in progression, survival, and metastasis. Hypoxia-inducible factor (HIF-1) and vascular endothelial growth factor (VEGF) play a determinant role in promoting tumor cell growth and survival. Hypoxia contributes to immune suppression by activating HIF-1 and VEGF pathways. Accumulating evidence suggests a link between hypoxia and tumor tolerance to immune surveillance through the recruitment of regulatory cells (regulatory T cells and myeloid derived suppressor cells). In this regard, hypoxia (HIF-1α and VEGF) is emerging as an attractive target for cancer therapy. How the microenvironmental hypoxia poses both obstacles and opportunities for new therapeutic immune interventions will be discussed.
Oxidative stress in tumor microenvironment—Its role in angiogenesis
Armando ROJAS,Raúl SILVA,Héctor FIGUEROA,Miguel A MORALES
Chinese Journal of Lung Cancer , 2008,
Abstract: The tumor angiogenesis process is believed to be dependent on an "angiogenic switch" formed by a cascade of biologic events as a consequence of the "cross-talk" between tumor cells and several components of local microenvironment including endothelial cells, macrophages, mast cells and stromal components. Oxidative stress represents an important stimulus that widely contributes to this angiogenic switch, which is particularly relevant in lungs, where oxidative stress is originated from different sources including the incomplete reduction of oxygen during respiration, exposure to hypoxia/reoxygenation, stimulated resident or chemoattracted immune cells to lung tissues, as well as by a variety of chemicals compounds. In the present review we highlight the role of oxidative stress in tumor angiogenesis as a key signal linked to other relevant actors in this complex process.
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.
Dual Roles of Immune Cells and Their Factors in Cancer Development and Progression
Brian F. Zamarron, WanJun Chen
International Journal of Biological Sciences , 2011,
Abstract: Traditional wisdom holds that intact immune responses, such as immune surveillance or immunoediting, are required for preventing and inhibiting tumor development; but recent evidence has also indicated that unresolved immune responses, such as chronic inflammation, can promote the growth and progression of cancer. Within the immune system, cytotoxic CD8+ and CD4+ Th1 T cells, along with their characteristically produced cytokine IFN-γ, function as the major anti-tumor immune effector cells, whereas tumor associated macrophages (TAM) or myeloid-derived suppressive cells (MDSC) and their derived cytokines IL-6, TNF, IL-1β and IL-23 are generally recognized as dominant tumor-promoting forces. However, the roles played by Th17 cells, CD4+ CD25+ Foxp3+ regulatory T lymphocytes and immunoregulatory cytokines such as TGF-β in tumor development and survival remain elusive. These immune cells and the cellular factors produced from them, including both immunosuppressive and inflammatory cytokines, play dual roles in promoting or discouraging cancer development, and their ultimate role in cancer progression may rely heavily on the tumor microenvironment and the events leading to initial propagation of carcinogenesis.
Expression of Toll-Like Receptors on Breast Tumors: Taking a Toll on Tumor Microenvironment  [PDF]
Debika Bhattacharya,Nabiha Yusuf
International Journal of Breast Cancer , 2012, DOI: 10.1155/2012/716564
Abstract: Breast cancer remains a major cause of death in women in the developed world. As Toll-like receptors (TLRs) are widely expressed on tumor cells and play important roles in the initiation and progression of cancer, they may thus serve as important targets and have an effective perspective on breast cancer treatment. Expression of TLRs on breast cancer cells and mononuclear inflammatory cells can promote inflammation and cell survival in the tumor microenvironment. Inflammation and cancer are related. It is well known that persistent inflammatory conditions can induce cancer formation, due to production of cytokines and chemokines, which play a crucial role in promoting angiogenesis, metastasis, and subversion of adaptive immunity. TLR signaling in tumor cells can mediate tumor cell immune escape and tumor progression, and it is regarded as one of the mechanisms for chronic inflammation in tumorigenesis and progression. This paper delineates the expression of various TLRs in promotion of inflammation and development of mammary tumors. Understanding the mechanisms through which TLRs on breast cancer cells and inflammatory cells regulate growth, survival, and metastatic progression can make them potential targets for breast cancer therapy. 1. Introduction Breast cancer is the most common cancer among American women, except for skin cancers. The chance of developing invasive breast cancer at some time in a woman’s life is a little less than 12%. It is the second leading cause of cancer death in women, exceeded only by lung cancer. The chance that breast cancer will be responsible for a woman’s death is about 3% [1]. Although clinical signs of disseminated disease occur in fewer than 10% of women at the time of diagnosis, the disease relapses in the form of metastasis within 5 years of surgery in about half of apparently localized tumors. It is difficult to predict the occurrence of distant metastases since breast cancer is a heterogeneous disease encompassing complex pathologic entities [2]. Thus, there is a need for new and effective breast cancer therapies. A dynamic interaction between tumors and the immune system is essential for tumor survival, growth, and metastasis [3]. Tumors are infiltrated with large number of immune cells that constitute a major cell population in the tumor microenvironment. Tumor cells depend on their microenvironment to provide signals for growth, anti-apoptosis, angiogenesis, and metastasis [4]. However, tumor cells are also under the surveillance due to their recognition by immune cells as foreign. Therefore, tumors have to
Tumor-Associated Glycans and Immune Surveillance  [PDF]
Behjatolah Monzavi-Karbassi,Anastas Pashov,Thomas Kieber-Emmons
Vaccines , 2013, DOI: 10.3390/vaccines1020174
Abstract: Changes in cell surface glycosylation are a hallmark of the transition from normal to inflamed and neoplastic tissue. Tumor-associated carbohydrate antigens (TACAs) challenge our understanding of immune tolerance, while functioning as immune targets that bridge innate immune surveillance and adaptive antitumor immunity in clinical applications. T-cells, being a part of the adaptive immune response, are the most popular component of the immune system considered for targeting tumor cells. However, for TACAs, T-cells take a back seat to antibodies and natural killer cells as first-line innate defense mechanisms. Here, we briefly highlight the rationale associated with the relative importance of the immune surveillance machinery that might be applicable for developing therapeutics.
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